Phase II Multi-Center Trial of Trabectedin in Combination With Olaparib in Advanced Unresectable or Metastatic Sarcoma
Phase: PHASE2
Conditions: Sarcoma, Sarcoma Metastatic
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2018.132 
    Trabectedin in Combination With Olaparib in 
Advanced Unresectable or Metastatic Sarcoma 
    NCT04076579 
 

 
 
UMCC 2018.132 
 
Phase II Multi-Center Trial of Trabectedin in Combination with Olaparib in Advanced Unresectable 
or Metastatic Sarcoma 
 
Sponsor/ 
 
 
Rashmi Chugh, MD 
Principal Investigator:  
University of Michigan 
 
 
 
 
1500 E Medical Center Drive 
 
 
 
 
Ann Arbor, MI 48109 
 
 
 
 
Phone: (734) 936-0453 
 
 
 
 
Fax: (734) 936-6267 
 
 
 
 
rashmim@med.umich.edu  
 
 
Biostatistician: 
 
Lili Zhao 
 
 
 
 
University of Michigan 
 
 
 
 
1415 Washington Heights 
 
 
 
 
M2541, SPH II 
 
 
 
 
Ann Arbor, MI 48109 
 
 
 
 
Phone: (734) 763-6898 
 
 
 
 
Fax: (734) 936-4540 
 
 
 
 
zhaolili@umich.edu  
 
Coordinating Center 
 
University of Michigan 
 
Study Drug: 
 
 
Trabectedin (Yondelis®)  
 
 
 
 
Olaparib (Lynparza®) 
 
 
IND # 
 
 
IND Exempt 
 
Initial version:  
 
v 1.0 
24Mar2019 
Amended: 
 
 
v 1.1 
12Apr2019 
v 1.2 
01Jun2019 
 
 
 
v 1.3 
27Jun2019 
 
 
 
v.2.0 
10Nov2020 
 
 
 
v 3.0      12Jan2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The study drug Trabectedin is provided by Janssen Scientific Affairs, LLC.  The study drug Olaparib is 
provided by AstraZeneca. 

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TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................1 
STUDY SYNOPSIS ..........................................................................................................4 
1.0 
BACKGROUND AND RATIONALE ...................................................................6 
1.1 
Disease Background........................................................................................................ 6 
1.2 
Study Agent(s) Background ............................................................................................. 6 
1.3 
Rationale .......................................................................................................................... 7 
1.4 
Exploratory Studies.......................................................................................................... 8 
2.0 
STUDY OBJECTIVES...........................................................................................9 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.3 
Exploratory Objectives ................................................................................................... 10 
2.4 
Endpoints ....................................................................................................................... 10 
3.0 
PATIENT ELIGIBILITY .......................................................................................10 
3.1 
Inclusion Criteria ............................................................................................................ 10 
3.2 
Exclusion Criteria ........................................................................................................... 11 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ..............13 
5.0 
TREATMENT PLAN ............................................................................................14 
5.1 
Treatment Dosage and Administration .......................................................................... 14 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 15 
5.3 
Concomitant Medications/Treatments ........................................................................... 20 
5.4 
Other Modalities or Procedures ..................................................................................... 23 
5.5 
Duration of Therapy ....................................................................................................... 23 
5.6 
Off Treatment Criteria .................................................................................................... 23 

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5.7 
Duration of Follow-Up .................................................................................................... 23 
5.8 
Off Study Criteria ........................................................................................................... 24 
6.0 
STUDY PROCEDURES ......................................................................................24 
6.1 
Screening/Baseline Procedures .................................................................................... 24 
6.2 
Time and Events Table .................................................................................................. 24 
7.0 
MEASUREMENT OF EFFECT ..........................................................................26 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 26 
7.2 
Safety/Tolerability .......................................................................................................... 30 
8.0 
ADVERSE EVENTS ............................................................................................30 
8.1 
Adverse Event Report Requirements ............................................................................ 30 
8.2 
Definitions ...................................................................................................................... 31 
8.3 
Adverse Event Characteristics ...................................................................................... 36 
8.4 
Serious Adverse Event Reporting Guidelines ............................................................... 36 
8.5 
Reporting procedures to Janssen Scientific Affairs, LLC .............................................. 37 
8.6 
Reporting procedures to AstraZeneca........................................................................... 38 
8.7 
Routine Reporting .......................................................................................................... 39 
8.8 
Reporting of Unanticipated Problems ............................................................................ 39 
9.0 
DRUG INFORMATION .......................................................................................39 
9.1 
Trabectedin .................................................................................................................... 40 
9.2 
Olaparib ......................................................................................................................... 41 
10.0 
CORRELATIVES/SPECIAL STUDIES .........................................................43 
10.1 
Next Generation Sequencing ........................................................................................ 44 
10.2 
Defects in DNA Damage Repair .................................................................................... 44 
10.3 
Cardiotoxicity ................................................................................................................. 44 
11.0 
STATISTICAL CONSIDERATIONS .............................................................44 

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11.1 
Study Design/Study Endpoints ...................................................................................... 44 
11.2 
Sample Size and Accrual .............................................................................................. 44 
11.3 
Data Analyses Plans...................................................................................................... 45 
12.0 
DATA AND SAFETY MONITORING ............................................................46 
13.0 
QUALITY ASSURANCE AND AUDITS .......................................................46 
14.0 
DATA MANAGEMENT....................................................................................46 
15.0 
CLINICAL MONITORING PROCEDURES ..................................................47 
16.0 
REFERENCES .................................................................................................48 

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ABBREVIATIONS 
 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALC 
Absolute Lymphocyte Count 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BER 
Base Excision Repair 
BID 
Twice Daily 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CK 
Creatine Phosphokinase 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DDLPS 
Dedifferentiated Liposarcoma 
DLT 
Dose Limiting Toxicity 
DRD 
DNA Repair Defects 
DSBs 
Double-strand Breaks 
DSMC 
Data and Safety Monitoring Committee 
DSMR 
Data and Safety Monitoring Report 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
ES 
Ewing’s Sarcoma 
exOS 
Extraskeletal Osteosarcoma 
FSA 
Fibrosarcoma 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
H&P 
History & Physical Exam 
HIV 
Human Immunodeficiency Virus 
HR 
Homologous Recombination 
HRCT 
High Resolution Computed Tomography 
HRD 
Homologous Recombination Deficiencies 

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HRPP 
Human Research Protections Program 
HRT 
Hormone Replacement Therapy 
IB 
Investigators Brochure 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
LLN 
Lower Limit of Normal 
LMS 
Leiomyosarcoma 
LPS 
Liposarcoma 
LVEF 
Left Ventricular Ejection Fraction 
MDS 
Myelodysplastic syndrome 
NCI 
National Cancer Institute 
NER 
Nucleoside Excision Repair 
NGS 
Next Generation Sequencing 
ORR 
Overall Response Rate 
OS 
Overall Survival 
p.o. 
per os/by mouth/orally 
PARP 
Poly-(adenosine diphosphate ribose)-polymerase 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PQC 
Product Quality Complaint 
PR 
Partial Response 
QARC 
Quality Assurance Review Committee 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SS 
Synovial Sarcoma 
SSBs 
Single-Strand Breaks 
STS 
Soft Tissue Sarcoma 
suPAR 
Soluble urokinase Plasminogen Activator Receptor 
TTE 
Transthoracic Echocardiogram 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
UPS 
Undifferentiated Pleomorphic Sarcoma 
WBC 
White Blood Cells 
WDLPS 
Well-differentiated Liposarcoma 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
Patients with advanced sarcoma 
(Section 3.0 Eligibility Criteria) 
Screening 
Administer olaparib PO BID continuously and trabectedin IV every 21 days. 
Assess disease after 2 cycles (±7 days) then every 3 cycles (±7 days) thereafter 
with 21-day cycle length 
Treatment will continue for up to a maximum of 18 months or 
until disease progression or until meets criteria for termination 
of treatment (Section 5.5) 
OFF STUDY: 
Patients will be followed every 3 months for a minimum of 2 years from 
registration or until study closure or until death, whichever occurs first. 
Cohort 1: 
Leiomyosarcoma (LMS) 
Liposarcoma (LPS) 
Cohort 2: 
Other sarcoma histologies 

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STUDY SYNOPSIS 
Title 
Phase II Multi-Center Trial of Trabectedin in Combination with Olaparib in 
Advanced Unresectable or Metastatic Sarcoma 
Phase 
Phase II 
Methodology 
Uncontrolled, Open label, Single-arm 
Study Duration 
3 years 
Study Center(s) 
Multi-center: 2 centers 
Objectives 
Primary Objective: 
a. To estimate the overall response rate (ORR) of combined 
trabectedin and olaparib in patients with advanced unresectable or 
metastatic sarcoma using a primary endpoint of complete + partial 
response as defined by RECIST 1.1. 
 
Secondary Objectives: 
a. To estimate the median progression-free survival (PFS) and 6-month 
PFS as defined by RECIST 1.1 
b. To estimate the median, 1- and 2-year overall survival (OS) 
c. To describe the safety and tolerability of combined trabectedin and 
olaparib 
 
Exploratory Objectives: 
a. To characterize next generation sequencing (NGS) findings on 
available reports from archival tumor samples to identify predictors 
of clinical response to therapy.   
b. To evaluate expression of DNA damage repair pathways by IHC in 
available archival tumor samples and correlate with response to 
therapy 
c. To assess the impact of treatment on levels of novel cardiovascular 
biomarkers, and determine whether levels predict cardiotoxicity 
 
Number of Subjects 
This study will be conducted using a Simon Minimax two-stage design, 
with an interim analysis for efficacy to be performed after first stage.  
Cohort 1 (LMS/LPS): First stage – 16 patients, Second stage – additional 
10 patients 
 
Cohort 2 (other sarcoma histologies): First stage – 13 patients, Second 
stage – additional 14 patients 
 
Key Inclusion Criteria 
• 
Age ≥ 16 years 
• 
Advanced unresectable or metastatic sarcoma 
• 
Received at least 1 prior standard chemotherapy. For cohort 1 
patients, this must have included a prior anthracycline. 
• 
Measurable disease by RECIST 1.1 
• 
Adequate hematologic, renal, hepatic function 
• 
Adequate creatine phosphokinase 
• 
ECOG performance status ≤ 1 
• 
LVEF ≥ institutional LLN 
• 
Women of childbearing age and men must agree to use adequate 
contraception from signing informed consent to at least 6 months 
(females) and 5 months (men) after study drug treatment 

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Key Exclusion Criteria 
• 
Prior therapy with PARP inhibitor 
• 
Prior therapy with trabectedin  
• 
Additional active malignancy or treatment for alternative cancer 
(excluding non-melanoma skin cancer) requiring treatment within the 
past two years 
• 
Pregnant or breastfeeding women 
• 
Known hypersensitivity to trabectedin 
Study Product(s), Dose, 
Route, Regimen 
Olaparib 150 mg PO BID continuously 
Trabectedin 1.1 mg/m2 IV every 21 days 
Duration of Administration 
Treatment consists of 21-day cycles. Therapy will continue until disease 
progression or patient meets one of the off-study criteria for a maximum 
of 18 months.  
Reference Therapy 
No comparator. Historical controls of single agent trabectedin in soft 
tissue sarcoma.  
Statistical Methodology 
A Simon Minimax two-stage design is utilized for this study. Based on 
currently available phase III data, the ORR for LMS/LPS subgroup to 
trabectedin monotherapy is 9%. We will target a response rate (RR) of 
25% with combination trabectedin and olaparib. In cohort 2, the ORR is 
approximately 5% with trabectedin monotherapy. We will target a RR of 
20% for this combination. This trial is designed with a type 1 error of 10% 
in cohort 1 and 5% in cohort 2 with a power of 80%. 
 
Cohort 1:  
16 patients will be enrolled in stage 1. If ≤ 1 patient has an objective 
response, we will terminate the study. If > 1 objective response, an 
additional 10 patients will be enrolled. If ≥ 5 of 26 patients have an 
objective response, we will declare the combination as promising and 
worthy of further study. 
 
Cohort 2: 
13 patients will be enrolled in stage 1. If 0 patients have an objective 
response, we will terminate the study. If ≥ 1 objective response, an 
additional 14 patients will be enrolled. If ≥ 4 of 27 patients have an 
objective response, we will declare the combination as promising and 
worthy of further study. 
 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Sarcomas are a group of rare, aggressive malignancies that are often fatal despite 
aggressive therapies. The American Cancer Society predicts approximately 12,300 new 
sarcoma diagnoses in 2017, with 5000 sarcoma-related deaths. Surgery remains the 
mainstay of treatment in localized disease, however even optimal local treatment does 
not prevent the occurrence of distant metastases in some patients, particularly those with 
high-grade tumors.  Approximately 50% of patients present with or develop advanced, 
unresectable or metastatic disease. Unfortunately, available systemic treatment options 
in this setting have limited efficacy, and thus prognosis remains poor, underscoring the 
need for development of novel treatment strategies. 
1.2 
Study Agent(s) Background  
Trabectedin 
Trabectedin is a synthetic marine-derived drug that is known to have activity in advanced 
soft-tissue sarcoma (STS) and is currently approved for treatment in unresectable or 
metastatic leiomyosarcoma (LMS) and liposarcoma (LPS) previously treated with an 
anthracycline. A phase II study of trabectedin after standard chemotherapy as compared 
to best supportive care in various subtypes of STS showed a median progression free 
survival (PFS) of 5.6 months versus 0.9 months with a hazard ratio (HR) of 0.70 [1]. The 
most common adverse events were nausea, anorexia, neutropenia, and increased 
alanine aminotransferase. A subsequent phase III trial was conducted to evaluate the 
safety and efficacy of trabectedin versus dacarbazine in metastatic LMS and LPS. A total 
of 518 patients were enrolled and trabectedin-treated patients had a significantly 
improved PFS as compared to dacarbazine, 4.2 vs 1.5 months respectively with a HR of 
0.55 [2]. Trabectedin has also been evaluated in the front-line setting in a phase IIb study 
comparing trabectedin to doxorubicin in patients with advanced or metastatic untreated 
STS. There was no significant improvement in PFS in the trabectedin arm as compared 
to doxorubicin, therefore doxorubicin remains standard of care as first-line therapy [3].  
 
Olaparib 
Investigators should be familiar with the current olaparib (AZD2281) Investigator 
Brochure (IB). 
 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly 
(ADP ribose)] polymerization (PARP) inhibitor (PARP-1, -2 and -3) that is being 
developed as an oral therapy, both as a monotherapy (including maintenance) and for 
combination with chemotherapy and other anti-cancer agents.  It is currently approved for 
treatment of both ovarian and breast cancer (patients selected for therapy based on an 
FDA-approved companion diagnostic for Lynparza [olaparib] and for the maintenance 
treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary 
peritoneal cancer). 
 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks 
(SSBs).  Inhibiting PARPs leads to the persistence of SSBs, which are then converted to 
the more serious DNA double strand breaks (DSBs) during the process of DNA 
replication.  During the process of cell division, DSBs can be efficiently repaired in normal 
cells by homologous recombination repair (HR).  Tumors with HR deficiencies (HRD), 
such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair 
the DNA damage, which may become lethal to cells as it accumulates.  In such tumor 

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types, olaparib may offer a potentially efficacious and less toxic cancer treatment 
compared with currently available chemotherapy regimens.  
 
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in 
tumor models in vivo[4, 5]  and in the clinic [6]. The mechanism of action for olaparib 
results from the trapping of inactive PARP onto the single-strand breaks preventing their 
repair[7, 8].  Persistence of SSBs during DNA replication results in their conversion into 
the more serious DNA DSBs that would normally be repaired by HR repair.  Olaparib has 
been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone 
treatment or in combination with established chemotherapies. 
 
1.3 
Rationale 
Trabectedin has a unique mechanism of action, which includes binding to the minor 
groove of DNA and bending the helix to the major groove, thus impairing the cell cycle 
[9]. Studies have demonstrated a complex mechanism of action that includes direct killing 
of cancer cells by interfering with the cell cycle and by inhibiting activated transcription. 
Specifically, trabectedin is thought to trap members of the nucleoside-excision repair 
(NER) mechanism forming large complexes that inhibit NER activity resulting in single-
strand DNA breaks (SSBs) [10]. These SSBs subsequently stall replication forks leading 
to double-strand DNA breaks (DSBs), thus resulting in cell death. Interestingly, cell lines 
deficient in NER proteins have been shown to be less sensitive to trabectedin [10-12]. 
Furthermore, defects in homologous recombination (HR), a mechanism used to repair 
DSBs, have been associated with higher sensitivity to trabectedin, suggesting induction 
of synthetic lethality [12, 13].  
 
PARP enzymes are essential for repair of SSBs. Upon binding to the area of DNA 
damage, PARP is activated and catalyzes addition of long polymers of ADP-ribose on 
several proteins including histones and DNA repair proteins[14]. Intracellular signaling is 
activated resulting in activation of BER and SSB repair pathways. Inhibition of PARP thus 
allows propagation of SSBs, ultimately resulting in DSBs and cell apoptosis. 
 
Based on the mechanisms of action of PARP inhibitors and trabectedin, potential for 
synthetic lethality was hypothesized. Synthetic lethality is a concept in which a single 
gene defect is compatible with cell viability, but the combination of gene defects results in 
cell death [15, 16]. Synthetic lethality provides a potential mechanism for therapeutic 
targeting of genetic abnormalities in cancers. One example includes inhibition of PARP 
leading to enhanced platinum sensitivity in breast and ovarian cancer models harboring 
mutations in BRCA1/2 genes.  The accumulation of lethal DSBs in a setting of HR 
deficiency, such as in BRCA 1/2 mutants, suggests increased sensitivity to PARP 
inhibition in the presence of DNA repair defects [17, 18].    
 
Avila-Arroyo et al. combined trabectedin with the PARP inhibitors olaparib, veliparib and 
iniparib in BRCA1 proficient and deficient breast tumor cells. Synergistic anti-proliferative 
effects were observed in all breast cancer cell lines  with the combination of trabectedin 
and olaparib [19]. Importantly, this synergy was noted regardless of BRCA1 status, 
suggesting rationale for this combination in BRCA proficient tumors.  
 
 
Role for combination in Sarcoma 
Pignochino et al. explored the role of trabectedin in combination with olaparib in various 
bone and soft tissue sarcoma cell lines including LMS, undifferentiated pleomorphic 
sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), fibrosarcoma (FSA), synovial 
sarcoma (SS), osteosarcoma and Ewing’s sarcoma (ES) [20]. They noted a significant 

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increase in gamma H2AX (P-H2AX), a marker of DNA DSBs, in cell lines treated with 
trabectedin. The combination of trabectedin with olaparib resulted in further increase in 
H2AX compared to monotherapy, and irreparable DNA fragmentation was significantly 
increased after 48 hours of therapy. They subsequently found that olaparib inhibited both 
basal and trabectedin-induced PARP1 activation in 50% of treated cell lines. Strong 
synergistic antitumor activity was found with combination of trabectedin plus olaparib in 
18/20 tested cells lines. Synergy was also noted in 15/19 cell lines treated with 
trabectedin plus veliparib, a PARP inhibitor. Interestingly, a doxorubicin-resistant LMS 
cell line showed cross-resistance to single-agent trabectedin. Addition of olaparib to 
trabectedin significantly restored sensitivity, suggesting a role for trabectedin-PARP 
inhibitor combination in previously treated, trabectedin-resistant patients. In mouse 
xenograft models, Pignochino et al. also noted a significant reduction in tumor volume 
with combination therapy compared to control or monotherapy. 
  
Additional in vivo and in vitro studies have been conducted utilizing sarcoma cell lines 
derived from patients with UPS, DDLPS, LMS, well-differentiated liposarcoma (WDLPS) 
and extraskeletal osteosarcoma (exOS) by Laroche et al. They noted 9/9 cell lines to be 
sensitive to trabectedin and 3/9 sensitive to rucaparib, a PARP inhibitor monotherapy 
[21]. The combination of rucaparib with trabectedin increased DNA damage, induced 
apoptosis and cell cycle arrest in all treated cell lines. UPS mice xenografts treated with 
the combination had a longer tumor volume doubling time as compared to monotherapy 
(17.1 days with combination, 14.8 days with trabectedin (p=0.045), 6.6 days with 
rucaparib (p<0.0001)). Twenty-five percent of tumors in the combination group had at 
least 60% necrosis, and the authors noted no observed signs of toxicity with the 
combination.  
 
A phase 1b study combining trabectedin and olaparib in advanced sarcoma reported the 
combination was safe and tolerable [22]. Dose-limiting toxicities were thrombocytopenia 
and prolonged neutropenia and the recommended phase 2 dose was trabectedin 1.1 
mg/m2 on day 1 and olaparib 150 mg twice daily[23].  Other treatment-related adverse 
events included anemia, leukopenia, febrile neutropenia, fatigue, nausea, elevated liver 
enzymes, mucositis and elevated amylase/lipase. There was no significant drug-drug 
interaction noted on pharmacokinetic evaluation and pharmacodynamics evaluation 
confirmed PARP1 inhibition.  
 
Based on these data, we propose to combine trabectedin with olaparib in patients with 
previously treated advanced sarcoma. The use of this combination in sarcoma is 
investigational, and we hypothesize that the combination of olaparib and trabectedin will 
be safe and effective in patients with advanced sarcoma. 
 
1.4 
Exploratory Studies 
 
1.4.1 
Next Generation Sequencing 
The presence of DNA repair defects (DRD) was correlated to PARP inhibitor 
response in men with metastatic castration resistant prostate cancer receiving 
abiraterone with or without the PARP inhibitor veliparib stratified by presence or 
absence of ETS fusion [24]. Molecular analysis included evaluation for BRCA1/2, 
ATM, FANCA, PALB2, RAD51B/RAD51C, PTEN, TP53, PIK3CA. Eighty patients 
underwent tissue sequencing with 42 (53%) being ETS-positive and 19 (25%) 
had DRD. Irrespective of treatment arm, patients with DRD had a higher ORR 
(58% vs 39%, p=0.002) and longer median PFS (16.6 vs 8 mo, p=0.02) 
compared to placebo. PFS was also longer in patients with normal PTEN, TP53 
and PIK3CA. Controlling for clinical factors, the authors concluded that DRD, 
PTEN, TP53 and PIK3CA were associated with PFS, with DRD having the most 

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impact. These data suggest a role for correlating disease response to PARP 
inhibition in the setting of DRD in other tumor types.  
 
Results of comprehensive next generation sequencing performed on existing or 
available archival tumor samples will be evaluated for genomic alterations in 
order to identify predictors of clinical response to therapy.  
 
1.4.2 
DNA Damage Repair Defects 
 
Presence of DNA repair defects has been correlated with improved response to 
trabectedin[25]. A retrospective analysis of BRCA mRNA in tumor samples from 
patients with advanced sarcoma noted improved response to trabectedin and 
better disease control rate in patients with low tumor BRCA mRNA expression 
[26].  
 
We will evaluate existing samples for defects in DNA repair pathways by 
immunohistochemistry (IHC) which may include H2AX, RAD51, RAD52, 
XRCC1, PARP1, Schlafen-11, BRCA1/2, amongst others. The decrease or 
increase in expression level of DNA repair pathways genes will be correlated with 
disease response to therapy. 
 
1.4.3 
Cardiotoxicity 
 
Whether trabectedin use in the treatment of sarcoma is associated with 
increased risk of cardiotoxicity is unclear. Earlier studies have suggested that the 
risk of drug-related cardiac adverse events was low, ranging from 0.2% to 
7%.[27, 28] More recent studies have suggested that ventricular dysfunction 
occurs in up to 14% of patients with 3% in overt heart failure compared to 11% 
and 1% with dacarbazine.[29]  
Soluble urokinase plasminogen activator receptor (suPAR) is a marker of 
immune activation and pathogenic factor in kidney disease. Levels of suPAR 
have been strongly associated with heart failure and incident cardiovascular 
disease.[30-32] We will measure suPAR along with traditional cardiovascular 
markers (BNP, high sensitivity troponin-I and high-sensitivity CRP) levels at 
baseline and after 2 doses of trabectedin, and determine whether levels are 
significantly altered by therapy, and whether baseline or early changes in levels 
are predictive of a later decline in left ventricular function.   
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To estimate the overall response rate (ORR) of combined trabectedin and 
olaparib in patients with advanced unresectable or metastatic sarcoma as 
measured by complete response + partial response using RECIST 1.1. 
2.2 
Secondary Objectives  
2.2.1 
To estimate the median progression-free survival (PFS) and 6-month PFS as 
defined by RECIST 1.1 
 
2.2.2 
To estimate the median, 1- and 2-year overall survival (OS) 
 
2.2.3 
To describe the safety and tolerability of combined trabectedin and olaparib 

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2.3 
Exploratory Objectives 
2.3.1 
To characterize next generation sequencing (NGS) findings on available reports 
from archival tumor samples to identify predictors of clinical response to therapy.   
 
2.3.2 
To evaluate expression of DNA damage repair genes by IHC in available archival 
tumor samples and correlate with response to therapy. 
2.3.3 
To assess the impact of treatment on levels of novel cardiovascular biomarkers 
and determine whether levels predict cardiotoxicity. 
2.4 
Endpoints 
The primary endpoint is objective response (CR + PR) as based on RECIST 1.1 criteria 
anytime within a minimum of 18 months after start of treatment but no more than 2 years 
from registration. Disease response will be assessed after 2 cycles (± 7 days), then every 
3 cycles thereafter. 
 
Secondary endpoints include progression-free survival as time from start of treatment to 
progression or death, or censored at the date of last tumor assessment if no progression 
and alive; overall survival, as time from start of treatment to death, or censored at the 
date of last follow-up if alive and occurrence of adverse events as graded by CTCAE 
v5.0.  
 
Exploratory endpoints include the presence of mutations in DNA repair genes identified 
by next generation sequencing, presence of DNA repair defects identified by IHC 
changes in novel cardiovascular biomarkers.  
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
 
3.1.1 
Advanced unresectable or metastatic sarcoma 
• 
Cohort 1: LMS/LPS 
• 
Cohort 2: Other histologies (excluding Gastrointestinal Stromal Tumors) 
 
3.1.2 
Must have received at least 1 prior standard systemic therapy regimen.  For 
cohort 1 patients, this must have included a prior anthracycline.  
 
3.1.3 
Measurable disease by RECIST 1.1 criteria 
 
3.1.4 
Age ≥ 16 years 
 
3.1.5 
ECOG ≤ 1 
 
3.1.6 
Adequate hematologic, renal and hepatic function within 14 days prior to 
administration of study treatment as defined below: 
Hemoglobin 
≥ 10 g/dL with no blood transfusion within 28 days 
Absolute neutrophil count 
≥ 1.5 x 10 9/L 
Platelets 
≥ 100 x 10 9/L 

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Total Bilirubin 
≤ 1.5 x institutional upper limit of normal (ULN).  
 
NOTE: patients with elevated bilirubin secondary to 
Gilbert’s disease are eligible to participate (<2.0x ULN 
should be used)  
Aspartate aminotransferase 
(AST) & alanine 
aminotransferase (ALT) 
≤ 2.5 x institutional ULN unless liver metastases are 
present in which case AST and ALT must be ≤ 5 x ULN 
Serum creatinine 
Estimated or calculated creatinine clearance (Cockcroft-
Gault formula) ≥51 mL/min using the Cockcroft-Gault 
equation or based on a 24-hour urine test: 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg) (x F)a 
       serum creatinine (mg/dL) x 72 
a where F=0.85 for females and F=1 for males. 
 
3.1.7 
Creatine phosphokinase ≤ 2.5 x institutional ULN 
 
3.1.8 
Women must be postmenopausal or have a negative urine or serum pregnancy 
test within 28 days of study treatment.  
 
Postmenopausal is defined as any of the following: 
• 
Amenorrheic for 1 year or more following cessation of exogenous 
hormonal treatments 
• 
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels 
in the post-menopausal range for women under 50 
• 
radiation-induced oophorectomy with last menses >1 year ago 
• 
chemotherapy-induced menopause with >1-year interval since last 
menses 
• 
surgical sterilization (bilateral oophorectomy or hysterectomy) 
 
3.1.9 
Women of childbearing potential must agree to use adequate contraception from 
signing informed consent to at least 6 months after the last dose of study 
treatment. ([see Appendix B for acceptable methods]) 
 
3.1.10 Men must agree to use barrier contraception or abstinence and not donate sperm 
during treatment and for 5 months after the last dose of study treatment. Female 
partners of male patients should also use a highly effective form of contraception 
([see Appendix B for acceptable methods]) if they are of childbearing potential. 
 
3.1.11 Left ventricular ejection fraction ≥ institutional LLN 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent. 
 
3.1.13 Must have a life expectancy ≥ 16 weeks 
3.2 
Exclusion Criteria 
3.2.1 
Prior therapy with PARP inhibitor, including olaparib 
 
3.2.2 
Prior therapy with trabectedin 
 

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3.2.3 
Other malignancy unless curatively treated with no evidence of disease for ≥2 
years except: adequately treated non-melanoma skin cancer, curatively treated 
in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 
endometrial carcinoma.   
 
3.2.4 
Current pregnancy or breast feeding. Pregnant women are excluded because the 
teratogenicity of both trabectedin and olaparib are unknown. Because there is an 
unknown risk to nursing infants from treatment of the mother trabectedin and/or 
olaparib, breastfeeding should be discontinued. 
 
3.2.5 
Known hypersensitivity to trabectedin or olaparib or any of the excipients of the 
products 
 
3.2.6 
Patients with symptomatic uncontrolled brain metastases.  A scan to confirm the 
absence of brain metastases is not required. The patient can receive a stable 
dose of corticosteroids before and during the study as long as these were started 
at least 4 weeks prior to treatment.  Patients with spinal cord compression unless 
considered to have received definitive treatment for this and evidence of clinically 
stable disease for 28 days. 
 
3.2.7 
Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.  
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, 
recent (within 3 months) myocardial infarction, 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 psychiatric disorder that prohibits obtaining 
informed consent. 
 
3.2.8 
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as 
judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic 
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte 
disturbances, etc.), or patients with congenital long QT syndrome. 
 
3.2.9 
Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) 
grade 2) caused by previous cancer therapy, excluding alopecia. 
 
3.2.10 Patients with myelodysplastic syndrome (MDS) /acute myeloid leukemia (AML) 
or with features suggestive of MDS/AML 
 
3.2.11 Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study 
medication. 
 
3.2.12 Immunocompromised patients, e.g., patients who are known to be serologically 
positive for human immunodeficiency virus (HIV). 
 
3.2.13 Patients with known active hepatitis (i.e. Hepatitis B or C). 
 
3.2.14 Patients receiving any systemic chemotherapy or radiotherapy (except for 
palliative reasons) within 3 weeks prior to study treatment 
 
3.2.15 Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 

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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. 
 
3.2.16 Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) 
or moderate CYP3A inducers (eg. 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. 
 
3.2.17 Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
 
3.2.18 Participation in another clinical study with an investigational product administered 
in the last 30 days prior to anticipated study treatment.   
 
3.2.19 Judgment by the investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements. 
 
3.2.20 Has received a live vaccination with 2 weeks of enrollment.  
 
3.2.21 Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation 
 
3.2.22 Involvement in the planning and/or conduct of the study 
 
3.2.23 Previous enrollment in the present study 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
 
 
Patient registration for this trial will be centrally managed by the Oncology Clinical Trials Support 
Unit (i.e. the Coordinating Center) of The University of Michigan Rogel Cancer Center as 
described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on a Screening and 
Enrollment Log. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent redacted 
source documents will be submitted by the requesting site to the Coordinating Center, by email to 
CTSU-Oncology-Multisite@med.umich.edu.    
 
A Multi-Site Coordinator of the Coordinating Center, who acts as the registrar, will review the 
submitted documents and process the registration. Sites should inform the Multi-Site Coordinator 
of a potential registration by 5 p.m. on the day prior to registration.  Same day registrations 
cannot be guaranteed.   
 
The registrar will send an email to the requesting site registrar to confirm patient registration and 
to provide the study identification number assigned to the patient. In addition, a copy of the 

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completed Eligibility Worksheet signed and dated by the registrar will be sent back to the 
requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them and will not receive study treatment. 
 
Patients will be enrolled to cohort 1 if they have a leiomyosarcoma or liposarcoma. All other 
sarcoma histologies will be enrolled to cohort 2. All patients receive the same treatment. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 business days of registration to the study. 
 
Trabectedin 1.1 mg/m2 will be administered intravenously over a 24-hour continuous 
infusion once every 21 days. Actual body weight from screening will be used to calculate 
dose. If weight changes by more than 10% from baseline, recalculate the dose. 
 
Olaparib 150 mg tablets will be taken orally twice daily with a cycle length of 21 days. 
Olaparib should be taken at the same time every day, 12 hours apart with one glass of 
water. Olaparib can be taken with or without food. Tablets should be taken whole, not 
crushed or mixed into food.  It is prohibited to consume grapefruit juice 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 for whatever reason (e.g., as a result 
of forgetting to take the tablets or vomiting), the patient will be allowed to take the 
scheduled dose up to a maximum of 2 hours after that scheduled dose time.  If greater 
than 2 hours after the scheduled dose time, the missed dose is not to be taken and the 
patient should take their allotted dose at the next scheduled time.   
 
Patients will be requested to maintain a medication diary of each dose of medication. The 
medication diary should be returned and/or reviewed by clinic staff at each scheduled 
clinic visit during the course of treatment. 
 
 
REGIMEN DESCRIPTION 
 
Agent 
Pre-medications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Trabectedin 
Pre-medicate with 
dexamethasone 20 mg IV 
approximately 30 min prior 
to trabectedin.  
Pre-medicate with 
palonosetron 0.25 mg IV 
(or similar anti-emetic per 
institutional guidelines) 
prior to trabectedin  
1.1 
mg/m2 
IV 
continuous 
infusion over 
24 hours  
(+/- 2 hours) 
Day 1 
3 weeks 
(21 
days) 
 
Olaparib 
It is prohibited to consume 
grapefruit, grapefruit juice 
and Seville oranges for 
duration of therapy. 
No routine prophylactic 
anti-emetic treatment is 
150 
mg 
PO 
BID, 
continuous 

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required; however, 
patients should receive 
appropriate anti-emetics in 
accordance with local 
treatment practice 
guidelines.  Alternatively, 
olaparib tablets can be 
taken with a light 
meal/snack (i.e. 2 pieces 
of toast or biscuits). 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.2). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity. Any toxicity observed 
during the course of the study could be managed by interruption of the dose of study 
treatment or dose reductions. Repeat dose interruptions are allowed as required, for a 
maximum of 4 weeks on each occasion. If the interruption is any longer, the study team 
must be informed. Once dose is reduced, escalation is not permitted 
 
Table 1. Dose Level Reductions of Trabectedin and Olaparib 
 
Dose Levels 
Trabectedin 
Olaparib 
1 (starting) 
1.1 mg/m2 
150 mg BID 
-1 
0.94 mg/m2 
100 mg BID 
-2 
0.8 mg/m2 
 
 
Criteria for start of new cycle: 
• 
Platelet > 100,000/microliter 
• 
Absolute neutrophil count ≥1000/microliter 
• 
Hemoglobin > 9g/dl 
• 
Total bilirubin ≤ 1.5 upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
• 
Alkaline phosphatase (ALP) ≤ 2.5 x ULN 
• 
Creatine phosphokinase (CK) ≤ 2.5 x ULN 
• 
All non-hematologic toxicities considered related to study treatment must be ≤ grade 2 
• 
Absence of any subjectively intolerable grade 2 adverse event not controlled by 
supportive therapy 
 
If a patient does not meet criteria to initiate a new cycle of treatment within 28 days of initial 
medication hold, or requires more than two dose reductions of trabectedin or one dose reduction 
of olaparib, they should be removed from study treatment. 
 
For hematologic toxicities which meet parameters for dose hold, medication should be held per 
guidance below. Medication should be resumed at the reduced dose designated below. If AE is 
recurrent/persistent despite dose reduction as specified below, drug should be discontinued. 
 
 
Table 2. Criteria for Dose modification of Thrombocytopenia, Neutropenia and Leukopenia 
 

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Laboratory Result  
Dose Adjustments 
Grade 2 Thrombocytopenia 
• 
If does not cause clinically significant symptoms or 
require a platelet transfusion, continue treatment at 
current dose and monitor blood counts weekly. 
• 
If clinically significant symptoms, hold olaparib. 
When symptoms resolve and platelets recover to 
grade 1 (for a maximum of 4 weeks), may resume 
treatment at any time during the cycle at current 
dose. 
 
Grade 3 Thrombocytopenia 
• 
Interrupt dosing of olaparib for up to 4 weeks and 
perform at least weekly blood counts. 
• 
If platelet count recovers to grade 1 or better within 
one week and does not cause clinically significant 
symptoms or require a transfusion, resume 
olaparib at reduced dose upon recovery or at start 
of next cycle, and trabectedin at current dose at 
start of next cycle. 
• 
If platelet recovery to CTCAE grade 1 or better 
occurs within > 1 week-4 weeks, or causes 
clinically significant symptoms or requires a 
transfusion, hold olaparib for the remainder of the 
cycle and reduce olaparib and trabectedin by one 
dose level at first occurrence at the start of the next 
cycle.  At second recurrence of recovery within >1 
week-4 weeks, clinically significant symptoms or 
transfusion, hold olaparib for the remainder of the 
cycle and reduce trabectedin by one dose level at 
the start of the next cycle. 
Grade 4 Thrombocytopenia 
• 
Interrupt dosing of olaparib for up to 4 weeks and 
perform at least twice weekly blood counts until 
platelets improve to grade 3 and then at least 
weekly. 
• 
At first occurrence, if platelet count recovers to 
grade 1 or better within one week and does not 
cause clinically significant symptoms or require a 
transfusion, resume olaparib at reduced dose upon 
recovery or at start of next cycle. If recovery occurs 
within >1week-4weeks, hold olaparib for the 
remainder of the cycle.  Reduce olaparib and 
trabectedin by one dose level at the start of next 
cycle. 
• 
At second recurrence of any length, hold olaparib 
for the remainder of the cycle and reduce 
trabectedin by one dose level at the start of the 
next cycle.  
Grade 4 Neutropenia 
• 
Interrupt dosing of olaparib for up to 4 weeks and 
perform at least weekly blood counts. 
• 
If neutrophil counts increase to ≥1000/microliter 
within one week and is not associated with fever or 
infection, resume olaparib at reduce dose upon 
recovery or at next cycle, and trabectedin at 
current dose level at start of next cycle.   
• 
If neutrophil count recovery to CTCAE grade 2 or 

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Laboratory Result  
Dose Adjustments 
better occurs within > 1 week-4 weeks, or is 
associated with fever or infection, hold olaparib for 
the remainder of cycle and reduce Olaparib and 
trabectedin by one dose level at first occurrence at 
the start of the next cycle.  At second recurrence of 
recovery to grade 2 within >1week-4 weeks, or is 
associated with fever or infection, hold olaparib for 
the remainder of cycle and reduce trabectedin by 
one dose level at the start of the next cycle. 
 
Management of hematologic toxicities while on study treatment 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and potential interruption of study drug if CTC grade 3 or worse 
neutropenia occurs as above. Primary prophylaxis with Granulocyte colony-stimulating factor (G-
CSF) is not recommended for first cycle, however, if a patient develops febrile neutropenia, study 
treatment should be stopped and appropriate management including G-CSF should be given 
according to local hospital guidelines if felt to be clinically appropriate and in subsequent cycles.  
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. Appropriate 
supportive treatment and causality investigation should be performed as indicated clinically. 
 
Management of anemia 
 
Table 3. Management of anemia 
Hemoglobin 
  Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
  First occurrence: 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue study treatment with 
supportive treatment (e.g. transfusion) or interrupt olaparib for a 
maximum of 4 weeks. Study treatment can be restarted if Hb 
has recovered to > 9g/dl. 
Subsequent occurrences: 
If Hb< 10 but ≥ 9 g/dl investigator judgement to continue olaparib 
with supportive treatment (e.g. transfusion) or dose interrupt (for 
max of 4 weeks) and upon recovery dose reduction of olaparib 
may be considered (to 100 mg twice daily). 
If Hb< 9 but ≥ 8 g/dl, interrupt olaparib (for max of 4 weeks) until 
Hb ≥ 9 g/dl and upon recovery dose reduction of olaparib may 
be considered (to 100 mg twice daily).  
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥ 9 
g/dl. 
Upon recovery dose reduce olaparib to 100 mg twice daily. 
 
Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
• 
≥2-week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence 
• 
≥2-week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 

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• 
≥2-week interruption/delay in study treatment due to CTC grade 3 or worse thrombocytopenia 
and/or development of platelet transfusion dependence (Platelets < 50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
blood parameter abnormalities remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to a hematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice. Study treatment should be discontinued if blood counts do not recover to 
CTC grade 1 or better within 4 weeks of dose interruption. 
 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the investigator to AstraZeneca Patient 
Safety.  Study treatment should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed. 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases, management 
of anemia may require blood transfusions. For cases where patients develop prolonged 
hematological toxicity (≥2-week interruption/delay in study treatment due to CTC grade 3 or worse 
anemia and/or development of blood transfusion dependence, refer to guidance earlier in this 
section for the management of this. 
 
 
Table 4. Criteria for Dose Modification of Non-Hematologic Laboratory Adverse Events 
Laboratory Result  
Dose Adjustments 
Total bilirubin >1.5x 
ULN* 
• 
Hold trabectedin and olaparib 
• 
Monitor weekly total bilirubin until recovery to ≤ 1.5x ULN, 
and then resume olaparib at current dose upon recovery. 
• 
If peak bilirubin ≤ 3x ULN, reduce trabectedin by one dose 
level at start of next cycle. 
• 
At second recurrence, reduce trabectedin by next dose level 
• 
If third recurrence or peak bilirubin> 3x ULN, permanently 
discontinue study treatment  
AST or ALT*> 2.5x ULN 
     
• 
Hold trabectedin and olaparib 
• 
Monitor weekly LFTs until recovery ≤ 2.5x ULN and then 
resume olaparib at current dose upon recovery. 
• 
If peak value > 2.5x ULN and ≤ 5x ULN, resume trabectedin 
at same dose at start of next cycle. 
• 
If peak value> 5x ULN, reduce trabectedin by one dose level  
• 
At second recurrence of peak value>5x ULN, reduce 
trabectedin by one dose level. 
ALP > 2.5x ULN 
• 
Hold trabectedin  
• 
Monitor weekly ALP until recovery to ≤ 2.5x ULN 
• 
Reduce trabectedin by one dose level  
• 
At second occurrence, reduce trabectedin by one dose level  
CK >2.5x ULN 
 
• 
Hold trabectedin  
• 
Monitor weekly CK until recovery 
• 
If peak value >2.5x ULN-5x ULN, resume trabectedin at 
same dose. 
• 
If peak value >5x ULN, reduce trabectedin by one dose level 
• 
At second occurrence of peak value >5x ULN, reduce 
trabectedin by one dose level  
 

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*In case a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN please refer to 
Appendix A ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for 
further instructions.  
 
Table 5. Criteria for Dose modification of Non-Hematologic Adverse events 
 
Adverse Event 
Dose Adjustment 
Grade 2 toxicity that is 
subjectively intolerable and not 
controlled by optimal supportive 
medication 
• 
Interrupt dosing for up to 4 weeks. May resume 
olaparib at current dose or reduced dose when 
toxicity improves to tolerable or grade 1 at first 
recurrence. 
• 
Upon resumption of study treatment, can continue  
trabectedin at current dose or reduce by one dose 
level at first occurrence at the start of the next 
cycle.  At second recurrence, reduce trabectedin 
by one dose level at the start of the next cycle 
• 
Patient to be withdrawn from study if unable to 
resume within 4 weeks 
Grade 3 or 4 toxicity not 
controlled by optimal supportive 
medication 
• 
Interrupt dosing for up to 4 weeks. Do not resume 
olaparib until start of next cycle. 
• 
Upon resumption of treatment, reduce trabectedin 
and olaparib by one dose level at first occurrence. 
At second recurrence, reduce trabectedin by one 
dose level 
• 
Patient to be withdrawn from study if unable to 
resume within 4 weeks 
 
Guidance on renal impairment: 
If subsequent to study entry and while still on study therapy, a patient’s estimated creatinine 
clearance (CrCl) falls below the threshold for study inclusion (≥51 ml/min), retesting should be 
performed promptly.  
 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24-hour urine test of 
between 31 and 50 ml/min) for any reason during the course of the study: the dose of olaparib 
should be reduced to 100 mg twice daily. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl 
falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
 
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance ≤ 30 
ml/min) or end-stage renal disease; if patients develop severe impairment or end stage disease it 
is recommended that olaparib be discontinued. 
 
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further diagnostic workup (including a high resolution CT scan) should be performed to exclude 
pneumonitis. 
 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator. If 

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significant pulmonary abnormalities are identified, these need to be discussed with the Study 
Principal Investigator. 
 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. These events 
are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and manageable on 
continued treatment. The first onset generally occurs in the first month of treatment for nausea 
and within the first 6 months of treatment for vomiting. For nausea, the incidence generally 
plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of olaparib treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea or 
vomiting and as required thereafter, in accordance with local treatment practice 
guidelines.  Alternatively, olaparib tablets can be taken with a light meal/snack (i.e. 2 pieces of 
toast or a couple of biscuits). 
 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered (e.g.) dopamine receptor antagonist, antihistamines 
or dexamethasone. 
 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the Principal Investigator. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the patient’s record.  
 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
 
Because the AEs related to study treatment may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
 
Special Considerations: 
• 
For ejection fraction reduction to < LLN or clinical evidence of cardiomyopathy, 
trabectedin should be held until normalization of EF. For absolute reduction in EF 10% 
or more from baseline and < LLN, reduce trabectedin to DL-1.  
5.3 
Concomitant Medications/Treatments 
• 
The use of any natural/herbal products or other traditional remedies should be 
discouraged, but use of these products, as well as any medication or vaccine 
including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements that the patient is receiving at the time of enrolment or receives during 
the study must be recorded along with: 
o 
Reason for use 
o 
Dates of administration including start and end dates 
o 
Dosage information including dose and frequency 

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• 
Anti-emetics/Anti-diarrheal medications 
From screening onwards, should a patient develop nausea, vomiting and/or diarrhea, 
then these symptoms should be reported as AEs (see section 8) and appropriate 
treatment of the event given. 
 
Prohibited Concomitant Medications: 
 
*Hormone Replacement Therapy (HRT) is acceptable 
________________________________________________________________________ 
 
 
Restricted Concomitant Medications: 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed): 
Strong CYP3A inhibitors (examples): 
itraconazole, telithromycin, 
clarithromycin, boosted protease 
inhibitors, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir 
 
Moderate CYP3A inhibitors (examples): 
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil 
Strong and moderate CYP3A inhibitors should not be 
taken with olaparib. If there is no suitable alternative 
concomitant medication, then olaparib should be held 
for the period of concomitant administration for 3 half 
live afterwards for a maximum period of up to 4 
weeks. 
Prohibited medication/class of drug: 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Hormonal therapy* 
Radiotherapy (except palliative) 
Biological therapy 
Other novel agents 
Not permitted while the patient is receiving study 
medication 
Live virus vaccines 
Live bacterial vaccines 
 
 
 
Not permitted while the patient is receiving study 
medication and during the 30 day follow up period.  
An increased risk of infection by the administration of 
live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the 
effects with olaparib are unknown. 

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Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed): 
Strong CYP3A inducers (examples): 
phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s 
Wort 
 
Moderate CYP3A inducers (examples): 
bosentan, efavirenz and modafinil 
Strong or moderate CYP3A inducers should not be 
taken with olaparib. 
 
If the use of any strong or moderate CYP3A inducers 
are considered necessary for the patient’s safety and 
welfare this could diminish the clinical efficacy of 
olaparib. 
 
If a patient requires use of a strong or moderate 
CYP3A inducer, then they must be monitored 
carefully for any change in efficacy of Olaparib 
• 
CYP3A4 substrates: hormonal 
contraceptive, simvastatin, 
cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, 
sirolimus, tacrolimus and quetiapine 
• 
CYP2B6 substrates: bupropion, 
efavirenz 
• 
OATP1B1substrates: bosentan, 
glibenclamide, repaglinide, statins 
and valsartan 
• 
OCT1, MATE1 and MATE2K 
substrates:  metformin 
• 
OCT2 substrates: serum creatinine 
• 
OAT3 substrates: furosemide, 
methotrexate 
Effect of olaparib on other drugs 
 
Based on limited in vitro data, olaparib may increase 
the exposure to substrates of CYP3A4, OATP1B1, 
OCT1, OCT2, OAT3, MATE1 and MATE2K. 
  
Based on limited in vitro data, olaparib may reduce 
the exposure to substrates of 2B6. 
 
Caution should be observed if substrates 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 
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. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment 
of pain at the site of bony metastases that were 
present at baseline, provided the investigator does 
not feel that these are indicative of clinical disease 
progression during the study period.  Study treatment 
should be discontinued for a minimum of 3 days 
before a patient undergoes therapeutic palliative 
radiation treatment.  Study treatment should be 
restarted within 4 weeks as long as any bone marrow 
toxicity has recovered.   

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Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed): 
Administration of other anti-cancer 
agents 
 
Patients must not receive any other concurrent anti-
cancer therapy, including investigational agents, 
while on study treatment. Patients may continue the 
use of bisphosphonates or denosumab for bone 
disease and corticosteroids for the symptomatic 
control of brain metastases provided the dose is 
stable before and during the study and they were 
started at least 4 weeks prior to beginning study 
treatment.  
 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a patient develops febrile neutropenia, study treatment should be stopped and 
appropriate management including G-CSF should be given according to local hospital guidelines.  
Please note that G-CSF should not be used within at least 24 h (7 days for pegylated G-CSF) of 
the last dose of study treatment unless absolutely necessary. 
5.4 
Other Modalities or Procedures 
Palliative radiation therapy may be permitted to a non-target lesion while on study 
treatment upon discussion with the principal investigator.  
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for up 
to 18 months on study until one of the following criteria apply: 
• 
Disease progression as defined in Section 7.0 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient voluntarily withdraws from treatment 
• 
Bone marrow findings consistent with myelodysplastic syndrome 
(MDS)/acute myeloid leukemia (AML) OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.6 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.5 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.7. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.7 
Duration of Follow-Up 
Patients will be followed every 3 months for a minimum of 2 years from registration or 
until study closure or until death, whichever occurs first. As long as the study remains 
open with patients on treatment, patients will be followed for survival follow up for at least 
2 years from the time of registration.  If all patients have completed treatment, the study 
may be terminated for further follow up before the 2 years from registration for survival 
follow up for the last patients. Patients removed from treatment for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event.  
 

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5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
• 
Patient withdraws consent (termination of treatment and follow-up); 
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
• 
Patient is unable to comply with protocol requirements; 
• 
Treating physician judges continuation on the study would not be in the 
patient’s best interest; 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines 
as a serious adverse event); 
• 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment which would 
interfere with this study; 
• 
Lost to Follow-up. If a research subject cannot be located to document 
survival after a period of 2 years, the subject may be considered “lost to 
follow-up.” All attempts to contact the subject during the two years must be 
documented 
• 
Termination of the study by The University of Michigan; 
• 
Patient completes protocol treatment and follow-up criteria. 
 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
6.2 
Time and Events Table 
All screening labs must be performed within 14 days prior to registration unless otherwise stated. 
Baseline imaging must be obtained within 28 days prior to registration. 
 
 
Screening* 
Cycle 1 
Day 1 
Day 1  
All Cyclesn 
Day 8, 
Cycles 1 
and 2**n 
Day 15 
All 
Cyclesn 
Off 
Treatmentn 
Follow
-Upm 
Olapariba 
 
X 
X----------------------------------------X 
 
 
Trabectedin 
 
X 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
History, vitals and 
PE 
Height & Weightb 
X 
X 
X 
 
 
X 
 
ECOG 
Performance 
Status 
X 
X 
X 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 

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Concomitant 
medication 
review 
X 
X 
X 
 
 
 
 
Toxicity  
Evaluations 
 
X 
X------------------------------------------------------X 
 
Tumor 
Measurementsc 
X 
 
Xc 
 
 
X 
 
CBC w/diff, PLTd 
X 
X 
X 
X 
X 
X 
 
Serum 
Chemistrye 
X 
X 
X 
X 
X 
X 
 
APTT, INRf 
X 
 
 
 
 
 
 
Creatine 
phosphokinase 
X 
X 
X 
 
 
X 
 
Urinalysisg 
X 
 
 
 
 
 
 
B-HCGh 
X 
X 
X 
 
 
X 
 
Transthoracic 
echocardiogrami 
X 
 
Xi  (every 
3 cycles) 
 
 
 
 
Cardiovascular 
Biomarkersj 
X 
 
Xj (C3D1 
only) 
 
 
 
 
Archival Tissue k 
X 
 
 
 
 
 
 
Bone marrow or 
blood cytogenetic 
samplesl 
 
 
 
 
 
 
 
a. Olaparib is administered with continuous twice daily dosing 
b. Vitals = temperature, pulse, respirations, blood pressure.  
c. CT and/or MRI scans to cover bodily areas in which there is disease or suspected disease. 
Baseline scans to be obtained within 28 days of registration. Restaging scans will be 
repeated at C3D1 (±7 days) then every 3 cycles (±7 days) until disease progression. If 
clinical concerns for progression or significant delays in cycle length, imaging assessment 
may be obtained early at the discretion of the treating physician and continued at an interval 
of every 3 cycles at minimum.  Scans should be obtained at the end of treatment visit if 
there is no prior radiographic confirmation of disease progression. The same method of 
assessment (i.e. CT, MRI) and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. RECIST 1.1 guidelines will 
be used. 
d. Hematology: CBC with differential to include WBC, hemoglobin, platelet count, absolute 
neutrophil count, absolute lymphocyte count and mean cell volume 
e. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, SGOT (AST), SGPT (ALT), sodium 
f. 
Activated partial thromboplastin time (APTT) and International normalized ratio (INR) will be 
performed at screening and if clinically indicated. For patients on warfarin it is 
recommended that INR monitored at least weekly for the first cycle and then on day 1 of 
each cycle thereafter, if stable. Each coagulation test result will be recorded in CRF. 
g. Urinalysis to include measurement of hemoglobin/red blood cells/ or blood, protein or 
albumin, and glucose 
h. Pregnancy tests on blood or urine samples will be performed for women of childbearing 
potential within 28 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment and at start of each cycle and at the 30 day follow up visit. Tests will 
be performed by the hospital’s local laboratory. If results are positive the patient is 
ineligible/must be discontinued from study treatment immediately.  Details of the pregnancy 
tests must be recorded in the patient’s medical records. 

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i. 
Transthoracic echocardiogram (TTE) will be obtained at baseline to ensure adequate LVEF. 
Repeat TTE will be obtained every 3 cycles (±1 cycles) while on trabectedin or if clinical 
concern of decline in ejection fraction. MUGA can be performed if inadequate assessment 
by TTE per standard practice. 
j. 
 Assessment of cardiovascular biomarkers including suPAR, BNP, high-sensitive troponin-I 
and high-sensitivity CRP will be obtained at baseline and after 2 doses of trabectedin on 
cycle 3 day 1. 
k. Results of NGS (if available) and archival tumor tissue to test for the presence of alterations 
in DNA repair pathways. Patients will not be asked to undergo an additional biopsy to obtain 
tumor sample. Full reports must be provided by the investigator for documentation on the 
Patient Safety database. These data are not required to be entered into CRF.    
l. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities at any timepoint as clinically indicated as defined in Section 5.2.  
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity. If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, 
then attempts should be made to carry out the tests on a blood sample.  
m. Patients will be followed every 3 months via phone for documentation of progression and 
survival status for a minimum of 2 years from registration.  If patient is unavailable, then 
survival status will be determined if possible, by public available information. 
n. Visits on day 1 of each cycle, lab measurements at days 1, 8 and 15 of each cycle, and the 
end of treatment visit, can be completed +/-3 days. 
* Screening labs to be obtained within 14 days of initiation of therapy. Baseline imaging to be 
obtained within 28 days of initiation of therapy. 
** Laboratory assessment will be done on day 8 for first 2 cycles to monitor for cytopenias. 
Continued day 8 laboratory assessment beyond cycle 2 is at the discretion of the treating physician. 
  
7.0 
MEASUREMENT OF EFFECT 
7.1 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [Eur J Cancer 45(2): 228-47, 2009]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1. 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least 1 cycle(s) of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 

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• 
10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
• 
10mm caliper measurement by clinical exam (lesions which cannot be 
             accurately measured with calipers should be recorded as  
             non-measurable)          
• 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
                         All tumor measurements must be recorded in millimeters (or decimal fractions of     
                         centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organ, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, and these lesions should 

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be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, since CT is more sensitive 
than X-ray, particularly in identifying new lesions. However, lesions on chest X-
ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances. 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 

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Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions (with a minimum absolute increase of 5 mm), taking as 
reference the smallest sum LD recorded since the treatment started, or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
7.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation 
CR 
Non-
CR/SD 
No 
PR 
 
>4 wks. 
Confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 

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Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
7.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). Patients without disease progression 
should be censored at the last time point for which their disease was known to 
not have progressed. 
 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented.  
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
7.2 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 5.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html). 
8.0 
ADVERSE EVENTS 
8.1 
Adverse Event Report Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of informed consent through 30 days after the last dose of study treatment. Any 
serious adverse event that occurs more than 30 days after the last study treatment and is 
considered related to the study treatment must also be reported. Serious Adverse Events 
(SAEs) will continue to be followed until: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 

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Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.2, 
occurring from informed consent through 30 days following the last dose of the study 
treatment must be recorded as an adverse event in the patient’s source documents and 
on the CRF regardless of frequency, severity (grade) or assessed relationship to the 
study treatment.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. 
 
Adverse events after the 30 day follow up period  
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new 
primary malignancy occurring after the 30 day follow up period should be reported to the 
Coordinating Center who in turn will report to AstraZeneca Patient Safety regardless of 
investigator’s assessment of causality or knowledge of the treatment arm.  Investigators 
will be asked during the regular follow up for overall survival if the patient has developed 
MDS/AML or a new primary malignancy and prompted to report any such cases.  
  
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator 
should notify the Coordinating Center who in turn will notify AstraZeneca, Patient Safety. 
 
If patients who are gaining clinical benefit are allowed to continue study treatment post 
data cut off and/or post study completion, then all SAEs must continue to be collected 
and reported to Patient Safety within the usual timeframe. 
 
Otherwise, after study treatment completion (i.e. after any scheduled post treatment 
follow-up period has ended) there is no obligation to actively report information on new 
AEs or SAEs occurring in former study patients. This includes new AEs/SAEs in patients 
still being followed up for survival but who have completed the post treatment follow up 
period (30 days). 
8.2 
Definitions 
8.2.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention. 
 
• 
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition.  
• 
Diagnostic and therapeutic non-invasive and invasive (i.e. surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it meets 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 

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• 
Symptoms of the original or targeted disease are not to be considered 
adverse events for this study. The following symptoms are indicative of 
underlying disease and will not be reported as adverse events (unless the 
event is considered serious): 
o 
Cancer-related pain  
• 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
8.2.2 
Adverse Event of Special Interest 
Adverse events of special interest (AESI) are events of scientific and medical 
interest resulting from a previously identified signal (even if non-serious) or are 
specific to the further understanding of a drug’s safety profile. AESIs require 
close monitoring and rapid communication by the Coordinating Center to 
AstraZeneca and Janssen.  
 
There are currently no Adverse Events of Special Interest for Yondelis 
(trabectedin) that will be reported to the Company.  
 
Additional safety events of interest for trabectedin that require expedited 
reporting and/or safety evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a 
Janssen medicinal product 
• 
Medication error involving a Janssen medicinal product (with or without 
patient exposure to the Janssen medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a 
medicinal product 
• 
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
 
Olaparib 
Adverse Events of Special Interest for olaparib are the Important Potential Risks 
of MDS/AML, new primary malignancy (other than MDS/AML) and pneumonitis. 
   
A questionnaire will be sent to any investigator reporting an AESI, as an aid to 
provide further detailed information on the event.  During the study there may be 
other events identified as AESIs that require the use of a questionnaire to help 
characterize the event and gain a better understanding regarding the relationship 
between the event and study treatment. 
 
AESIs should not be reported as SAEs unless they meet the SAE reporting 
criteria per section 8.2.4.  
 
Any AESI that is to be reported to Janssen and AstraZeneca by the Coordinating 
Center should be recorded on a Serious Adverse Event Report Form and be 
reported to Janssen and AstraZeneca within 24 hours of knowledge of the 
event.  

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8.2.3 
Product Quality Complaint (PQC) (for trabectedin only) 
A product quality complaint is defined as any suspicion of a product defect 
related to a potential quality issue during manufacturing, packaging, release 
testing, stability monitoring, dose preparation, storage or distribution of the 
product, or delivery system.  Not all PQCs involve a subject.  Lot and batch 
numbers are of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g., autoinjector button not working, 
needle detaching from syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
8.2.4 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the Sponsor-
Investigator, it results in any of the following outcomes: 
  
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
The cause of death of a subject in a study within 30-days of the last dose of 
study treatment, whether or not the event is expected or associated with the 
study drug, is considered a serious adverse event. 
 
NOTE: DEATHS FOR ANY REASON SHOULD BE REPORTED WITHIN 
THE PROTOCOL SPECIFIED SAE REPORTING PERIOD AS OUTLINED 
IN SECTION 8.4 
 
o 
A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
 
o 
Inpatient hospitalization or prolongation of existing hospitalization  
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
 
 
o 
Important medical event 
 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition of 
“Serious Adverse Event”. Examples of such medical events include allergic 

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bronchospasm requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the development of 
drug dependency or drug abuse; or suspected transmission of any infectious 
agent via a medicinal product. 
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs 
during the study must be reported as a serious adverse event, except 
hospitalizations for the following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., 
social reasons such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and 
where the underlying condition for which the hospitalization was planned has 
not worsened will not be considered serious adverse events. Any adverse 
event that results in a prolongation of the originally planned hospitalization is 
to be reported as a new serious adverse event.] 
 
Life-Threatening Conditions 
Disease progression should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae resulting 
from disease progression/lack of efficacy will be reported if they fulfill the serious 
adverse event definition. 
 
8.2.5 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 and 9.2 for the list of expected adverse events related to the 
drugs under study. 
8.2.6 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  

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8.2.7 
Pregnancy  
Any subject who becomes pregnant during the study must promptly discontinue 
further study treatment. 
 
All study subject pregnancies occurring during the study participation or within 5 
months of last dose must be reported to the Coordinating Center within the same 
time lines as for an SAE even if the patient was discontinued from the study.  All 
pregnancies should be followed through to outcome (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
whenever possible.  The Coordinating Center should be notified once the 
outcome of the pregnancy is known.  Follow-up information regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. 
 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion 
that the investigational product under study may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth 
defects, spontaneous miscarriages and abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic 
pregnancy) should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  
 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the 
study and for 5 months following the last dose. 
 
All pregnancies in partners of male subjects occurring during the study 
participation or within 5 months of last dose must be reported to the Coordinating 
Center within the same time lines as for an SAE even if the patient was 
discontinued from the study.   
 
Pregnancy of the patient’s partners is not considered to be an adverse event. 
However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) occurring 
from the date of the first dose until 5 months after the last dose should, if 
possible, be followed up and documented. 
 
The Coordinating Center will be responsible for reporting to Janssen Scientific 
Affairs, LLC and AstraZeneca within 24 hours of becoming aware of any patient 
or patient partner pregnancy using the Serious Adverse Event Form. 
8.2.8 
Overdose - Olaparib 
There is currently no specific treatment in the event of overdose with olaparib 
and possible symptoms of overdose are not established.  
 
Olaparib must only be used in accordance with the dosing recommendations in 
this protocol. Any dose or frequency of dosing that exceeds the dosing regimen 
specified in this protocol should be reported as an overdose. The Maximum 
Tolerated Dose is 150 mg twice daily (tablet). 
 
Adverse reactions associated with overdose should be treated symptomatically 
and should be managed appropriately. 
• 
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF. 

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If an overdose on olaparib occurs in the course of the study, then the Investigator 
or other site personnel inform the Coordinating Center and appropriate 
AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. The designated AstraZeneca representative works 
with the Investigator to ensure that all relevant information is provided to the 
AstraZeneca Patient Safety data entry site. 
 
For overdoses associated with a SAE, the standard reporting timelines apply.  
For other overdoses, reporting must occur within 30 days. 
8.3 
Adverse Event Characteristics 
8.3.1 
CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.3.2 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.4 
Serious Adverse Event Reporting Guidelines  
8.4.1 
Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless 
of causality to study drug, will be reported to the Principal Investigator and also to 
the Coordinating Center.  All SAEs and UPs must be reported to the 
Coordinating Center within 24 hours of first awareness of the event.  Events 
should be reported using the Coordinating Center SAE form as available in the 
study database.  A copy of the SAE form should be sent to the Coordinating 
Center via fax at 734-232-0744 or via email to CTSU-Oncology-
Multisite@med.umich.edu within 24 hours of the site’s knowledge of the event.  
 
Follow-up information must also be reported within 24 hours of receipt of the 
information by the investigator.  
 
All SAEs and UPs will be reported to the IRB per current institutional standards.  
 
The Coordinating Center will disseminate information regarding SAEs and UPs to 
the participating sites within 5 days of review of the information by the 
Coordinating Center’s Principal Investigator (or designee in the event of 
extended absence) only in the case that the event(s) is believed to be related 
(i.e., possibly, probably, or definitely) to the study drug. The Coordinating Center 
will be responsible for reporting of events to the FDA and supporters, as 
appropriate (outlined below).  
 

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8.5 
Reporting procedures to Janssen Scientific Affairs, LLC 
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to Janssen Scientific Affairs, LLC 
 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to a Janssen medicinal product are to be documented by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators 
must record in the CRF their opinion concerning the relationship of the adverse event to a 
Janssen medicinal product. 
 
All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed-up in accordance with clinical practice. 
 
SAEs, Adverse Events of Special Interest and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts) 
 
The Sponsor-Investigator, or designee will transmit all SAEs, Adverse Events of Special 
Interest and special situations following exposure to a Janssen product under study 
within 24-hours of the site becoming aware of the event(s). 
 
All follow-up information for serious adverse events that are not resolved at the end of the 
study or by the time of patient withdrawal must be reported directly by the Sponsor-
Investigator or designee, within 24 hours of the site becoming aware, to Janssen 
Scientific Affairs.  
 
All available clinical information relevant to the evaluation of a related SAE, Adverse 
Events of Special Interest, serious ADR or special situation is required. 
• 
The Sponsor-Investigator or designee is responsible for ensuring that these 
cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are 
received. Reporting of follow-up information should follow the same timeline as 
initial reports. 
 
• 
Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the Janssen Product under study, are to be provided to Janssen 
Scientific Affairs, LLC within 24 hours of such report or correspondence being 
sent to applicable health authorities. 
 
Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC 
according to the timeframe outlined in the Research Agreement section entitled 
Reporting of Data. 
 

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PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, LLC, and are 
mandated by regulatory agencies worldwide. Janssen Scientific Affairs, LLC has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information. Lot and/or Batch #s shall be collected or any 
reports failure of expected pharmacological action (i.e., lack of effect). The product 
should be quarantined immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to 
Janssen Scientific Affairs, LLC by the Sponsor-Investigator, or designee within 24 hours 
after being made aware of the event. The Janssen contact will provide additional 
information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a 
serious adverse event or non-serious adverse event, the Sponsor-Investigator, or 
designee must report the PQC to Janssen Scientific Affairs, LLC according to the serious 
adverse event reporting timelines.  A sample of the suspected product should be 
maintained for further investigation if requested by Janssen Scientific Affairs, LLC. 
 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the Sponsor-Investigator, or designee should notify the 
appropriate regulatory/competent authority or the manufacturer of that medicinal product 
(in the absence of appropriate local legislation) as soon as possible. 
 
Transmission Methods 
• 
The following methods are acceptable for transmission of safety information to 
the Janssen Scientific Affairs LLC: Electronically via Janssen SECURE Email 
service (preferred) IIS-BIO-VIRO-GCO@its.jnj.com  
• 
For business continuity purposes, if SECURE Email is non-functional: to 1-866-
451-0371 
• 
Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• 
Telephone (if fax is non-functional). 
 
8.6 
Reporting procedures to AstraZeneca 
All Serious Adverse Events (SAEs) occurring from the informed consent through 30 days 
following the last dose of the study treatment will be reported by the Coordinating Center 
to AstraZeneca.  Any SAEs occurring after 30 days following the last dose of the study 
treatment that are believed to be related to study drug will also be reported to 
AstraZeneca.  
 
The Coordinating Center will send the initial completed SAE Form within 24 hours of 
receipt via email to AEMailboxClinicalTrialTCS@astrazeneca.com.    
 
If only limited information is initially available or an ongoing SAE changes in its intensity 
or relationship to the study drug, or if new information becomes available, a follow-up 
report will be generated and sent to AstraZeneca within 24 hours of receipt.   
 

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If any SAE occurs in the course of the study, then the Coordinating Center will inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of awareness. 
 
The designated AstraZeneca representative works with the Coordinating Center to 
ensure that all the necessary information is provided to the AstraZeneca Patient Safety 
data entry site within 1 calendar day of initial receipt for fatal and life threatening events 
and within 5 calendar days of initial receipt for all other SAEs. 
 
For fatal or life-threatening adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately. The Coordinating Center informs 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
8.7 
Routine Reporting 
All other adverse events – such as those that are expected or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
 
All non-serious adverse events should be reported by the Coordinating Center to 
Janssen and AstraZeneca as outlined in the Research Agreements. 
8.8 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Another example of a UAP would be a product quality compliant (PQCs).  A PQC is 
defined as any suspicion of a product defect related to a potential quality issue during 
manufacturing, packaging, release testing, stability monitoring, dose preparation, storage 
or distribution of the product, or delivery system.  Not all PQCs involve a subject.  Lot and 
batch numbers are of high significance and need to be collected whenever available.   
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days 
of the study team becoming aware of the problem. 
9.0 
DRUG INFORMATION 

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9.1 
Trabectedin 
• 
Other names for the drug: Yondelis® 
 
• 
Description: 1 mg sterile lyophilized powder in a single-dose vial.  
 
• 
Classification - type of agent: alkylating agent 
 
• 
Mode of action: Trabectedin is an alkylating drug that binds guanine residues in the 
minor groove of DNA, forming adducts and resulting in a bending of the DNA helix 
towards the major groove. Adduct formation triggers a cascade of events that can 
affect the subsequent activity of DNA binding proteins, including some transcription 
factors, and DNA repair pathways, resulting in perturbation of the cell cycle and 
eventual cell death. 
 
• 
Pharmacokinetics: The pharmacokinetics is characterized by a rapid decline phase at 
the end of the infusion and slower exponential phases. Population pharmacokinetic 
analyses suggest that the pharmacokinetics of trabectedin is dose-proportional and 
exposure is time-independent. No accumulation in plasma is observed upon 
repeated administrations every 3 weeks.  
 
Binding of trabectedin to human plasma proteins was approximately 97%. Steady 
state volume of distribution exceeds 5000 L. The estimated mean clearance of 
trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 
175 hours. 
 
CYP3A is the predominant CYP enzyme responsible for the hepatic metabolism of 
trabectedin. Trabectedin was extensively metabolized with negligible unchanged 
drug in urine and feces. 
 
In patients with solid tumors, following a 3-hour and 24-hour intravenous infusion of 
14C-labeled trabectedin, 64% of the total administered radioactive dose was 
recovered in 24 days with 58% in feces and 6% in urine. 
 
• 
Side effects: The most common (≥20%) adverse reactions are nausea, fatigue, 
vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, 
and headache. Please refer to the agent’s package insert for a comprehensive list of 
adverse events.  
 
• 
Special Warnings and Precautions for Use 
Please refer to the agent’s package insert  
 
• 
Drug Interactions: Co-administration of trabectedin with strong CYP3A inhibitors 
results in increased trabectedin dose. Co-administration with strong CYP3A inducers 
results in decreased trabectedin dose.  
 
• 
Storage and stability: Store trabectedin vials in a refrigerator at 2oC to 8oC (36oF to 
46oF). Trabectedin is a cytotoxic drug. Follow applicable special handling and 
disposable procedures.   
 
Trabectedin must be stored in a secure, limited access area.   
 
• 
Preparation and Dispensing:  
• 
Using aseptic technique, inject 20 mL of Sterile Water for Injection, USP into the 

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vial. Shake the vial until complete dissolution. The reconstituted solution is clear, 
colorless to pale brownish-yellow, and contains 0.05 mg/mL trabectedin. 
• 
Inspect for particulate matter and discoloration prior to further dilution. Discard 
vial if particles or discoloration are observed. 
• 
Immediately following reconstitution, withdraw the calculated volume of 
trabectedin and further dilute in 500 mL of 0.9% Sodium Chloride, USP or 5% 
Dextrose Injection, USP. 
• 
Do not mix with other drugs. 
• 
Discard any remaining solution within 30 hours of reconstitution the lyophilized 
powder. 
• 
Trabectedin diluted solution is compatible with Type 1 colorless glass vials, 
polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, PE and 
polypropylene (PP) mixture bags, polyethersulfone (PES) in-line filters, titanium, 
platinum or plastic ports, silicone and polyurethane catheters, and pumps having 
contact surfaces made of PVC, PE, or PE/PP. 
 
• 
Administration:  
• 
Infuse the reconstituted, diluted solution over 24 hours through a central venous 
line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter to 
reduce the risk of exposure to adventitious pathogens that may be introduced 
during the solution preparation. 
• 
Complete infusion within 30 hours of initial reconstitution. Discard any unused 
portion of the reconstituted product or of the infusion solution. 
 
• 
Availability: Trabectedin is provided by Janssen.  
 
 
 
 
 
 
 
 
 
 
Under no circumstance will the study medication (Trabectedin®) provided by 
Janssen be used other than as directed by the protocol.  
 
• 
Do Not Use Commercially Available Product. Return and Retention of Study Drug: 
The investigators will be instructed by the Coordinating Center on the return or 
destruction of unused trabectedin. If any trabectedin is lost or damaged, its 
disposition should be documented in the source documents. Trabectedin supplies will 
be retained at the clinical site pending instructions for disposition by the Coordinating 
Center.  
 
If instructed to do so, unused supplies of trabectedin should be destroyed according 
to institutional policies. Destruction will be documented in the drug accountability 
forms. 
 
• 
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the inventory and disposition of the investigational drug 
trabectedin. The drug accountability records will capture drug receipt, drug 
dispensing, drug return and final disposition.   
 
9.2 
Olaparib 
• 
Other names for the drug: Lynparza 
 
• 
Description: Olaparib is available as 100 mg and 150 mg tablets.  
 

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• 
Classification - type of agent: PARP inhibitor 
 
• 
Mode of action: Olaparib is an inhibitor of PARP enzymes including PARP1, PARP2 
and PARP3. PARP enzymes are involved in normal cellular functions such as DNA 
transcription and repair. Olaparib has been shown to inhibit growth of select tumor 
cells in vitro and decrease tumor growth in mouse xenograft models of human cancer 
cells. In vitro studies have shown that olaparib-induced cytotoxicity may involve 
inhibition of PARP enzymatic activity and increased formation of PARP-DNA 
complexes resulting in DNA damage and cancer cell death. 
 
• 
Pharmacokinetics: Olaparib is available as a tablet and capsule formulation. The oral 
bioavailability of the tablet formulation is higher. Olaparib showed time-dependent PK 
that the steady state clearance decreased by 15% after multiple doses. 
 
Following oral administration, absorption is rapid with median peak plasma 
concentrations typically achieved 1.5 hours after dosing. Systemic exposure (single 
dose AUC) increases approximately proportionally with doses over the dose range of 
25 mg to 450 mg. Co-administration with high-fat meal slowed the rate of absorption 
but did not significantly alter the extent of absorption (mean AUC increased by 
approximately 8%). 
 
Olaparib has a mean apparent volume of distribution of 158 L after a single 300 mg 
dose. In vitro protein binding is approximately 82%.  
 
CYP3A4/5 were shown to be enzymes primarily responsible for metabolism of 
olaparib. 
 
The mean terminal plasma half-life of olaparib is 14.9 hours. Following a single dose 
of 14C-labele olaparib, 86% of the dosed radioactivity was recovered within a 7-day 
collection period, 44% via urine and 42% via feces. The majority of the material was 
excreted as metabolites. 
 
• 
Side effects: The most common adverse reactions (≥20%) in clinical trials were 
anemia, nausea, fatigue (including asthenia), vomiting, neutropenia, leukopenia, 
nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, 
diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, 
constipation and stomatitis. Refer the reader to the agent’s package insert for a 
comprehensive list of adverse events. 
 
• 
Special Warnings and Precautions for Use 
• 
Myelodysplastic syndrome/Acute myeloid leukemia (AML/MDS): occurred in 
<1.5% of patients exposed to olaparib monotherapy and the majority of events 
had a fatal outcome. Monitor patients for hematologic toxicity at baseline and 
monthly thereafter. Discontinue if MDS/AML is confirmed. 
• 
Pneumonitis: occurred in <1% of patients exposed to olaparib, and in some 
cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if 
pneumonitis is confirmed. 
• 
Embryofetal toxicity: olaparib can cause fetal harm. Advise of the potential risk to 
a fetus and to use effective contraception.  
 
Women of childbearing potential and their partners, who are sexually active, must 
agree to the use of TWO highly effective forms of contraception in combination (as 
described in Appendix B).  This should be started from the signing of the informed 

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consent and continue throughout the period of taking study treatment and for at least 
6 months after last dose of study drug(s), or they must totally/truly abstain from any 
form of sexual intercourse (as described in Appendix B). 
 
Male patients must use a condom during treatment and for 5 months after the last 
dose of olaparib when having sexual intercourse with a pregnant woman or with a 
woman of childbearing potential.  Female partners of male patients should also use a 
highly effective form of contraception (as described in Appendix B) if they are of 
childbearing potential.  Male patients should not donate sperm throughout the period 
of taking olaparib and for 5 months following the last dose of olaparib. 
 
For details of acceptable methods of contraception refer to Appendix B Acceptable 
Birth Control Methods. 
 
• 
Drug Interactions: Olaparib is increased with co-administration of strong or moderate 
CYP3A inhibitors. Conversely, olaparib is decreased with co-administration of strong 
or moderate CYP3A inducers. Olaparib is both an inhibitor and inducer of CYP3A 
and an inducer of CYP2B6. 
 
• 
Storage and stability: Store at 20oC to 25oC (68oF to 77oF), excursions permitted to 
15oC to 30oC (59oF to 86oF). Store in original bottle to protect from moisture.  
 
Olaparib must be stored in a secure, limited access area.   
 
• 
Administration:  
• 
See Section 5.1 
 
• 
Availability: Provided by AstraZeneca. 
 
Under no circumstance will the study medication (olaparib) be used other than as 
directed by the protocol. Do Not Use Commercially Available Product. 
• 
Return and Retention of Study Drug: 
Investigators will be instructed by the Coordinating Center on the return or 
destruction of unused olaparib. If any olaparib is lost or damaged, its disposition 
should be documented in the source documents. Olaparib supplies will be retained at 
the clinical site pending instructions for disposition by the Coordinating Center. 
Participants will be instructed to return all bottles (empty bottles or unused tablets). 
 
If instructed to do so, empty bottles and unused supplies of olaparib should be 
destroyed according to institutional policies. Destruction will be documented in the 
drug accountability forms. 
 
• 
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the inventory and disposition of the investigational drug olaparib. 
The drug accountability records will capture drug receipt, drug dispensing, drug 
return and final disposition.   
 
10.0 
CORRELATIVES/SPECIAL STUDIES 
The goal of the planned laboratory correlative studies is to evaluate for mutations/alteration in 
genes responsible for DNA repair and correlate with disease response to therapy. Findings from 

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any and all correlative studies performed on subject samples will be shared with Janssen and 
Astra Zeneca for assessment of clinical (safety and efficacy) and/or commercial value.  
 
10.1 
Next Generation Sequencing 
Results of comprehensive next generation sequencing performed on existing or available 
tumor samples will be evaluated for genomic alterations to identify predictors of clinical 
response to therapy. Patients will not be asked to undergo an additional biopsy to obtain 
tumor sample. Coded data will be stored on a secured server. 
 
10.2 
Defects in DNA Damage Repair 
In addition to NGS, available tumor samples will be evaluated by changes in DNA 
damage repair pathways and DNA damage induction by IHC which may include BRCA1, 
SLFN11, RAD 51/52, PARP1, amongst others. The decrease or increase in expression of 
DDR genes will be correlated with disease response to therapy.  
 
Specimen Banking 
Patient samples retrieved for analysis will be coded and stored in a secure lab for 
optional unspecified future research. Specimens will be stored indefinitely or until they 
are used up. If future use is denied or withdrawn by the patient, best efforts will be made 
to stop any additional studies and to destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are 
subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories. 
 
10.3 
Cardiotoxicity 
Serum suPAR, BNP, high sensitivity troponin-I and high sensitivity CRP levels will be 
obtained at baseline and after 2 doses of trabectedin to determine whether levels change 
with therapy and whether baseline or changes in levels are predictive of a decline in 
LVEF.  
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is a prospective, single-arm, multi-site study evaluating combination trabectedin and 
olaparib. Eligible patients will be assigned to one of two cohorts. Cohort 1 consists of 
patients with leiomyosarcoma or liposarcoma. Cohort 2 consists of patients with other 
bone or soft tissue sarcoma histologies. An independent Simon-minimax two-stage 
design will be used in each cohort. 
 
The primary objective is to estimate the overall response rate (CR+PR) with an endpoint 
of objective response as based on RECIST 1.1 criteria anytime within a minimum of 18 
months after start of treatment but no more than 2 years from registration. Secondary 
endpoints include PFS, OS and occurrence of adverse events. Exploratory endpoints 
include the presence of DNA repair defects by NGS and/or IHC and cardiovascular 
biomarkers.  
11.2 
Sample Size and Accrual 
In cohort 1, based on currently available phase III data, the ORR for LMS/LPS subgroup 
to trabectedin monotherapy (including best response of complete or partial response) is 
9% with a 43% clinical benefit rate (CBR). Therefore, we will target a RR of 25% with 
trabectedin plus olaparib to conclude that combination therapy is meaningful. In stage 1, 

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we will enroll 16 patients. If ≤1 patient had an objective response in the first stage, we will 
terminate the trial early. If > 1 patients have an objective response in the first stage, then 
an additional 10 patients will be enrolled in stage 2, for a total of 26 patients. If ≥ 5 out of 
26 patients have an objective response, then we will declare that the combination is 
promising and worthy of further study. The type 1 error rate is 10% and the power is 80%.  
 
In cohort 2, the ORR is approximately 5% to trabectedin monotherapy. Therefore, we will 
target a RR of 20% for the combination to be meaningful. In stage 1, we will enroll 13 
patients; if zero patients had an objective response, we will terminate the study early. 
Otherwise, if ≥1 patient had an objective response, we will enroll an additional 14 patients 
in stage 2, for a total of 27 patients. If ≥4 out of 27 patients have an objective response, 
then we will declare that the combination is promising and worthy of further study. The 
type 1 error rate is 5% and the power is 80%.  
 
In cohort 1, we require a minimum of 16 patients and a maximum of 26 patients. 
Assuming we can enroll 2 LMS/LPS patients per month, we will require a minimum of 9 
months and a maximum of 14 months to complete accrual. Assuming we will follow the 
last patient for an additional 24 months, the expected study duration for cohort 1 is 
expected to be between 33 and 38 months. 
 
In cohort 2, we require a minimum of 13 patients and a maximum of 27 patients. 
Assuming we can enroll 2 patients with other sarcoma histologies per month, we will 
require a minimum of 7 months and a maximum of 14 months to complete accrual. 
Assuming we will follow the last patient for an additional 24 months, the expected study 
duration for cohort 2 is expected to be between 31 and 38 months. 
 
The total expected duration to complete accrual and follow-up for cohorts 1 and 2 is 33 
and 38 months. 
11.3 
Data Analyses Plans 
To address the primary objective, the overall response rate will be calculated as the 
proportion (and exact binomial 95% confidence interval) of patients with complete or 
partial response as defined by RECIST 1.1, within each cohort. 
 
To address the secondary objectives: 
a. Progression free survival (PFS) will be calculated by the Kaplan-Meier method with 
errors according to Peto, within each cohort. Median and 6-month PFS will be 
estimated along with their 95% confidence intervals. 
b. Overall survival (OS) will be calculated by the Kaplan-Meier method with errors 
according to Peto, within each cohort. Median, 1- and 2-year OS will be estimated 
along with their 95% confidence intervals. 
c. The frequency and rates of adverse events occurring in at least 5% of participants 
and rates of grade 3-5 adverse events will be tabulated by system organ class and 
preferred term using Common Terminology Criteria of Adverse Events (CTCAE), 
within each cohort. 
 
 
To address the exploratory objectives: 
a. The frequency and proportion of alterations in tumor sequencing will be summarized 
within each cohort. 
b. The frequency and proportion of alterations in DNA damage repair pathways will be 
summarized within each cohort. 
c. Changes in levels of novel cardiovascular biomarkers will be summarized and 
compared to clinical and echocardiographic cardiotoxicity. 
 

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12.0 
DATA AND SAFETY MONITORING 
 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data 
and Safety Monitoring Committee (DSMC). 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of data 
and patient safety in this trial and conduct regular data review with participating sites. 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate 
will review data and patient safety issues with participating sites per a defined quarterly meeting 
cadence. Depending on the protocol activity, the meeting cadence may be more frequent. This 
data review meeting may be achieved via a teleconference or another similar mechanism to 
discuss matters related to: 
 
• 
Enrollment rate relative to expectations, characteristics of participants 
• 
Safety of study participants (SAE reporting, unanticipated problems) 
• 
Adherence to protocol (protocol deviations) 
• 
Completeness, validity and integrity of study data 
• 
Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review 
period and their site’s data are in alignment with the data reported in the database. Written 
confirmation is to be provided to the Project Manager/Delegate within the timeline requested to 
retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File.  
 
The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document 
the data review meeting discussion.  
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a quarterly basis for independent 
review. 
 
13.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of the 
trial if the committee identifies a need for a more rigorous evaluation of study-related issues.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory authority, 
the site investigator must immediately inform the Coordinating Center that such a request has been 
made. 
14.0 
Data Management 

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All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-
based electronic data capture (EDC) system of the University of Michigan. Online access will be 
provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior 
to and between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The 
investigator or study coordinator will be responsible for providing resolutions to the data queries, 
as appropriate. The investigator must ensure that all data queries are dealt with promptly.  
 
The data submission schedule is as follows:  
• 
At the time of registration   
o 
Subject entry into the EDC 
▪ 
Subject Status 
▪ 
Demographics 
• 
During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
[Information on dose limiting toxicity events must be entered within one business 
day.] Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 8.4 of the protocol.  
 
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
15.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the University of 
Michigan Rogel Cancer Center. Monitoring visits will be made during the conduct of the study and 
at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and his study 
staff should make every effort in attending the site initiation meeting. Study–related questions or 
issues identified during the site initiation meeting will be followed-up by the appropriate 
Coordinating Center personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first ‘Centralized’ 
visit should occur after the first subject enrolled completes the first treatment cycle.  The study 
site will send the redacted source documents to the Coordinating Center for monitoring.  
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment requires 
changes to the protocol procedures. The site will send in pertinent redacted source documents, 
as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 

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➢ Adherence to the protocol 
➢ Completeness and accuracy of study data and samples collected 
➢ Proper storage, dispensing and inventory of study medication 
➢ Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without 
16.0 
REFERENCES 
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Lebedinsky C, Gomez J, Park YC, Nieto A, Soto-Matos A, Parekh T, Alfaro V, Roy E, Lardelli P, 
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Koller L, Stojkovic S, Richter B, Sulzgruber P, Potolidis C, Liebhart F, Mortl D, Berger R, Goliasch 
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Appendix A 
Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report cases of 
Hy’s Law.  It is not intended to be a comprehensive guide to the management of elevated liver 
biochemistries.  Specific guidance on the managing liver abnormalities can be found in Section 5.2 of the 
protocol. 
 
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry.  The 
investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) criteria at 
any point during the study. 
 
The Investigator participates, in review and assessment of cases meeting PHL criteria to agree whether 
Hy’s Law (HL) criteria are met.  HL criteria are met if there is no alternative explanation for the elevations 
in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal 
Product (IMP).  
 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse 
Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment 
in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal (ULN) 
together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study following the start of study 
medication irrespective of an increase in Alkaline Phosphatase (ALP).  
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, 
another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the same day) 
the elevation in TBL, but there is no specified timeframe within which the elevations in transaminases and 
TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data for 
any patient who meets any of the following identification criteria in isolation or in combination: 
• 
ALT ≥ 3xULN 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN 
The Investigator will without delay review each new laboratory report and if the identification criteria are 
met will: 
• 
Determine whether the patient meets PHL criteria (see Definitions within this Appendix for 
definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 

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Follow-up 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment) 
• 
Notify the Company 
The Coordinating Center/Study Principal Investigator contacts the Investigator, to provide guidance, 
discuss and agree an approach for the study patients’ follow-up and the continuous review of data.  
Subsequent to this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated  
• 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. << For studies using a central laboratory add: This includes 
deciding which the tests available in the Hy’s law lab kit should be used>>  
• 
Complete the three Liver CRF Modules as information becomes available  
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study Physician 
contacts the Investigator in order to review available data and agree on whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP.  The AstraZeneca Medical 
Science Director and Global Safety Physician will also be involved in this review together with other 
subject matter experts as appropriate.   
 
According to the outcome of the review and assessment, the Investigator will follow the instructions 
below. 
 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a determination of 
whether the alternative explanation is an AE will be made and subsequently whether the AE meets the 
criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes 
 

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If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations other 
than the IMP: 
 
• 
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting Study 
Treatment  
This section is applicable to patients << with liver metastases>> who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the Investigator will: 
• 
Determine if there has been a significant change in the patients’ condition# compared with 
the last visit where PHL criteria were met#  
− 
If there is no significant change no action is required 
− 
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria met of this Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a 
clinically relevant change in associated symptoms.  The determination of whether there has been a 
significant change will be at the discretion of the Investigator, this may be in consultation with the Study 
Physician if there is any uncertainty. 
 
 

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Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has already met PHL 
criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based 
on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being met and 
answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study e.g. chronic or progressing malignant disease, severe 
infection or liver disease,  << or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit as described in Actions Required 
When Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment >>? 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met 
• 
If there is no significant change no action is required 
• 
If there is a significant change follow the process described above 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, 
or a clinically relevant change in associated symptoms.  The determination of whether there has 
been a significant change will be at the discretion of the Investigator; this may be in consultation 
with the Study Physician if there is any uncertainty. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M174090.pdf 
 
 

UMCC 2018.132 
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Page 55 of 55 
 
 
 
Appendix B 
Acceptable Birth Control Methods 
 
Olaparib is regarded as a compound with medium/high fetal risk. 
• 
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination [as listed below], throughout the period 
of taking study treatment and for at least 6 months after last dose of study drug(s), or they must 
totally/truly abstain from any form of sexual intercourse (see below). 
• 
 Male patients and their partners, who are sexually active and of childbearing potential, must 
agree to the use of TWO highly effective forms of contraception in combination [as listed below], 
throughout the period of taking study treatment and for 5 months after last dose of study drug(s) due to 
the unknown effects of the study drug on the sperm, or they must totally/truly abstain from any form of 
sexual intercourse (see below). Male patients should not donate sperm throughout the period of taking 
study treatment and for 5 months following the last dose of study drug(s).  
Acceptable Non-hormonal birth control methods include: 
• 
Total sexual abstinence.  Abstinence must continue for the total duration of study treatment and for at 
least 6 months after the last dose. <<for 5 months after last dose for male patients>>. Periodic 
abstinence (e.g., calendar ovulation, symptothermal post ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
• 
Vasectomised sexual partner PLUS male condom.  With participant assurance that partner received 
post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom  
• 
IUD PLUS male condom.  Provided coils are copper-banded 
 
Acceptable hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom  
• 
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly efficacious 
progesterone-based pill. 
• 
Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom 
• 
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom  
• 
Norelgestromin / EE transdermal system PLUS male condom  
• 
Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS male condom  
• 
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom