Clinical trial NCT05126433
Conditions: Advanced Solid Tumor Metastatic Solid Tumor Urothelial Cancer Poorly Differentiated Neuroendocrine Carcinomas Homologous Recombination Deficient-Positive Malignancies Agnostic
Keywords: Lurbinectedin Monotherapy Urothelial cancer Poorly differentiated neuroendocrine carcinomas Homologous recombination deficient-positive malignancies agnostic
Sponsor: Jazz Pharmaceuticals
Start date: 2022-03-03; Completion date: 2023-12-20
Enrollment: 47 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, multicenter, phase 2 study of lurbinectedin monotherapy in participants with advanced (metastatic and/or unresectable) solid tumors.

Detailed description:
This phase 2, multicenter, open-label study is designed to assess the safety and efficacy of lurbinectedin monotherapy in 3 cohorts of participants with high-unmet medical need: advanced (metastatic and/or unresectable) urothelial cancer (UC), poorly differentiated neuroendocrine carcinomas (PD-NEC), and a homologous recombination deficient-positive malignancies agnostic cohort.

Arms: arm 1: Participants with advanced (metastatic and/or unresectable) urothelial carcinoma who have progressed on platinum-containing regimen (prior therapies may include but are not limited to immune checkpoint inhibitor, enformumab vendotin, or sacituzumab govitecan) will receive Lurbinectedin 3.2 mg/m\^2 intravenous (IV) on Day 1 of every 3 weeks (Q3W) cycle until confirmed disease progression, withdrawal of participant consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort may be terminated by the sponsor for lack of efficacy signal or any other reason. arm 2: Participants with advanced (metastatic and/or unresectable) poorly differentiated neuroendocrine carcinomas who received at least 1 prior line of therapy will receive Lurbinectedin 3.2 mg/m\^2 intravenous (IV) on Day 1 of every 3 weeks (Q3W) cycle until confirmed disease progression, withdrawal of participant consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort may be terminated by the sponsor for lack of efficacy signal or any other reason. arm 3: Participants with advanced (metastatic and/or unresectable) endometrial, biliary tract, urothelial, breast (TNBC or HR+HER2- breast cancer), pancreas, gastric, or esophageal solid tumors with preidentified germline and/or somatic pathogenic mutation and received at least 1 prior line of therapy will receive Lurbinectedin 3.2 mg/m\^2 intravenous (IV) on Day 1 of every 3 weeks (Q3W) cycle until confirmed disease progression, withdrawal of participant consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort may be terminated by the sponsor for lack of efficacy signal or any other reason.
Interventions: intervention 1: Lurbinectedin
Intervention descriptions: intervention 1: Lurbinectedin 3.2 mg/m\^2 intravenous (IV) every 3 weeks (Q3W)

Protocol documents:
Prot_002.pdf: 
Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
TITLE PAGE 
Protocol Title: EMERGE-201: A phase 2, multicenter, open-label study of lurbinectedin 
efficacy and safety in participants with advanced or metastatic solid tumors 
Protocol (and Amendment) Number: JZP712-201-02  
Compound: Lurbinectedin (JZP712, also known as PM01183) 
Brief Title: Lurbinectedin monotherapy in participants with advanced or metastatic solid tumors 
Study Phase: Phase 2 
Acronym: EMERGE-201 
Sponsor Name: Jazz Pharmaceuticals, Inc.  
Legal Registered Address:  
Jazz Pharmaceuticals Ireland Limited 
Waterloo Exchange, Waterloo Road 
Dublin 4, Ireland 
US Sponsor Representative: 
Jazz Palo Alto 
3170 Porter Drive 
Palo Alto, CA 94304 
Regulatory Agency Identifier Number(s) 
IND: 
 
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Document Date: October 6, 2022


Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
Sponsor Signatory: 
   {Please see appended electronic signature page} 
 MD, PhD  
Executive Director, Clinical Development 
Jazz Pharmaceuticals, Inc. 
Date 
Investigator Signatory: 
[Name] 
[Title] 
Date 
Medical monitor name and contact information can be found in the Investigator Site 
Binder (or equivalent).  
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment 02 
Refer to the appended electronic signature page 
for date 
Amendment 01 
12 August 2021 
Original Protocol 
14 July 2021 
Amendment 02 
Overall Rationale for the Amendment: 
The overall rationale for the changes in this protocol amendment was to 1) align with the updated 
approved lurbinectedin IB to include safety updates and 2) broaden enrollment criteria and assess 
antitumor activity in a wider population. The following is a list of important changes in 
Amendment 02; editorial changes are not included in this list. 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Changed the patient inclusion 
criteria from LCNET to 
PD-NEC.  
To identify the signal of efficacy in 
PD-NECs.  
Global 
Updated the nomenclature of the 
former HRD-positive tumor 
agnostic malignancies cohort to 
the HRD-positive malignancies 
agnostic cohort. 
For consistency in naming and 
presentation.  
1.3 Schedule of 
Activities; 5.5.1 Dose 
Adjustment Due to 
Changes in Body Surface 
Area 
Regarding BSA, updated (in 
Section 1.3)/added (in new 
Section 5.5.1) language to 
indicate that “dose of study 
intervention should be 
recalculated if the participant’s 
%6$ KDV D   FKDQJH KLJKHU
or lower) compared with the 
predose Cycle 1 Day 1 value or 
the BSA recorded for dosing 
calculation at the previous 
cycle.”  
To clarify that dose adjustments per 
BSA changes will be based on the 
predose Cycle 1 Day 1 value or the 
BSA recorded for dosing calculation 
at the previous cycle. 
1.3 Schedule of Activities 
Regarding hematology, 
biochemistry-A, and 
biochemistry-B assessments, 
updated description of the 
To clarify the sampling window and 
ensure Screening laboratory results 
are reviewed prior to first dosing.  
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
Section # and Name 
Description of Change 
Brief Rationale 
sampling windows. Also added 
statement that “Screening 
laboratory results must be 
reviewed before first dosing on 
C1D1.”  
Hematology and biochemistry-B 
samples no longer required on 
C1D1. 
1.3 Schedule of 
Activities; 8.6.1 Required 
Analyses 
Revised “blood sample for 
ctDNA somatic mutational 
analysis (required)” to “Baseline 
blood for mutational analysis 
(required in all cohorts).” 
To monitor for changes and/or 
emergence of resistance mutations and 
to clarify this is required for all 
cohorts. 
1.3 Schedule of 
Activities; 8.6.1 Required 
Analyses; 8.6.2 Optional 
Analyses 
Revised “blood sample for 
longitudinal ctDNA somatic 
mutational analysis” to “blood 
for longitudinal mutational 
analysis.” Also revised this 
assessment as required for the 
HRD-positive malignancies 
agnostic cohort. 
To monitor for changes and/or 
emergence of resistance mutations and 
to clarify this is required only for the 
HRD-positive malignancies agnostic 
cohort 
1.3 Schedule of 
Activities; 4.1 Overall 
Design; 6.6 Prophylactic 
Medication; 6.7 Study 
Intervention Dose Delay 
and Reduction Rules; 
6.10.1 Allowed 
Concomitant Medications 
To specify administration of 
G-CSF or GM-CSF as
mandatory from Cycle 1
onwards.
To align with the known safety profile 
of lurbinectedin as well as the 
updated, approved lurbinectedin IB. 
2.2.2 Poorly 
Differentiated 
Neuroendocrine 
Carcinomas 
Modified introductory text for 
the LCNET cohort to a broader 
PD-NEC population. 
To provide accurate background 
information regarding the study 
cohorts. 
2.2.3 Homologous 
Recombination 
Deficient-positive 
Malignancies Agnostic 
Cohort 
Updated introductory text 
relative to the HRD-positive 
malignancies agnostic cohort and 
added additional clarification on 
enrollment of participants 
previously exposed to PARPi.  
To provide clarification on 
background information, particularly 
related to PARPi usage. 
2.3.1 Risk Assessment 
Added text describing the risk of 
rhabdomyolysis. 
To align with the updated approved 
lurbinectedin IB. 
4.1 Overall Design 
Added text regarding preferential 
enrollment; applicable only to 
To clarify enrollment procedures for 
the HRD-positive malignancies 
agnostic cohort and ensure adequate 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
Section # and Name 
Description of Change 
Brief Rationale 
the HRD-positive malignancies 
agnostic cohort. 
and even enrollment across the 
various tumor types under study. 
4.4 End of Study 
Definition 
Revised EOS definition. 
To clarify the definition of the EOS. 
5.1 Inclusion Criteria 
Revised inclusion criteria for 
former LCNET cohort to criteria 
for to PD-NEC cohort. 
Revised inclusion criteria for the 
HRD-positive malignancies 
agnostic cohort relative to 
PARPi and germline/somatic 
pathogenic mutations. 
To ensure inclusion of appropriate 
participant population per updated 
protocol. 
5.2 Exclusion Criteria 
Added criterion regarding 
PARPi for the HRD-positive 
malignancies agnostic cohort. 
To ensure inclusion of appropriate 
participant population. 
5.5 Criteria for Treatment 
Continuation 
Added information for treatment 
continuation (Cycle 2 and after) 
relative to events of 
rhabdomyolysis. 
To align with the updated approved 
lurbinectedin IB. 
6.1.1 Precautions During 
Study Treatment 
Administration 
Added this new subsection to 
include information regarding 
extravasation and 
co-administration of 
lurbinectedin and other IV drugs. 
To align with the updated approved 
lurbinectedin IB. 
6.7 Study Intervention 
Dose Delay and 
Reduction Rules 
Added information regarding 
*UDGH  3 rhabdomyolysis. 
To align with the updated approved 
lurbinectedin IB. 
7.1 Discontinuation of 
Study Intervention 
Added language regarding 
continuation of radiographic 
assessment for participants who 
discontinued treatment due to 
reasons other than disease 
progression, death, withdrawal 
of consent from study, or lost to 
follow-up. Language in 
“radiological tumor assessment” 
row of 1.3 Schedule of Activities 
revised accordingly. 
Added Grade  3 
hypersensitivity reaction and 
Grade  3 rhabdomyolysis as 
reasons a participant must be 
discontinued from study 
intervention. 
To clarify radiographic imaging 
procedures for participants who 
discontinue treatment and to align 
with the updated approved 
lurbinectedin IB. 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
Section # and Name 
Description of Change 
Brief Rationale 
8.6 Genetics and/or 
Mutational Analyses 
Revised description of analyses 
which may be performed on 
blood and tumor samples. 
For consistency with changes made in 
Section 1.3. 
8.6.2 Optional Analyses 
Regarding pretreatment and 
on-treatment tumor samples, 
added text that “every effort 
should be made to collect 
archival or post-treatment tissue 
samples from all PD-NEC 
participants.” 
To ensure collection of all necessary 
study samples. 
9.4 Statistical Analyses 
Added text regarding planned 
timing of the primary analysis. 
To clarify timing of the primary 
analysis. 
9.5 Interim Analysis 
Added text that “there will be no 
pause in enrollment during the 
interim analysis of the first 
12 evaluable participants of a 
cohort…” 
To clarify that the interim analysis 
will not affect enrollment. 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
Protocol Amendment Summary of Changes Table .........................................................................3 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
1.
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Schema ........................................................................................................................16 
1.3. 
Schedule of Activities .................................................................................................17 
2.
INTRODUCTION ......................................................................................................26 
2.1. 
Study Rationale ...........................................................................................................26 
2.2. 
Background .................................................................................................................26 
2.2.1. 
Urothelial Cancer ........................................................................................................27 
2.2.2. 
Poorly-Differentiated Neuroendocrine Carcinoma .....................................................28 
2.2.3. 
Homologous Recombination Deficient-Positive Malignancies Agnostic 
Cohort .........................................................................................................................28 
2.3. 
Benefit/Risk Assessment ............................................................................................30 
2.3.1. 
Risk Assessment .........................................................................................................30 
2.3.2. 
Benefit Assessment .....................................................................................................30 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................30 
3.
OBJECTIVES AND ENDPOINTS ............................................................................31 
4.
STUDY DESIGN .......................................................................................................32 
4.1. 
Overall Design ............................................................................................................32 
4.2. 
Scientific Rationale for Study Design ........................................................................33 
4.3. 
Justification for Dose ..................................................................................................33 
4.4. 
End of Study Definition ..............................................................................................33 
5.
STUDY POPULATION .............................................................................................34 
5.1. 
Inclusion Criteria ........................................................................................................34 
5.2. 
Exclusion Criteria .......................................................................................................37 
5.3. 
Lifestyle Considerations .............................................................................................38 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................38 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
5.4. 
Screen Failures ............................................................................................................38 
5.5. 
Criteria for Treatment Continuation ...........................................................................39 
5.5.1. 
Dose Adjustment Due to Changes in Body Surface Area ..........................................39 
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................41 
6.1. 
Study Intervention(s)/Treatment(s) Administered ......................................................41 
6.1.1. 
Precautions During Study Treatment Administration ................................................43 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................43 
6.3. 
Preparation of Study Intervention ...............................................................................43 
6.4. 
Measures to Minimize Bias ........................................................................................43 
6.5. 
Study Intervention/Treatment Compliance .................................................................44 
6.6. 
Prophylactic Medication .............................................................................................44 
6.7. 
Study Intervention Dose Delay and Reduction Rules ................................................44 
6.8. 
Continued Access to Study Intervention After the End of the Study .........................45 
6.9. 
Treatment of Overdose, Medication Errors, or Misuse ..............................................45 
6.10. 
Concomitant Therapy .................................................................................................46 
6.10.1. 
Allowed Concomitant Medications ............................................................................46 
6.10.2. 
Prohibited Concomitant Medications .........................................................................47 
6.10.3. 
Lurbinectedin Drug-Drug Interactions .......................................................................47 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................48 
7.1. 
Discontinuation of Study Intervention........................................................................48 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................49 
7.3. 
Lost to Follow-up .......................................................................................................49 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................50 
8.1. 
General Administrative Procedures ............................................................................50 
8.1.1. 
Informed Consent .......................................................................................................50 
8.1.2. 
Assignment of Participant Number ............................................................................50 
8.1.3. 
Primary Diagnosis and Prior Treatment .....................................................................50 
8.1.4. 
Medical History ..........................................................................................................51 
8.1.5. 
Demographics .............................................................................................................51 
8.1.6. 
Medication Review (Prior and Concomitant Medications) ........................................51 
8.1.7. 
Inclusion and Exclusion Criteria Review ...................................................................51 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
8.2. 
Efficacy Assessments .................................................................................................51 
8.3. 
Safety Assessments .....................................................................................................51 
8.3.1. 
Physical Examinations ................................................................................................52 
8.3.2. 
Vital Signs ..................................................................................................................52 
8.3.3. 
Electrocardiograms .....................................................................................................52 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................52 
8.3.5. 
Other Laboratory Assessment .....................................................................................53 
8.3.6. 
Pregnancy Testing ......................................................................................................53 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................53 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................53 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................54 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................54 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................54 
8.4.5. 
Pregnancy ...................................................................................................................55 
8.4.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................55 
8.4.7. 
Overdose, Medication Errors, and Misuse .................................................................56 
8.5. 
Pharmacokinetics ........................................................................................................56 
8.6. 
Genetics and/or Mutational Analyses .........................................................................56 
8.6.1. 
Required Analyses ......................................................................................................57 
8.6.2. 
Optional Analyses .......................................................................................................57 
8.7. 
..................................................................................................................57 
8.8. 
Immunogenicity Assessments ....................................................................................57 
8.9. 
Health Economics .......................................................................................................57 
9.
STATISTICAL CONSIDERATIONS .......................................................................58 
9.1. 
Statistical Hypotheses .................................................................................................58 
9.2. 
Sample Size Determination ........................................................................................58 
9.3. 
Analysis Sets ...............................................................................................................59 
9.4. 
Statistical Analyses .....................................................................................................59 
9.4.1. 
General Considerations ...............................................................................................60 
9.4.1.1. 
Definition of Study Periods for Analysis....................................................................60 
9.4.1.2. 
Statistical Methods ......................................................................................................60 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
9.4.1.3. 
Dropouts and Missing Data ........................................................................................61 
9.4.2. 
Primary Endpoint(s) ....................................................................................................61 
9.4.3. 
Secondary Endpoint(s) ................................................................................................61 
9.4.4. 
Safety Analyses ..........................................................................................................62 
9.4.4.1. 
Adverse Events ...........................................................................................................62 
9.4.4.2. 
Vital Signs, Clinical Laboratory Results, and ECOG Performance Status ................63 
9.4.4.3. 
Concomitant Medications ...........................................................................................63 
9.4.5. 
 ..........................................................................................63 
9.4.6. 
 ..................................................................................................63 
9.5. 
Interim Analysis ..........................................................................................................63 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................65 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................65 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................65 
10.1.2. 
Financial Disclosure ...................................................................................................65 
10.1.3. 
Informed Consent Process ..........................................................................................66 
10.1.4. 
Data Protection ...........................................................................................................66 
10.1.5. 
Safety Monitoring .......................................................................................................67 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................67 
10.1.7. 
Data Quality Assurance ..............................................................................................67 
10.1.8. 
Source Documents ......................................................................................................67 
10.1.9. 
Study and Site Start and Closure ................................................................................68 
10.1.9.1. 
First Act of Recruitment .............................................................................................68 
10.1.9.2. 
Study/Site Termination ...............................................................................................68 
10.1.10. 
Publication Policy .......................................................................................................69 
APPENDIX 1. ABBREVIATIONS AND DEFINITIONS ........................................................70 
APPENDIX 2. REFERENCES ...................................................................................................74 
APPENDIX 3. CLINICAL LABORATORY TESTS ................................................................77 
APPENDIX 4. AES AND SAES: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................78 
APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE .........................................83 
APPENDIX 6. GENETICS .........................................................................................................85 
APPENDIX 7. CYP3A INHIBITORS AND INDUCERS .........................................................86 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
APPENDIX 8. TUMOR ASSESSMENTS GUIDELINES ........................................................88 
APPENDIX 9. PROTOCOL AMENDMENT HISTORY ..........................................................90 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints ...........................................................................................13 
Table 2: 
Overall Study Design ..................................................................................................14 
Table 3: 
Schedule of Activities .................................................................................................17 
Table 4: 
Criteria for Treatment Continuation (Cycle 2 and After) ...........................................39 
Table 5: 
Study Treatment/Intervention .....................................................................................42 
Table 6: 
Lurbinectedin Dose Reduction Levels........................................................................45 
Table 7: 
Two-sided, Exact CI of ORR Under Varying Scenarios for n = 20 ...........................58 
Table 8: 
Two-sided, Exact CI of ORR Under Varying Scenarios for n = 35 and 
n = 100 ........................................................................................................................59 
Table 9: 
 ................................................................................63 
Table 10: Posterior Probability for Interim Futility Monitoring .................................................64 
Table 11: Protocol-required Safety Laboratory Tests .................................................................77 
Table 12: Examples of Clinical Inhibitors for P450-mediated Metabolisms (for 
Concomitant Use Clinical DDI Studies and/or Drug Labeling) (03/06/2020) ...........86 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................16 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
Overall Design 
Study Type 
Interventional 
Type of Design 
Open-label, multicenter study of lurbinectedin 
monotherapy  
Type of Control 
None 
Study Blinding 
Open-label 
Population 
Participants with 1 of the following advanced 
(metastatic and/or unresectable) tumors (as per 
eligibility criteria):  
urothelial cancer 
poorly differentiated neuroendocrine carcinoma 
homologous recombination deficient-positive 
solid tumor malignancy 
Number of Participants 
Approximately 12 to 20 participants/cohort with 
approximately 60 total participants to be 
enrolled in the study for evidence of efficacy. 
The study may be expanded to up to 
100 participants/cohort for a total approximately 
300 total participants, see Section 9.5. 
Duration of Participation 
Each participant will participate in the study 
from the time he/she signs the informed consent 
form through the end-of-the-study visit. The 
study comprises a Screening Period, 
Intervention Period, a Safety Follow-up Period, 
and an OS Follow-up Period. The overall 
duration of study participation for each 
participant is projected to be approximately 17 
months, comprising 28 days for screening, 
10 months for treatment and safety follow-up 
and approximately 6 additional months of 
follow-up over the telephone for survival 
assessment.  
Number of Treatment Cohorts 
3 
Treatment Group 
Lurbinectedin 3.2 mg/m2 IV on Day 1 of Q3W 
cycle until confirmed disease progression, 
withdrawal of participant consent, participant 
lost to follow-up, unacceptable toxicity, or the 
study or individual cohort is terminated by the 
sponsor 
Data Monitoring Committee 
Not applicable 
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Jazz Pharmaceuticals
JZP712
Protocol JZP712-201-02
Amendment 02
1.2.
Schema
Figure 1: 
Study Schematic
Abbreviations: C = cycle; D = day; DCR = disease control rate; DOR = duration of response; E/D = early discontinuation; EOS = end of study; EOT = end of 
treatment; HRD = homologous recombination deficient; IV = intravenous; ORR = objective response rate; OS = overall survival; PFS = progression-free 
survival;
Q3W = every 3 weeks; TTR = time-to-response; wks = weeks.
*Note: See Section 9 of the protocol for details on sample size and futility analysis.
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
2.
INTRODUCTION
The proposed study is a multicenter, phase 2 clinical trial to evaluate the efficacy and safety of 
lurbinectedin monotherapy in participants in 3 cohorts: advanced (metastatic and/or unresectable) 
UC, advanced (metastatic and/or unresectable) PD-NEC, and HRD-positive malignancies 
agnostic.  
2.1. 
Study Rationale 
Lurbinectedin is a novel alkylating agent that inhibits oncogenic transcription through the 
preferential binding of guanines located in GC rich regulatory areas (Deaton, 2011; Nuñez, 2016). 
Lurbinectedin also exerts immunomodulatory activity by inhibiting transcription in macrophages 
in the tumor microenvironment (Belgiovine, 2017; Cespedes, 2016), which may contribute to its 
antitumor efficacy.  
To date, over 1700 participants with multiple types of advanced solid tumors have been treated in 
clinical trials with lurbinectedin monotherapy or in combination with chemotherapy, and 
antitumor efficacy has been shown across multiple indications (Data on file, Pharma Mar 
PBRER/PSUR, 2021). In Study PM1183-B-005-14, antitumor activity of lurbinectedin 
monotherapy was assessed in participants across several advanced solid tumors (Trigo, 2020), 
namely advanced SCLC, head and neck carcinoma, NETs, biliary track carcinoma, endometrial 
carcinoma, carcinoma of unknown primary site, GCTs, and Ewing’s family of tumors. Among 
these participants, a dose of 3.2 mg/m2 lurbinectedin in the second-line SCLC cohort 
demonstrated a substantial clinical benefit with an acceptable and manageable safety profile. 
Based on these data, lurbinectedin was granted accelerated approval by the FDA (FDA, 2020). In 
addition to this trial, objective responses have been observed in participants with several other 
advanced tumors, including ovarian cancer, pancreatic cancer, breast cancer, NSCLC, SCLC, 
NETs, endometrial carcinoma, bladder carcinoma, and soft tissue sarcoma 
(Pharma Mar IB, 2022), suggesting antitumor activity of lurbinectedin either as monotherapy or 
in combination with other therapeutic agents in many advanced tumors.  
The proposed study is designed to assess the efficacy and safety of lurbinectedin monotherapy in 
3 cohorts of participants with high-unmet medical need: (1) advanced (metastatic and/or 
unresectable) UC, (2) advanced (metastatic and/or unresectable) PD-NEC, and (3) HRD-positive 
malignancies agnostic.  
2.2. 
Background 
Treatment failures are very common in patients with advanced or metastatic disease, especially in 
patients with disease progression after treatment with one or more lines of anticancer therapies. 
Their prognosis is poor and could benefit from participating in clinical trials. In recent years, 
immune CPIs have been tested in many new tumors, including advanced or metastatic diseases, 
with a remarkable long-term efficacy (La-Beck, 2015). However, this long-term benefit is limited 
to only a small percentage of patients and most of these patients eventually progress. 
Cytotoxic chemotherapy remains a crucial component of the therapeutic armamentarium for many 
of these advanced cancer patients; lurbinectedin is a novel transcription inhibitor that may offer a 
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treatment benefit to these patients. Lurbinectedin has previously shown antitumor activity in 
many advanced cancers, including tumors with DNA damage repair deficiencies (Cruz, 2018) and 
histological variants such a neuroendocrine tumors; a detailed description of the chemistry, 
pharmacology, efficacy, and safety of lurbinectedin is provided in the IB (Pharma Mar IB, 2022). 
This study includes up to a total of 60 participants in the initial assessment of efficacy in which 
each tumor cohort includes up to 20 participants. If there is evidence of efficacy, enrollment 
beyond 20 participants in the individual cohort may be considered. The study may be expanded to 
up to 100 participants/cohort for a total approximately 300 total participants, see Section 9.5. The 
following 3 cohorts with specific histologically or cytologically or pathogenic germline and/or 
somatic mutation tumors: 
x
Cohort 1: UC
x
Cohort 2: PD-NEC
x
Cohort 3: HRD-positive malignancies agnostic cohort
2.2.1. 
Urothelial Cancer
In recent years, the treatment paradigm for UC has evolved rapidly. Significant increases in OS 
and PFS were shown following avelumab maintenance treatment of patients with locally 
advanced or metastatic UC who had not progressed with first-line platinum-containing 
chemotherapy or who had disease progression within 12 months of neoadjuvant or adjuvant 
treatment with platinum-containing chemotherapy (Powles, 2020). These data led to recent FDA 
approval of avelumab in this indication, and avelumab is now the standard of care as the first-line 
maintenance treatment of advanced or metastatic UC (Bavencio, 2020). Enfortumab vendotin, an 
ADC that targets Nectin-4, which is highly expressed in UC, was granted an accelerated approval 
by the FDA for the treatment of patients with locally advanced or metastatic UC who have 
previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy; and is 
being used as the standard of care for second-line therapy for these patients (Padcev PI, 2021). 
More recently, sacituzumab govitecan, another ADC, was granted fast track designation and 
subsequently granted an accelerated approval by the FDA based on the phase 1/2 data for heavily 
pretreated bladder cancer patients (median number of prior therapies: 3; range 2 to 6; 
Trodelvy PI, 2021). 
Despite several new treatment options for patients with advanced or metastatic UC, an unmet 
need remains because few approved treatment options are available for these patients who 
progress beyond second or third-line therapies. These patients mainly receive monotherapy 
chemotherapies, such as taxane or vinflunine, in the salvage setting with a modest response 
(Bellmunt, 2009; Petrylak, 2017).  
In a mouse model with xenografted human-derived bladder cancer (Pharma Mar, data on file), 
lurbinectedin exhibited antitumor activity. In previously completed phase 1 studies either as 
lurbinectedin monotherapy or in combination with other chemotherapeutic agents, 2 participants 
with UC demonstrated stable disease (Pharma Mar IB, 2022). The proposed study will be the first 
to assess the efficacy and safety of lurbinectedin monotherapy in participants with advanced or 
metastatic UC. 
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2.2.2. 
Poorly-Differentiated Neuroendocrine Carcinoma 
Poorly differentiated neuroendocrine carcinomas are rare and aggressive neuroendocrine 
neoplasms with distinct clinical and pathological features with a high grade, high proliferative 
index, and either small or large cell morphology. Patients progressing from frontline 
platinum-based chemotherapy have limited options in the second and later lines of chemotherapy, 
and there is a high unmet medical need for patients with advanced/refractory PD-NECs. 
Lurbinectedin is an alkylating agent that inhibits oncogenic transcription through preferential 
binding to guanine residues in the DNA minor groove, triggering a cascade of events that can 
perturb the cell cycle and potentiate eventual cell death. In an earlier study, lurbinectedin 
monotherapy exhibited an 255 RI   CI, 0.8 WR  in patients with 
advanced/refractory (second line and beyond) Grade 2 and 3 NETs. Most patients had 
gastroenteropancreatic NETs (n =   DQG QRQ-functioning NETs (n =  
Thirty-one of 32 treated patients were evaluable for efficacy. Two out of 31 evaluable patients 
had PR, with a median DoR of 4.7 months, PFS of 1.4 months, and median OS of 7.4 months. 
The DCR in the evaluable patients (confirmed CR + PR + SD  4 PRQWKV ZDV   &,
14.2 WR . Lurbinectedin showed an acceptable, predictable, and manageable safety 
profile. The most common GUDGH  WR[LFLW\ ZDV QHXWURSHQLD  Grade   IHbrile 
QHXWURSHQLD  Although a heterogeneous patient population with Grade 2 and 3 NETs were 
enrolled in this study, the study met its primary endpoint, exhibiting a signal of efficacy 
(Longo-Muñoz, 2022). 
While most PD-1(&V a RULJLQDWH IURP WKH OXQJ QDPHO\ VPDOO FHOO OXQJ FDQFHU 6&/&; 
a DQG ODUJH FHOO SXOPRQDU\ NETs a D PLQRULW\ a DULVH IURP RWKHU DQDWRPLFDO
sites and are generally termed extrapulmonary neuroendocrine carcinomas. Large cell 
neuroendocrine tumor of the lung is an uncommon, aggressive, and preoperatively 
difficult-to-diagnose malignancy. Large cell neuroendocrine tumor represents a subtype of 
PD-NECs and has a poor prognosis, similar to SCLC. Data demonstrated that first-line 
platinum-based chemotherapies, especially platinum and etoposide, showed similar efficacy in 
patients with LCNET and SCLC (Derks, 2017). However, most of these patients progress rapidly 
and subsequent treatments with chemotherapies are not very effective (Russo, 2016).  
The FDA recently approved lurbinectedin for the treatment of adult patients with extensive-stage 
SCLC who progressed on prior platinum-containing regimens. Thus, lurbinectedin may show 
similar therapeutic benefit in patients with advanced/refractory LCNET or PD-NECs of other 
histological origin. Therefore, based on the available clinical data with an acceptable safety 
profile of lurbinectedin, a cohort of this study is designed to explore lurbinectedin monotherapy in 
patients with advanced/refractory PD-NEC of any origin, including LCNET of lung. 
2.2.3. 
Homologous Recombination Deficient-Positive Malignancies Agnostic Cohort 
Homologous recombination deficiency encompasses a broad spectrum of tumors with pathogenic 
mutations in the HR-DDR pathway. Such mutations and the associated cancer risk are well 
described (Radhakrishnan, 2014; Heeke, 2018). Loss of function mutations in BRCA1, BRCA2, 
RAD51C, RAD51D or PALB2, and/or promoter hypermethylation of the BRCA1 gene promoter 
(leading to loss of expression of BRCA1) have been associated with cancer development and may 
predict responsiveness to therapy, including PARP inhibitors. Several other DNA repair proteins 
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are involved in HR-DDR (eg, ATM, ARID1A, ATR, BAP1, CHEK2, RAD50, RAD54), and 
mutations or alterations to other less defined pathways can also lead to HRD (Miller, 2020).  
Heeke et al. reviewed the molecular profiles of 52,426 tumors and showed that in tumors that 
underwent NGS600 testing (n = 17,566), the overall frequency of HR-DDR mutations detected 
ZDV  7KH PRVW FRPPRQO\ PXWDWHG OLQHDJHV ZHUH HQGRPHWULDO  Q   ELOLDU\
WUDFW  Q   EODGGHU  Q   KHSDWRFHOOXODU  Q  
gastroesophageal (20.8 Q   DQG RYDULDQ  Q   Other lineages with a 
significant proportion of tumors that tested positive for HR-DDR deficiency by NGS included 
PHODQRPD  Q   EUHDVW  Q   SDQFUHDWLF  Q   DQG
colorectal FDQFHU  Q   Heeke, 2018). Examination of mutations in these genes 
using publicly available data in The Cancer Genome Atlas database (10,967 samples) aligns 
closely with these frequencies (NCI, 2021). 
Limited data are available from lurbinectedin clinical studies for malignancies associated with the 
HR-DDR pathway genes. Lurbinectedin is a selective inhibitor of the active transcription of 
protein-coding genes, and its mechanism of action involves the irreversible stalling of elongating 
RNA polymerase II on the DNA template followed by degradation by the ubiquitin/proteasome 
machinery. This results in recruitment of DNA repair factors, including XPF nuclease, and 
induces the accumulation of double-strand breaks and apoptosis as downstream events. Due to the 
inability to repair these breaks, effects are increased in homologous recombination 
repair-deficient cells (Cruz, 2018). In another study, Tumini et al reported that trabectedin and 
lurbinectedin were more sensitive in cancer cells with high levels of R-loops, which may be 
caused by loss of function of BRCA1/2 proteins or FANC family proteins (Tumini, 2019). 
In an earlier Phase 2 study, monotherapy lurbinectedin was evaluated in a cohort of 89 evaluable 
female patients with advanced or metastatic breast cancer, consisting of Arm A (n = 54) with 
germline BRCA-mutated patients and Arm B (n = 35) with unselected advanced or metastatic 
breast cancer patients. Lurbinectedin exhibited higher objective responses in participants with 
deleterious BRCA1/2 mutations compared to BRCA1/2 unselected participants, with ORR of 
  &,,  WR  DQG   &,,  WR  UHVSHFWLYHO\ ,Q Arm A, 
median PFS ZDV  PRQWKV  &,  WR  PRQWKV DQG PHGLDQ OS ZDV  PRQWKV 
CI, 1 WR  PRQWKV  DQG  RI SDWLHQWV FDUULHG GHOHWHULRXV %5&$ DQG %5&$
PXWDWLRQV DQG  DQG  SDWLHQWV KDG WULSOH-negative and HR+ disease, respectively. In 
contrast, mHGLDQ 3)6 ZDV  PRQWKV  &,  WR  PRQWKV DQG PHGLDQ 26 ZDV
12.5 PRQWKV  &,  WR  PRQWKV LQ $UP % SDWLHQWV Cruz, 2018).  
In a small cohort of 20 advanced or metastatic breast cancer patients with deleterious BRCA1/2 
mutations who received prior PARPi, monotherapy lurbinectedin had relatively lower antitumor 
activity with one patient achieving objective response (ORR 5;  &,,  WR  DQG
4 patients having 6' IRU  4 months (Pharma Mar IB, 2022). No further pharmacogenomic o 
molecular analysis was performed to determine the mechanisms of antitumor activity of 
lurbinectedin in these patients, specifically if there is any relationship with prior administration of 
PARPi or platinum compounds. Therefore, the current study is designed with a cohort of patients 
with malignancies consisting of both germline or somatic pathogenic mutations (a mutation that 
significantly affects the functions of genes associated with oncogenesis [NCI, 2022]) of HR-DDR 
pathways to explore the antitumor efficacy of lurbinectedin and conduct further 
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pharmacogenomic and molecular analyses. In addition, until further knowledge is gathered to 
understand the mechanism of action of lurbinectedin in patients who have received prior PARPi, 
patients with HRD deficient-positive malignancies who are primary resistant/refractory to PARPi 
SURJUHVVLRQ ZLWKLQ   PRQWKV RI WKH ILUVW GRVH RI 3$53L ZLOO EH H[FOXGHG LQ WKLV FRKRUW RI WKH
study. 
2.3. 
Benefit/Risk Assessment 
The approved dose regimen for lurbinectedin is 3.2 mg/m2 administered as a 1-hour IV infusion 
on Day 1 and Q3W (Pharma Mar IB, 2022). This dose regimen provides the optimal benefit to the 
participants and minimizes the potential risk/toxicity of lurbinectedin (Pharma Mar IB, 2022).  
2.3.1. 
Risk Assessment 
Potential risks to participants in this study are anticipated to be consistent with the known 
pharmacology and safety profile of lurbinectedin in previous clinical studies, as described in the 
lurbinectedin IB (Pharma Mar IB, 2022). The main risks associated with lurbinectedin are AEs 
related to reversible myelosuppression. There is also a risk of hepatotoxicity and gastrointestinal 
toxicity (specifically nausea and vomiting). Episodes of rhabdomyolysis were reported in 
2 patients treated with single-agent lurbinectedin, although none of them occurred at the 
recommended dose of 3.2 mg/m2 Q3W. A small number of reports of rhabdomyolysis have been 
received in the postmarketing setting. Based on animal studies and its mechanism of action, 
lurbinectedin may cause embryo-fetal toxicity, and effective methods of contraception are 
recommended to be used by study participants. 
2.3.2. 
Benefit Assessment 
The following potential benefits of lurbinectedin are anticipated: 
x
Receiving lurbinectedin may provide treatment benefit to study participants.
x
All participants will contribute to the process of developing new therapies in protocol-
specified advanced and metastatic solid tumors.
x
Participants will receive comprehensive clinical examinations and clinical monitoring
associated with the study.
2.3.3. 
Overall Benefit: Risk Conclusion
Lurbinectedin has an acceptable, predictable, and manageable safety profile, 
(Pharma Mar IB, 2022). Enrolled participants will be monitored closely for any safety signal on 
an ongoing basis throughout the study. Lurbinectedin has also exhibited antitumor activity in 
several other advanced tumors, including ovarian cancer, pancreatic cancer, breast cancer, 
NSCLC, SCLC, NETs, endometrial carcinoma, bladder carcinoma, and soft tissue sarcoma 
(Pharma Mar IB, 2022), suggesting antitumor activity of lurbinectedin either as a monotherapy or 
in combination with other therapeutic agents in many advanced tumors. Based on available safety 
and efficacy data from the ongoing and completed trials, overall, lurbinectedin has a positive 
benefit-risk profile for these participants.  
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4.
STUDY DESIGN
4.1. 
Overall Design
x
This is an open-label, multicenter, phase 2 study of lurbinectedin monotherapy in
participants with advanced (metastatic and/or unresectable) solid tumors.
x
The participant population comprises participants in 3 cohorts: advanced (metastatic
and/or unresectable) UC, advanced (metastatic and/or unresectable) PD-NEC, and an
HRD-positive malignancies agnostic cohort (specific criteria are presented in
Section 5.1).

Note that for the HRD-positive malignancies agnostic cohort only, the sponsor
may preferentially enroll participants with certain tumor types at any time during
the study to ensure adequate and even enrollment across the various tumor types
under study.
x
Participants will receive lurbinectedin 3.2 mg/m2 IV on Day 1 of Q3W cycle. Study
intervention will continue until confirmed disease progression, withdrawal of
participant consent, participant lost to follow-up, unacceptable toxicity, or the study or
individual cohort is terminated by the sponsor, whichever comes first.
x
This is a signal-seeking study of lurbinectedin 3.2 mg/m2 monotherapy. Review of the
safety and efficacy data will be performed on an ongoing basis by the sponsor. The
sponsor may decide to close a cohort or cohorts due to safety concerns, lack of
efficacy or any other reasons. A cohort or cohorts may be expanded at the sponsor’s
discretion to greater than 20 participants if an efficacy signal is observed without any
safety concerns.
x
This study includes up to a total of 60 participants in the initial assessment of efficacy
in which each tumor cohort includes up to 20 participants. If there is evidence of
efficacy, enrollment beyond 20 participants in the individual cohort may be
considered. Each cohort will have up to 4 stages: stage 1 at n = 12 and stage 2 at
n = 20 for futility testing (see Section 9.5); if a cohort enrolls beyond 20 participants,
the study may enroll stage 3 with an interim analysis to assess efficacy at n = 35, and a
final stage 4 at n = 100 for the final analysis.
x
Beginning on Cycle 1 Day 1, participants still on study treatment will undergo tumor
assessments every 6 weeks (± 7 days) through Week 36, regardless of treatment dose
delays. After Week 36, tumor assessments will be required every 12 weeks
(± 14 days). Participants will undergo tumor assessments until radiographic disease
progression per RECIST v1.1, withdrawal of consent, lost to follow-up, study
termination by the sponsor, or death, EOT visit, or study termination, whichever
occurs first. After the EOT visit, all participants will be followed for survival by a
telephone call every 3 months until at least 8 RI SDUWLFLSDQWV LQ HDFK FRKRUW KDYH
died or withdraw consent or are lost to follow-up. If a cohort closes due to futility, the
OS follow-up for that cohort will end.
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x
Administration of primary prophylaxis of colony-stimulating factors such as G-CSF or
GM-CSF is mandated starting from Cycle 1 and during all subsequent cycles, in
addition to the mandatory prophylactic medications listed in Section 6.6. The type,
dose, and scheme to be used may vary according per institutional/standard practices or
guidelines (see Section 6.6 for details).
x
The projected study duration for each participant is approximately 17 months
(including Screening Period [28 days], Intervention Period [9 months], Safety
Follow-up Period [30 days]), and OS Follow-up Period (6 months).
4.2. 
Scientific Rationale for Study Design
This is an open-label, nonrandomized, multi-cohort, signal-seeking study in advanced (metastatic 
and/or unresectable) tumors. The primary endpoint is the tumor response rate for each of 3 tumor 
cohorts. The ORR of each cohort will be assessed for a clinically meaningful improvement (see 
Section 9.5). The ORR is a direct measure of a drug antitumor activity, which can be evaluated in 
a single-arm study (FDA, 2018). If a cohort meets the predefined threshold of clinical efficacy, it 
may be further expanded to more than 20 participants and a discussion may be conducted with the 
FDA and other regulatory agencies for further clinical development of lurbinectedin in these 
tumors.  
There is no statistical hypothesis testing in this signal-seeking study. However, desired response 
UDWHV DUH GHILQHG DV  RU PRUH IRU HDFK FRKRUW IRU IXUWKHU H[SORUDWLRQ LQ WKHVH SDUWLFLSDQWV ZLWK
selected advanced (metastatic and/or unresectable) solid tumors with lurbinectedin monotherapy 
(Section 9.2).  
4.3. 
Justification for Dose 
Lurbinectedin was granted accelerated approval by FDA for the treatment of adult patients with 
metastatic SCLC with disease progression on or after platinum-based chemotherapy. The 
approved dose regimen for lurbinectedin is 3.2 mg/m2 administered as a 1-hour IV infusion on 
Day 1 and Q3W) (Zepzelca, 2022). This dose regimen provides the optimal benefit to the 
participants and minimizes the potential risk/toxicity of lurbinectedin (Fudio, 2021).  
In an exposure-response analysis of data for lurbinectedin in SCLC participants, the 
recommended lurbinectedin dosing regimen of 3.2 mg/m2 Q3W provided the maximum benefit in 
SCLC participants with disease progression on or after platinum-based chemotherapy. Lowering 
the dose resulted in reduced efficacy, whereas increasing it led to high incidence of severe 
hematological toxicity without improvement of efficacy (Fudio, 2021). Therefore, lurbinectedin 
3.2 mg/m2 Q3W was selected for the maximum benefit for these participants. 
4.4. 
End of Study Definition 
The EOS occurs when all dosed SDUWLFLSDQWV KDYH EHHQ IROORZHG XQWLO DW OHDVW  RI SDUWLFLSDQWV
in each cohort have died, withdrawn consent, or are lost to follow-up. After EOT, further 
follow-up of all participants will take place for an assessment of OS via a telephone call every 
3 months after their EOT visit until the EOS. The EOS for each participant is defined as the date 
of the last OS follow-up telephone call as shown in the SoA (Table 3). 
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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Disease Characteristics for Each Cohort 
Participants with advanced (metastatic and/or unresectable) cancer who meet the following 
criteria for individual cohorts. 
1. Urothelial Cancer Cohort:
a.
Has histologically or cytologically documented advanced (metastatic and/or
unresectable) urothelial (transitional cell) carcinoma of the bladder, urethra, ureter, or
renal pelvis (mixed histology tumors is allowed if predominant histology is urothelial
carcinoma. Small cell or NEC is NOT allowed if predominant).
b. Has progressed on a platinum-containing regimen (cisplatin ineligible participants who
have received only an immune CPI as their first-line treatment are allowed).

Prior therapies may include but are not limited to immune CPI, enfortumab
vendotin, or sacituzumab govitecan.

Platinum followed by avelumab maintenance is considered as one line of therapy.

Prior cytotoxic therapy in an adjuvant or neoadjuvant setting is not considered as a
prior line of systemic chemotherapy in the relapsed or metastatic setting if
administered > 12 months prior to enrollment.
2. Poorly Differentiated Neuroendocrine Carcinomas Cohort:
a.
Has histologically or cytologically confirmed advanced (metastatic and/or
unresectable) PD-NEC of any origin.

SCLC patients are not eligible in this cohort.

Histologically defined LCNET of lung are eligible regardless of their previous
diagnosis and treatment (as an example, patient may be diagnosed earlier as
NSCLC or SCLC and treated accordingly, but later biopsy results confirm the
diagnosis as LCNET).
b. Received at least 1 prior line of therapy.
3. Homologous Recombination Deficient-positive Malignancies Agnostic Cohort:
Note: participants must have previous mutational and genomic analysis results that will 
confirm the following eligibility criteria for potential participation.  
a.
Has histologically or cytologically confirmed advanced (metastatic and/or
unresectable) endometrial, biliary tract, urothelial, breast (TNBC or HR+HER2–
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breast cancer), pancreas, gastric, or esophageal solid tumor, irrespective of PD-L1 
status. 
b. Has a pre-identified germline and/or somatic pathogenic mutation (a mutation that
significantly affects the functions of genes associated with oncogenesis [NCI, 2022])
in one of the following genes: BRCA1/2, PALB2, RAD51/51B/51C/51D, ATR, ATM,
ARID1A, BAP1, CHEK2, RAD50, RAD54.
c.
Received at least 1 prior line of therapy.
d. Patients who have received prior PARPi are allowed unless they progressed within
 3 months after the first dose with PARPi
Informed Consent 
4. Is capable of giving signed informed consent as described in Section 10.1.3, which
includes compliance with the requirements and restrictions listed in the ICF and in this
protocol.
Age 
5. ,V   \HDUV RI DJH DW WKH WLPH Rf signing the informed consent.
Safety Parameters 
6. Has ECOG performance status of 0 or 1.
7. +DV D OLIH H[SHFWDQF\ RI   PRQWKV
8. Has adequate bone marrow function, as follows:
a.
$1&  PP3 RU   î 9/L,
b. 3ODWHOHWV  PP3 RU   î 9/L,
c.
+HPRJORELQ   JG/ QRWH PD\ KDYH EHHQ WUDQVIXVHG
9. +DV DV DGHTXDWH UHQDO IXQFWLRQ GHILQHG DV HVWLPDWHG FUHDWLQLQH FOHDUDQFH   P/PLQ DV
calculated using the Cockcroft-Gault equation or by 24-hour urine collection for creatinine
clearance or according to the local institutional standard method.
10. Has adequate liver function, as follows:
a.
7RWDO VHUXP ELOLUXELQ   î 8/1
b. $VSDUWDWH DPLQRWUDQVIHUDVH DQG DODQLQH DPLQRWUDQVIHUDVH   î 8/1 RU IRU
participants with documented metastatic liver disease, AST and ALT levels
 5 î ULN.
Tumor Assessment requirement 
11. Has measurable disease in accordance with RECIST v1.1.
Sex and Contraceptive/Barrier Requirements 
12. Male and female
a. Male participants:
Male participants are eligible to participate if they agree to the following during the study 
intervention period and for at least 4 months after the last dose of study intervention: 
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x
Refrain from donating sperm.
PLUS, either:
x
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
x
Must agree to use contraception/barrier as detailed below.

Agree to use a male condom [with female partner use of an additional highly
effective contraceptive method with a failure rate of <  SHU \HDU DV GHVFULEHG LQ
Appendix 5 Contraceptive and Barrier Requirements] when having sexual
intercourse with a woman of childbearing potential who is not currently pregnant.
Note: male participants who are azoospermic (vasectomized or due to a medical
cause) are still required to follow the protocol-specified contraception/barrier
criteria.
b. Female participants:
x
A female participant is eligible to participate if she is not pregnant or breastfeeding,
and one of the following conditions applies:

Is a woman of non-childbearing potential as defined in Appendix 5 Contraception
and Barrier Guidance.
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a
failure rate of <  SHU year), preferably with low user dependency, as described
in Appendix 5 Contraception and Barrier Guidance during the study intervention
period and for at least 6 months after the last dose of study intervention and agrees
not to donate eggs (ova, oocytes) for the purpose of reproduction during this
period. The investigator should evaluate the potential for contraceptive method
failure (eg, noncompliance, recently initiated) in relationship to the first dose of
study intervention.
x
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as
required by local regulations) within 7 days before the first dose of study intervention,
see Section 8.3.6: Pregnancy Testing.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum
pregnancy test is required. In such cases, the participant must be excluded from
participation if the serum pregnancy result is positive.
x
Additional requirements for pregnancy testing during and after study intervention are
located in Section 8.3.6 Pregnancy Testing.
x
The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy.
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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Has persisting toxicity (NCI CTCAE v5.0 Grade > 1) related to prior therapy; however,
DORSHFLD VHQVRU\ QHXURSDWK\ K\SRWK\URLGLVP DQG UDVK *UDGH  2 are acceptable, and
otKHU *UDGH  2 AEs not constituting a safety risk based on the investigator’s judgement
are acceptable.
2. Has known symptomatic CNS metastases requiring steroids. Participants with previously
diagnosed CNS metastases are eligible if they have completed their treatment and have
recovered from the acute effects of radiation therapy or surgery prior to enrollment, have
discontinued high dose corticosteroid treatment for these metastases for at least 2 weeks,
DQG DUH QHXURORJLFDOO\ VWDEOH  10 mg prednisone mg daLO\ RU  2 mg dexamethasone
daily are allowed).
3. Has a diagnosis of any other malignancy within 2 years prior to enrollment, except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the
breast or of the cervix, low gradH *OHDVRQ  6) prostate cancer on surveillance without
any plans for treatment intervention (eg, surgery, radiation, or castration), or prostate
cancer that has been adequately treated with prostatectomy or radiotherapy and currently
with no evidence of disease or symptoms. Other cancers not expected to affect health or
survival over 2 years may be approved by the medical monitor after case review.
4. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior
WR HQUROOPHQW XQVWDEOH DQJLQD FRQJHVWLYH KHDUW IDLOXUH  1HZ <RUN +HDUW $VVRFLDWLRQ
Classification Class II), or serious cardiac arrhythmia requiring medication.
5. Has significant neurological or psychiatric disorders that could harm participant ability or
compliance with the study assessments.
6. Has an active infection requiring systemic therapy.
7. Has significant non-neoplastic liver disease (eg, cirrhosis, active chronic hepatitis).
8. Has any other major illness that, in the investigator’s judgment, could substantially
increase the risk associated with the patient’s participation in this study.
9. Has any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the interpretation of
the results or render the participant at high risk for treatment complications.
10. Has illnesses or conditions that interfere with their capacity to understand, follow, and/or
comply with study procedures.
Prior/Concomitant Therapy 
11. Received prior treatment with lurbinectedin or trabectedin.
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants will be automatically assigned a new participant number 
for every screening/rescreening event. 
5.5. 
Criteria for Treatment Continuation 
Further treatment cycles (ie, Cycle 2 and after) will be administered Q3W if the participant fulfills 
all the retreatment criteria within 3 days prior to the scheduled lurbinectedin infusion (Table 3) 
and defined in Table 4.  
Table 4: 
Criteria for Treatment Continuation (Cycle 2 and After) 
Variable 
Retreatment Criteria (Day 1) 
Hemoglobina 
  JG/ 
ANC 
  î 9/L 
Platelets 
  î 9/L 
AST/ALT 
 3 î 8/1 IRU SDUWLFLSDQWV ZLWK GRFXPHQWHG
metastatic liver disease, AST and ALT levels 
 5 î 8/1 
Total serum bilirubin 
  î 8/1 
Serum creatinine 
  î 8/1 RU FUHDWLQLQH FOHDUDQFH   P/PLQ 
Events of rhabdomyolysis 
Withhold for Grade 2; resume at same dose if 
Grade  1 
Other nonhematological treatment-related AEs 
(except isolated increased GGT and/or AP; 
Grade 2 asthenia, constipation, alopecia, 
peripheral neuropathy, or nonoptimally treated 
nausea and/or vomiting) 
*UDGH  1 
Active infection (including sepsis) and/or 
bleeding (any grade) 
Absence 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AP = alkaline phosphatase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; ULN = upper 
limit of normal.  
a Participants may receive packed red blood cells transfusion and/or erythropoietin treatment, if clinically indicated, 
to increase or maintain adequate hemoglobin levels. 
If a participant does not meet the requirements for treatment continuation on Cycle 2 Day 1 or 
subsequent cycles, reassessments will be performed at least every 48 to 72 hours for evaluation of 
treatment continuation. Treatment can be withheld up to a maximum of 3 weeks. Lurbinectedin 
dose delay and reduction rules are presented in Section 6.7. 
5.5.1. 
Dose Adjustment Due to Changes in Body Surface Area 
Body surface area will be recalculated on Day 1 of each treatment cycle. The dose of study 
LQWHUYHQWLRQ VKRXOG EH UHFDOFXODWHG LI WKH SDUWLFLSDQW¶V %6$ KDV D   FKDQJH KLJKHU RU ORZHU
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compared with the predose Cycle 1 Day 1 value or the BSA recorded for dosing calculation at the 
previous cycle. Refer to Section 6.7 for additional guidance regarding dose adjustment criteria. 
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6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention/treatment is defined as any investigational intervention(s), marketed 
product(s), or placebo intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Intervention(s)/Treatment(s) Administered 
Refer to Table 5 for details regarding the study intervention. 
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Table 5: 
Study Treatment/Intervention 
Treatment 
Arm 
Intervention/Treatment 
Name 
Formulation Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Use 
Sourcing 
Pkg 
Labeling Storage 
Conditions 
1 
lurbinectedin (JZP712) 
Also known as PM01183 
Lyophilized 
powder for 
concentrate 
for solution 
for infusion 
4.0 mg/vial 
0.5 mg/mL 
after 
reconstitution 
3.2 mg/m2 
every 3 weeks 
Infusion/IV 
Experimental Provided centrally by 
the sponsor or locally 
by the trial site, 
subsidiary, or 
designee. 
Study 
intervention 
will be 
provided in 
4-mg/vial,
sterile 30-
mL, single-
dose, type I
clear-glass
vials and
labeled as
required per
country
requirement.
Child
resistant
packaging as 
required
Open 
labeling 
If not used 
immediately 
after 
reconstitution or 
dilution, the 
lurbinectedin 
solution can be 
stored prior to 
administration 
for up to 
24 hours 
following 
reconstitution, 
including 
infusion time, at 
either room 
temperature/ 
ambient light or 
under 
refrigeration at 
2ºC-8ºC (36ºF - 
46ºF) conditions. 
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6.1.1. 
Precautions During Study Treatment Administration 
If extravasation of lurbinectedin occurs, immediately discontinue the infusion, remove the 
infusion catheter, and monitor for signs and symptoms of tissue necrosis. Administer supportive 
care per the institutional guidelines as needed. Administer subsequent infusion at a site that was 
not affected by extravasation. Consider use of a central venous catheter to reduce the risk of 
extravasation, particularly in patients with limited venous access. Monitor patients for signs and 
symptoms of extravasation during the lurbinectedin infusion. 
Do not co-administer lurbinectedin and other IV drugs concurrently within the same IV line. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. Further guidance and information for the final disposition of unused study interventions
are provided in the Investigator Site Binder.
2. The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received and any discrepancies are
reported and resolved before use of the study intervention.
3. Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study intervention
must be stored in a secure, environmentally controlled, and monitored (manual or
automated) area in accordance with the labeled storage conditions with access limited to
the investigator and authorized site staff.
4. The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(ie, receipt, reconciliation, and final disposition records).
6.3. 
Preparation of Study Intervention 
Before use, the vials are reconstituted with water for injection (8 mL) to obtain a solution 
containing 0.5 mg/mL lurbinectedin. For administration to participants as IV infusion, the 
UHFRQVWLWXWHG YLDOV DUH GLOXWHG ZLWK JOXFRVH  PJP/  VROXWLRQ IRU LQIXVLRQ RU VRGLXP
FKORULGH  PJP/  VROXWLRQ IRU LQIXVLRQ  
In order to obtain reliable 
 information during the first dosing, the infusion rate should not be 
modified once the infusion begins, especially during the first cycle. Lurbinectedin is 
administered as a 1-hour IV infusion.  
6.4. 
Measures to Minimize Bias 
Specific measures to minimize bias are not applicable to this open-label, nonrandomized study. 
All participants who sign the ICF will receive a participant number. The participant number 
identifies the participant for all study procedures that occur throughout the study. This number is 
unique and once assigned, cannot be reassigned to another study participant.  
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6.5. 
Study Intervention/Treatment Compliance 
Participants who are dosed at the site will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification should be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.  
6.6. 
Prophylactic Medication 
All participants will receive mandatory prophylactic medications as indicated below. The IV 
formulation of these agents must be used in this setting:  
x
Corticosteroids (dexamethasone 8 mg or equivalent)
x
Serotonin (5-HT3) antagonists (ondansetron 8 mg or equivalent)
x
Extended treatment with oral 5-HT3 antagonists and oral dexamethasone for
2 consecutive days
x
If necessary, and in addition to the above, administration of 10 mg of oral or IV
metoclopramide (or equivalent) every 8 hours.
x
Administration of primary prophylaxis of colony-stimulating factors such as G-CSF
or GM-CSF is mandated starting from Cycle 1 and during all subsequent cycles. The
type, dose, and scheme to be used may vary according to institutional/standard
practices or guidelines. A mandatory window of at least 24 hours and up to 72 hours
must be allowed from the last dose of study intervention administration until G-CSF
or GM-CSF prophylaxis is started.
6.7. 
Study Intervention Dose Delay and Reduction Rules
For any treatment delay due to treatment-related AEs lasting more than 1 week, a dose reduction 
should be implemented upon recovery. 
Participants may continue the study treatment at a reduced dose if they present any of the 
following: 
x
*UDGH  3 treatment-related nonhematological toxicity. Exceptions are GUDGH  3
nausea and/or vomiting not optimally treated, GUDGH  DVWKHQLD ODVWLQJ  3 days,
Grade  GLDUUKHD ODVWLQJ  2 days or not optimally treated, Grade 3 transient
ALT/AST elevations that are rapidly reversible and not leading to subsequent delays,
and nonclinically relevant biochemical abnormalities
x
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia concomitantly with
Grade  3 bleeding
x
Grade 4 neutropenia, any grade febrile neutropenia or neutropenia associated with
infection/sepsis

Note: All participants receive mandatory colony-stimulating factors such as
G-CSF or GM-CSF starting from Cycle 1 and during all subsequent cycles.
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However, if the episode of neutropenia persists despite supportive care with 
G-CSF or GM-CSF, then the dose must be reduced
x
Frequent or prolonged (> 1 week) dose delays due to treatment-related AEs
x
Unacceptable toxicity in the judgement of the investigator
Participants who experience Grade  3 hypersensitivity reactions or Grade  3 rhabdomyolysis 
will be discontinued from study intervention.  
Dose reduction levels are shown in Table 6. 
Table 6: 
Lurbinectedin Dose Reduction Levels 
Dose Reduction 
Lurbinectedin Dose (mg/m2) 
1 (starting dose) 
3.2 
–1
2.6 
–2
2.0 
Up to 2 dose reductions are allowed per participant. Participants who continue to experience 
treatment-related toxicity and/or frequent dose delays after permitted dose reductions should be 
discontinued from the study. However, they can continue receiving the study intervention if 
objective clinical benefit is adequately documented by the Investigator, and upon agreement with 
the Sponsor. Once the dose has been reduced for an individual participant, it will not be 
re-escalated under any circumstance.  
Participants not meeting criteria for continuation after a maximum of 3-week delay should be 
discontinued from the study. For delays > 3 weeks, retreatment can be considered on 
case-by-case basis after discussion with the medical monitor. 
Details related to required follow-up laboratory tests to be performed after reporting of specific 
AEs are presented in Section 8.3.4. 
6.8. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.9. 
Treatment of Overdose, Medication Errors, or Misuse 
Overdose (defined as any dose administered or received that was higher than the intended dose), 
medication errors (defined as any unintentional error in the dispensing or administration of the 
study drug), and misuse of the study drug are considered reportable experiences. 
There is currently no specific treatment in the event of an overdose with lurbinectedin, and 
possible symptoms of overdose have not been established. Lurbinectedin 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. 
In the event of an overdose, the investigator should: 
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x
Contact the Medical Monitor immediately.
x
Evaluate the participant to determine, in consultation with the Medical Monitor,
whether study intervention should be interrupted or whether the dose should be
reduced.
x
Closely monitor the participant for any AE/SAE and laboratory abnormalities for at
least 14 days.
x
Document the quantity of the excess dose as well as the duration of the overdose.
6.10. 
Concomitant Therapy 
Any medication or vaccine, including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
x
Reason for use
x
Dates of administration including start and end dates
x
Dosage information including dose, frequency, and route
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.10.1. 
Allowed Concomitant Medications 
The following medications are allowed during study participation: 
x
Colony-stimulating factors such as G-CSF or GM-CSF

Primary G-CSF or GM-CSF is mandated during the first and all subsequent
cycles. The type, dose, and scheme to be used may vary according to
institutional/standard practices or guidelines. A mandatory window of at least
24 hours and up to 72 hours must be allowed from the last dose of study
intervention administration until G-CSF or GM-CSF prophylaxis is started.
x
Therapies for pre-existing and treatment-emergent medical conditions, including pain
management
x
Blood products and transfusions, as clinically indicated
x
Bisphosphonates
x
Primary and secondary prophylaxis and/or symptomatic treatment for emesis
according to ASCO guidelines for nausea or vomiting (see Section 6.6;
Hesketh, 2017)
x
Erythropoietin treatment according to ASCO guidelines
x
Anticoagulation therapy.
In addition to the above, all treatments that the Investigator considers necessary for a 
participant’s welfare may be administered at the discretion of the Investigator in keeping with the 
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community standards of medical care. All concomitant medication will be recorded in the case 
eCRF including all prescription, OTC, herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of the medication as per Section 6.10 may 
also be included in the eCRF. 
6.10.2. 
Prohibited Concomitant Medications 
The following medications are prohibited during study participation: 
x
Any other antineoplastic therapy
x
Any other investigational agents
x
Immunosuppressive therapies other than corticosteroids for antiemetic prophylaxis
and/or pain control
x
Aprepitant, fosaprepitant or related compounds (other NK-1 antagonists)
x
Radiotherapy
6.10.3. 
Lurbinectedin Drug-Drug Interactions 
In vitro studies with human liver microsomes have shown that CYP3A4 is a major metabolic 
enzyme involved in lurbinectedin metabolism, followed by CYP2E1, CYP2D6, and CYP2C9. 
The contribution of other CYP isoenzymes is negligible. Thus, concomitant drugs which induce 
or inhibit CYP3A4 should be carefully monitored or avoided, whenever possible (Appendix 7). 
A significant interaction with aprepitant (CYP3A4 inhibitor) is suggested by available 
lurbinectedin phase 2 data from ovarian cancer patients and a phase 1 Study PM1183-A-008-13 
LQ SDWLHQWV ZLWK DGYDQFHG VROLG WXPRUV ZKHUH OXUELQHFWHGLQ FOHDUDQFH ZDV UHGXFHG E\ 
approximately, in the presence of aprepitant and resulted in unusually long-lasting neutropenia, 
as well as thrombocytopenia with a worse outcome. Although all patients eventually recovered, 
the use of aprepitant is not permitted. 
Based on in vitro study results, lurbinectedin was shown to inhibit CYP2C8, CYP3A4, and 
CYP2B6. However, according to guidelines from European Medicines Agency and FDA (US), 
the calculated in vivo impact of lurbinectedin on those CYP isoenzymes was insignificant. 
Therefore, no potential drug-drug interaction is expected between lurbinectedin and drugs which 
are metabolized by CYP3A4, CYP2C8, or CYP2B6. 
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7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Discontinuation from study intervention does not represent discontinuation from the study 
(Section 7.2). Participants may discontinue from study intervention at any time for any reason, or 
at the discretion of the investigator. In addition, a participant may be discontinued from study 
intervention by the investigator or sponsor for safety, behavioral, compliance, and/or 
administrative reasons. For participants that discontinue study intervention, all effort should be 
made to complete the procedures listed in the EOT visit (Table 3).  
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will return to the 
site 30 days (± 7 days) later for an EOT visit, and the participant will be followed for OS. For 
participants who discontinue treatment due to reasons other than disease progression, death, 
withdrawal of consent from study, or lost to follow-up, radiographic assessment should continue 
until disease progression, initiation of new anticancer therapy, death, withdrawal of consent from 
study, EOT Visit, lost to follow-up, or study termination. A radiological tumor assessment will 
be performed at the EOT visit for these participants if not performed within 7 days of the last 
treatment assessment visit. See the SoA (Table 3) for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to 
be completed. 
A participant must be discontinued from study intervention for any of the following reasons: 
x
The participant requests to discontinue study intervention
x
The participant has an AE that may compromise the participant’s continued
participation (see Section 8.4.3 for follow-up guidelines)
x
The participant experiences a Grade ш 3 hypersensitivity reaction
x
The participant experiences Grade  3 rhabdomyolysis
x
The participant has any of the clinical conditions as noted in Section 6.7, which
cannot be resolved with either of the following attempts:

The participant requires > 2 dose reductions

The participant requires a treatment delay > 3 weeks from the due date because of
treatment-related toxicity (except if objective clinical benefit is observed, with the
Sponsor’s agreement)
x
The participant has a positive serum pregnancy test or becomes pregnant during the
study (Appendix 5 and Section 8.4.5)
x
The participant is noncompliant with study intervention or procedures
x
The sponsor decides to terminate the study or an individual cohort for any reason
x
The investigator determines the participant should not continue on study intervention
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x
The participant has confirmed radiological disease progression as per RECIST v1.1
7.2. 
Participant Discontinuation/Withdrawal From the Study
x
A participant may withdraw from the study at any time at his/her own request or may
be withdrawn at any time at the discretion of the investigator for safety, behavioral, or
compliance reasons.
x
At the time of discontinuing from the study, if possible, an E/D visit should be
conducted within 30 days, as shown in the SoA. See SoA for data to be collected at
the time of study discontinuation and follow-up and for any further evaluations that
need to be completed.

The participant will be permanently discontinued from both the study intervention
and from the study at that time.
x
If the participant withdraws consent for disclosure of future information, the sponsor
may retain and continue to use any data collected before such a withdrawal of
consent.
x
If a participant withdraws from the study, he/she may request destruction of any
samples taken and not tested, and the investigator must document this in the site study
records.
7.3. 
Lost to Follow-up
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether or not the participant wishes to and/or
should continue in the study.
x
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, [3] telephone
calls and, if necessary, a certified letter to the participant’s last known mailing
address or local equivalent methods). These contact attempts should be documented
in the participant’s medical record.
x
Should the participant continue to be unreachable, he/she will be considered to have
withdrawn from the study and lost to follow-up.

The rules for handling missing data for an individual participant will be specified
in Section 9 and the SAP for the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Study and Site 
Start and Closure Section 10.1.9. 
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8.
STUDY ASSESSMENTS AND PROCEDURES
x
Study procedures and their timing are summarized in the SoA.
x
Immediate safety concerns should be discussed with the sponsor immediately upon
occurrence or awareness to determine if the participant should continue or
discontinue study intervention.
x
Adherence to the study design requirements, including those specified in the SoA, is
essential and required for study conduct.
x
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator should maintain a screening
log to record details of all participants screened and to confirm eligibility or record
reasons for screening failure, as applicable.
x
Procedures conducted as part of the participant’s routine clinical management (eg,
blood count) and obtained before signing of the ICF may be utilized for screening or
baseline purposes provided the procedures met the protocol-specified criteria and
were performed within the time frame defined in the SoA.
x
The maximum amount of blood collected from each participant over the duration of
the study, including any extra assessments that may be required, will not exceed
415 mL.
x
Repeat or unscheduled samples may be taken for safety reasons or for technical issues
with the samples.
8.1. 
General Administrative Procedures
8.1.1. 
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must obtain 
documented consent from each potential participant/legal representative prior to participation in 
this study. A signed copy of the ICF should be given to the participant and the original should be 
placed in the participant’s medical records.  
8.1.2. 
Assignment of Participant Number 
Each participant who signs the ICF will be assigned a unique number that will identify the 
participant throughout the study. Once a number has been assigned, it cannot be reassigned to 
another study participant. See Section 5.4 for handling of participant numbers for screen failures 
who are rescreened. 
8.1.3. 
Primary Diagnosis and Prior Treatment 
The primary diagnosis and prior treatment(s), including best response and time to progression, if 
available should be recorded.  
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8.1.4. 
Medical History 
A medical history will be obtained by the investigator or a medically qualified designee 
(consistent with local regulations). All active conditions should be recorded and any condition 
diagnosed within the last 1 year that the investigator deems clinically significant.  
8.1.5. 
Demographics 
Demographics will include race, ethnicity, age, and sex.  
8.1.6. 
Medication Review (Prior and Concomitant Medications) 
The investigator or medically qualified designee should review the participant’s prior medication 
use within 30 days of the Screening assessment. All medication currently taken by the participant 
should be recorded.  
8.1.7. 
Inclusion and Exclusion Criteria Review 
All inclusion and exclusion criteria should be reviewed by the investigator to ensure the 
participant qualifies for the study. 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA. The efficacy 
assessments will measure antitumor activity and include: 
x
ORR, PFS, TTR, DOR, DCR
x
OS
Antitumor activity will be assessed by radiological tumor assessments and will be based on 
RECIST v1.1 criteria.  
The details related to tumor assessments are presented in Appendix 8.  
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. The safety assessments 
include: 
x
AEs and SAEs
x
Laboratory measurements
x
Other laboratory measurement (AAGP)
x
Physical examination findings
x
Vital signs
x
ECG findings
Any clinically significant changes in laboratory findings, PE findings, vital sign measurements, 
and ECG findings occurring during the study must be reported as an AE. 
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8.3.1. 
Physical Examinations 
x
A complete PE will be conducted according to the SoA (Table 3). Weight will be
collected at Day 1 of each cycle. Height will be collected at Screening only.
x
Investigators should pay special attention to clinical signs related to previous serious
illnesses.

Any abnormalities identified at the screening PE should be recorded as medical
history.

Any abnormalities identified after the screening PE should be recorded as an AE.
8.3.2. 
Vital Signs 
x
Temperature, pulse rate, respiratory rate, and BP will be assessed per institutional
guidelines.
x
If not otherwise directed by institutional guidelines, BP and pulse measurements
should be preceded by at least 5 minutes of rest for the participant in a quiet setting
without distractions (eg, television, cell phones).
8.3.3. 
Electrocardiograms
x
A single 12-lead ECG will be obtained as outlined in the SoA (Table 3) using an ECG
machine that automatically calculates the HR and measures PR, QRS, QT, and QTc
intervals.
8.3.4. 
Clinical Safety Laboratory Assessments
x
See Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA
(Table 3) for the timing and frequency.
x
The investigator must review the laboratory report, document this review, and record
any clinically significant changes occurring during the study as an AE. The laboratory
reports must be filed with the source documents.
x
Abnormal laboratory findings associated with the underlying disease are not
considered clinically significant unless judged by the investigator to be more severe
than expected for the participant’s condition.
x
All laboratory tests with abnormal values considered clinically significant during
participation in the study and/or considered by the investigator to be related to study
drug should be repeated until the values return to normal or baseline or are no longer
considered clinically significant by the investigator.

If clinically significant values do not return to normal/baseline within a period of
time judged reasonable by the investigator, the etiology should be identified, and
the sponsor notified.

All protocol-required laboratory tests, as defined in Appendix 3, must be
conducted in accordance with the SoA (Table 3).
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x
Any participants with febrile neutropenia of any grade, Grade 4 neutropenia, and/or
Grade 4 thrombocytopenia, should have relevant tests repeated daily until recovery to
GUDGH   DQG WKURXJh the day after fever resolution, if applicable.
x
For Cycle 3 and after, Hematology and Biochemistry “A” tests on Days 8 and 15 are
to be performed only in participants with GUDGH   biochemical or Grade 4
hematological treatment-related toxicities, or who required dose adjustments due to
hematological or biochemical abnormalities in the preceding cycle (Table 3).
8.3.5. 
Other Laboratory Assessment 
Levels of serum AAGP will be assessed. 
8.3.6. 
Pregnancy Testing 
x
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria.
x
Pregnancy testing (urine or serum as required by local regulations) should be
conducted according to the SoA (Table 3).
x
Pregnancy testing (urine or serum as required by local regulations) should be repeated
30 days after last dose of lurbinectedin.
x
Additional serum or urine pregnancy tests may be performed, as determined
necessary by the investigator or required by local regulation, to establish the absence
of pregnancy at any time during the participant's participation in the study.
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety
Reporting
The definitions of AEs and SAEs can be found in Appendix 4. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the start of intervention until the EOT or E/D visit as 
specified in the SoA (Table 3) and per Section 8.4.3. Participants’ discontinuation from study 
treatment with an ongoing treatment-related AE should be followed until satisfactory resolution 
per the investigator. Any spontaneous reporting of treatment-related SAE during the OS 
follow-up will be also collected and reported. 
Note: All SAEs that occur after the consent form is signed but before study 
intervention/treatment must be reported by the investigator if they cause the participant to be 
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excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to diet, placebo treatment, or a procedure. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded as Medical History/Current Medical Conditions, not as AEs.  
All SAEs will be recorded and reported to the sponsor or designee immediately and within 
24 hours of first knowledge of the event by study personnel, as indicated in Appendix 4. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. All treatment-related deaths will be reported as SAEs. Deaths due to progression of 
disease are not SAEs and should not be reported as SAEs.  
Investigators are not obligated to actively seek information on new AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the investigator should 
promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
Adverse events resulting in study termination will be followed to the satisfactory resolution and 
determination of outcome as ascertained by the investigator.  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 4. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
x
Prompt notification by the investigator to the sponsor of an SAE is essential so that
legal obligations and ethical responsibilities towards the safety of participants and the
safety of a study intervention under clinical investigation are met.
x
The sponsor has a legal responsibility to notify both the local regulatory authority and
other regulatory agencies about the safety of a study intervention under clinical
investigation. The sponsor will comply with country-specific regulatory requirements
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.
x
An investigator who receives an investigator safety report describing an SAE or other
specific safety information (eg, summary or listing of SAEs) from the sponsor will
review and then file it and will notify the IRB/IEC, if appropriate according to local
requirements.
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x
Investigator safety reports will be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary. The
RSI for the determination of expectedness of lurbinectedin can be found in the IB
(Pharma Mar IB, 2022).
8.4.5. 
Pregnancy
x
Details of all pregnancies in female participants and female partners of male
participants will be collected after the start of study intervention and until 30 days of
the last dosing of the study participant.
x
If a pregnancy is reported during treatment or within 30 days after the last dose of IP,
the investigator will record pregnancy information on the appropriate form and
submit it to the sponsor within 24 hours of learning of the female participant or
female partner of male participant (after obtaining the necessary signed informed
consent from the female partner) pregnancy.
x
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy for medical reasons will be
reported as an AE or SAE.
x
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported
as such.
x
The participant/pregnant female partner will be followed to determine the outcome of
the pregnancy. The investigator will collect follow-up information on the
participant/pregnant female partner and the neonate, and the information will be
forwarded to the sponsor.
x
Any post-study pregnancy-related SAE considered reasonably related to the study
intervention by the investigator will be reported to the sponsor as described in
Section 8.4.4. While the investigator is not obligated to actively seek this information
in former study participants/pregnant female partner, he or she may learn of an SAE
through spontaneous reporting.
x
Any female participant who becomes pregnant while participating in the study will
discontinue study intervention.
8.4.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
The following DREs are common in participants with advanced or metastatic solid tumors: 
x
Disease progression
x
Death
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
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9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses
This nonrandomized multi-cohort signal finding study will use estimation rather than hypothesis 
testing to characterize the ORR for each cohort. 
9.2. 
Sample Size Determination 
This study is designed to assess the antitumor activity of lurbinectedin in terms of the ORR 
according to the RECIST v1.1 in 3 different advanced (metastatic and/or unresectable) solid 
tumors cohorts. This study includes up to a total of 60 participants in the initial assessment of 
efficacy in which each tumor cohort includes up to 20 participants. If there is evidence of 
efficacy, enrollment beyond 20 participants in the individual cohort may be considered. 
Each cohort will have up to 4 stages: stage 1 at n = 12 and stage 2 at n = 20 for futility testing 
(see Section 9.5); if a cohort enrolls beyond 20 participants, the study may enroll stage 3 with an 
interim analysis to assess efficacy at n = 35, and a final stage 4 at n = 100 for the final analysis. 
,I WKHUH DUH   UHVSRQVHV D WDUJHW RI  255 RXW RI  participants in a cohort, the lower 
ERXQG RI  &, RI 255  WR  ZLOO H[FOXGH D  2RR (Table 7) and the cohort 
PD\ FRQWLQXH 7KLV ZLOO SURYLGH DSSUR[LPDWHO\  FRQILGHQFH WKDW WKH WUXH 255 UDWH LV ! 
ZKHUH D  RU ORZHU UHVSRQVH UDWH LV QRW FOLQLFDOO\ PHDQLQJIXO ,I WKHUH DUH   responses 
 255 RXW RI  SDUWLFLSDQWV LQ D FRKRUW WKH ORZHU ERXQG RI  &, RI 255  WR
 ZLOO H[FOXGH D  255 Table 8) and the cohort may continue enrollment up to a total 
RI  SDUWLFLSDQWV ,I WKHUH DUH   UHVSRQVHV  255 RXW RI  SDUWLFLSDQWV LQ D FRKRUW
WKH ORZHU ERXQG RI  &, RI 255  WR  ZLOO H[FOXGH D  255 Table 8). 
Table 7: 
Two-sided, Exact CI of ORR Under Varying Scenarios for n = 20 
Sample 
Size 
No of 
Responders 
Observed 
ORR (%) 
70% CI of 
ORR (%) 
80% CI of 
ORR (%) 
90% CI of 
ORR (%) 
95% CI of 
ORR (%) 
4 
20 
(10.5, 33.4) 
(9.0, 36.1) 
(7.1, 40.1) 
(5.7, 43.7) 
5 
25 
(14.4, 38.8) 
(12.7, 41.5) 
(10.4, 45.6) 
(8.7, 49.1) 
6 
30 
(18.5, 44.0) 
(16.6, 46.7) 
(14.0, 50.8) 
(11.9, 54.3) 
7 
35 
(22.8, 49.1) 
(20.7, 51.8) 
(17.7, 55.8) 
(15.4, 59.2) 
8 
40 
(27.2, 54.1) 
(24.9, 56.7) 
(21.7, 60.6) 
(19.1, 63.9) 
Abbreviations: CI = confidence interval; ORR = objective response rate. 
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9.4.1. 
General Considerations 
9.4.1.1. 
Definition of Study Periods for Analysis 
9.4.1.1.1. Baseline 
Baseline evaluations (eg, disease assessments, laboratory tests, vital signs, and ECOG 
performance status) will be defined as evaluations with a date on or prior to the date of first dose 
of study intervention. If there are multiple valid observations in the Screening Period, then the 
latest non-missing observation on or before the first dose of study intervention will be used as the 
baseline in the analyses. 
Detailed instructions for assigning baseline values will be given in the SAP. 
9.4.1.1.2. Post-baseline 
Post baseline evaluations will be defined as evaluations taken after the date of the first dose of 
study treatment. 
The post-baseline period is further characterized into a treatment period, a 30-day safety 
follow-up period after the last dose of study treatment, and an OS Follow-up Period. 
Treatment-emergent adverse events are defined as AEs with an onset date on or after the date of 
the first dose of study treatment. An AE is a TEAE if it occurs up to 30 days after the last dose of 
study intervention. TEAEs can be pre-treatment AEs that worsen in CTCAE grade after the start 
of study treatment. 
9.4.1.2. 
Statistical Methods 
The efficacy analyses will be performed on the Efficacy-evaluable analysis set, separately for 
each cohort. The safety analyses will be performed on the Safety analysis set. 
Unless otherwise noted, discrete measurements will be tabulated by the frequency and proportion 
of participants falling into each category within each cohort. Continuous measurements will be 
summarized using the sample size, mean, standard deviation, median, minimum, and maximum 
values for each cohort.  
Time-to-event measurements will be summarized using K-M estimates. This will be done for the 
following endpoints: TTR, DOR, PFS, and OS. The TTR will also be analyzed using summary 
statistics such as mean, standard deviation, median, minimum, and maximum values. Median 
VXUYLYDO WLPH ZLOO EH UHSRUWHG DORQJ ZLWK  &,V FRQVWUXFWHG EDVHG RQ D ORJ-log transformed CI 
for the survivor function (Brookmeyer, 1982). Rates at fixed times (3, 6, 9, and 12 months) will 
be derived from the K-M estimates if the data allow, and the corresponding CIs will be 
calculated based on Greenwood formula for variance derivation and on a log-log transformation 
applied to the survivor function (Greenwood, 1926; Kalbfleisch, 1980). 
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9.4.1.3. 
Dropouts and Missing Data 
9.4.1.3.1. Imputation of Non-date Missing Data 
Data used for evaluating efficacy and safety endpoints may be missing for technical reasons (eg, 
unreadable scan, participant missed appointment).  
The primary efficacy analysis will be performed on the Efficacy-evaluable analysis set in this 
study. For participants without any post baseline disease assessment, the response of this 
participant will be imputed as non-responder for sensitivity analyses of ORR in the Safety 
analysis set. 
Participants with the designation of treatment relationship for AEs and SAEs missing will have 
the worst case assumed to impute the relationship: if relationship to study treatment is missing it 
will be assumed to be “Yes.” 
The details of analyses with missing data will be specified in the SAP. 
9.4.1.3.2. Imputation of Partial Dates 
Imputed dates will not be used to derive study day or duration. In addition, imputed dates are not 
used for deriving the last contact date for OS. Imputed dates will be displayed in listings and 
identified as imputed. 
AEs with partial dates will have imputed dates used to identify treatment emergent AEs and for 
sorting in data listings. They will not be used to calculate duration of AEs. If an AE start or end 
date is completely missing, then the duration of the AE will be set to missing. 
Algorithms for imputing partial dates will be provided in the SAP. 
9.4.2. 
Primary Endpoint(s) 
Best overall response is defined as the best response recorded between the date of first dose and 
the date of objectively documented progression per RECIST v1.1, or the date of subsequent 
anticancer therapy, death due to any cause, loss to follow-up, or study discontinuation, 
whichever occurs first. BOR will be determined programmatically in the analysis of the study 
results. 
The ORR is defined as the proportion of participants whose BOR is investigator-assessed 
confirmed CR or PR using the RECIST v1.1 criteria. ORR will be summarized by a binomial 
response rate for each cohort and its corresponding two-VLGHG  H[DFW &,V XVLQJ WKH
Clopper-Pearson method (Clopper, 1934). 
9.4.3. 
Secondary Endpoint(s) 
The investigator-assessed objective response will be further characterized by the TTR and DOR. 
DOR and TTR will be evaluated for responders (confirmed CR and PR) only. 
TTR is defined as the time from first dosing date to the date of the first confirmed response (CR 
or PR), as assessed by the investigators.  
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Duration of response is defined as the time from first confirmed response (CR or PR) to the date 
of the first documented tumor progression as determined using RECIST v1.1 criteria or death 
due to any cause, whichever occurs first.  
The below censoring rules are applicable to both DOR and PFS. Participants who do not 
progress or die will be censored on the date of their last evaluable tumor assessment. Participants 
who started a new anticancer therapy without a prior reported progression will be censored on 
the date of their last evaluable tumor assessment on or prior to the initiation of first subsequent 
anticancer therapy. Participants who are lost to follow-up or discontinued from the study without 
a prior reported progression and without start of subsequent anticancer therapy will be censored 
on the date of their last evaluable tumor assessment on or prior to the date of loss to follow-up or 
study discontinuation.  
PFS is defined as the time from the first dosing date to the date of first documented disease 
progression or death due to any cause, whichever occurs first. Participants who did not have any 
on-study tumor assessments and did not die will be censored on their first dosing date. If a 
participant is to permanently discontinue study intervention before disease progression, the 
participant will be followed for survival by telephone visits every 3 months. 
The DCR is define as the proportion of participants whose BOR is confirmed CR, or PR, or 
stable disease using the RECIST v1.1 criteria. The point estimate and  CI of DCR will be 
calculated using the same method as the primary endpoint ORR. 
Overall survival is defined as the time from the first dosing date to the date of death from any 
cause. A participant who has not died will be censored at the last known alive date. 
9.4.4. 
Safety Analyses 
All safety analyses will be performed on the Safety analysis set. 
9.4.4.1. 
Adverse Events 
Adverse events will be coded using MedDRA to classify events under primary system organ 
class and preferred term; the severity will be graded using the NCI CTCAE v5.0. 
The number and percentage of participants who experienced TEAEs, treatment emergent SAEs, 
TEAEs by maximum severity, TEAEs leading to discontinuation of study drug, Grade 3 and 4 
TEAEs, treatment-related TEAEs, treatment-related SAEs, treatment-related TEAEs leading to 
discontinuation of study drug, treatment-related Grade 3 and 4 TEAEs, and Grade 5 TEAEs will 
be summarized using the Safety analysis set. Results will be presented by SOC and preferred 
term, or preferred term only. Summary will be separate and in an overview. 
All deaths will be summarized and listed. 
For all AE summaries, if a participant has more than 1 AE within a preferred term, the 
participant is counted only once at the maximum severity and with the closest relationship to 
study drug. If a participant has more than 1 AE within a SOC, the participant is similarly counted 
once when reporting results for that SOC. 
All AE data will be listed. Listing of AEs will include all enrolled participants as pretreatment 
SAEs and deaths are collected. The information presented will include participant number, 
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QR PRUH WKDQ  ,I WKHUH DUH  3 responses in the first 20 participants of a cohort, there is a 
 SRVWHULRU SUREDELOLW\ WKDW WKH DFWXDO UHVSRQVH UDWH LV QR PRUH WKDQ  
Table 10: 
Posterior Probability for Interim Futility Monitoring 
No Participants 
Futility 
Stopping 
Prob ݇_U
n) 
Prob ݇_U
n) 
Prob ݇_U
n) 
12 
0 
 
 
 
20 
1 
 
 
 
20 
2 
 
 
 
20 
3 
 
 
 
݇ 7UXH response rate; r = the observed responses; n = the number of participants 
The SAP will describe the planned interim analyses in greater detail. 
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Amendment 02 
 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
x
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations
x
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the investigator, reviewed and
approved by the IRB/IEC, and submitted to the national regulatory authority (as
applicable), before the study is initiated.
x
Any amendments to the protocol will require IRB/IEC approval and submission to the
national regulatory authority before implementation of changes made to the study
design, except for changes necessary to eliminate an immediate hazard to study
participants.
x
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation
536/2014 for clinical studies (if applicable), European Medical Device Regulation
2017/745 for clinical device research (if applicable), and all other applicable local
regulations.
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.5. 
Safety Monitoring 
Throughout the study, the sponsor will perform safety assessments of all enrolled participants on 
an ongoing basis. A thorough evaluation of the safety and efficacy will be performed after 
enrollment of the first 12 participants to determine whether to continue or stop a cohort. 
10.1.6. 
Dissemination of Clinical Study Data 
As the sponsor of the study, Jazz Pharmaceuticals is solely responsible for disclosing results on 
ClinicalTrials.gov, EudraCT, and other public registries in accordance with applicable global 
laws and regulations. By signing this protocol, the investigator acknowledges that all posting 
requirements are solely the responsibility of the sponsor, and agrees not to submit any 
information about the study or its results. 
10.1.7. 
Data Quality Assurance 
x
Investigators and site staff will be trained on protocol procedures and eCRF
completion prior to enrolling participants in the study.
x
All participant data relating to the study will be recorded on printed or eCRF unless
transmitted to the sponsor or designee electronically (eg, laboratory data). The
investigator is responsible for verifying that data entries are accurate and correct by
physically or electronically signing the eCRF.
x
Guidance on completion of eCRFs will be provided in the eCRF Completion
Guidelines.
x
The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
x
Monitoring details describing strategy are described in the Monitoring Plan.
x
The sponsor or designee is responsible for the data management of this study,
including quality checking of the data.
x
The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).
x
Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the investigator or institution/site as applicable, for the
period of time established in the clinical study agreement entered into by the
investigator’s study site unless local regulations or institutional policies require a
longer retention period. No records may be destroyed during the retention period
without the written approval of the sponsor. No records may be transferred to another
location or party without written notification to the sponsor.
10.1.8. 
Source Documents 
x
Source documents provide evidence for the existence of the participant and
substantiate the integrity of the data collected. Source documents are filed at the
investigator’s site.
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x
Data entered in the eCRF that are transcribed from source documents must be
consistent with the source documents or the discrepancies must be explained. The
investigator may need to request previous medical records or transfer records,
depending on the study. Also, current medical records must be available.
x
The investigator must maintain accurate documentation (source data) that supports
the information entered in the eCRF.
x
Study monitors will perform ongoing source data verification to confirm that data
entered into the eCRF by authorized site personnel are accurate, complete, and
verifiable from source documents; that the safety and rights of participants are being
protected; and that the study is being conducted in accordance with the currently
approved protocol and any other study agreements, ICH GCP, and all applicable
regulatory requirements.
10.1.9. 
Study and Site Start and Closure 
10.1.9.1. First Act of Recruitment 
The study start date is the date on which the first participant has the first study-related procedure 
(typically signing the ICF). 
10.1.9.2. Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been accounted for and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
x
Discontinuation of further study intervention development
For site termination: 
x
Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines
x
Inadequate or no recruitment (evaluated after a reasonable amount of time) of
participants by the investigator
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
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10.1.10. 
Publication Policy 
x
The results of this study may be published or presented at scientific meetings. If this
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the
sponsor at least 30 days prior to submission. This allows the sponsor to protect
proprietary information and to provide comments. In addition, this allows the sponsor
to protect the publication rights of other investigators in multicenter trials.
x
The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally
support publication of multicenter studies only in their entirety and not as individual
site data. In this case, a coordinating investigator will be designated by mutual
agreement.
x
Authorship will be determined by mutual agreement and in line with International
Committee of Medical Journal Editors authorship requirements.
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APPENDIX 1. ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Description 
AAGP 
alpha-1 acid glycoprotein 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ANC 
absolute neutrophil count 
BP 
blood pressure 
BOR 
best overall response 
BPP 
Bayesian Posterior Probability 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRO 
Contract Research Organization 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBL 
database lock 
DCR 
disease control rate 
DOR 
duration of response 
DRE 
disease-related event 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
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Abbreviation 
Description 
eCRF 
electronic case report form 
E/D 
early discontinuation 
EOS 
end-of-study 
EOT 
end of treatment 
EU 
European Union 
EV 
enfortumab vendotin 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor 
GCT 
germ cell tumor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRD 
homologous recombination deficient 
HR-DDR 
homologous recombination deficient DNA damage repair 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
K-M
Kaplan-Meier 
LCNET 
large cell neuroendocrine tumor 
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Abbreviation 
Description 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEC 
neuroendocrine carcinoma 
NET 
neuroendocrine tumor 
 
 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PARP 
poly-ADP ribose polymerase 
PARPi 
poly-ADP ribose polymerase inhibitor 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death ligand-1 
PD-NEC 
Poorly differentiated neuroendocrine carcinoma 
PE 
physical examination 
PFS 
progression-free survival 
 
 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RSI 
Reference Safety Information 
Q3W 
every 3 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SoA 
Schedule of Activities 
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Abbreviation 
Description 
SUSARS 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
TTR 
time-to-response 
UC 
urothelial cancer 
US 
United States 
USPI 
United States Prescribing Information 
WOCBP 
woman of childbearing potential 
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APPENDIX 2. REFERENCES 
Bavencio (avelumab) for injection, for intravenous use. US Prescribing Information. Merck 
kGaA. Darmstadt, Germany. November 2020. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf.  
Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated macrophages 
and the inflammatory tumour microenvironment in preclinical models. Br J Cancer. 2017 
Aug;117(5):628-38. 
Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care 
compared with best supportive care alone after a platinum-containing regimen in patients with 
advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 
20;27(27):4454-61. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982 
Mar 1:29-41. 
Céspedes MV, Guillén MJ, López-Casas PP, et al. Lurbinectedin induces depletion of tumor-
associated macrophages, an essential component of its in vivo synergism with gemcitabine, in 
pancreatic adenocarcinoma mouse models. Dis Model Mech. 2016 Dec 1;9(12):1461-71. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934 Dec 1;26(4):404-13. 
Cruz C, Llop-Guevara A, Garber JE, et al. Multicenter phase II study of lurbinectedin in BRCA-
mutated and unselected metastatic advanced breast cancer and biomarker assessment substudy. J 
Clin Oncol. 2018 Nov 1;36(31):3134. 
Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011 May 
15;25(10):1010-22. 
Derks JL, Van Suylen RJ, Thunnissen E, et al. Chemotherapy for pulmonary large cell 
neuroendocrine carcinomas: does the regimen matter?. Eur Respir J. 2017 Jun 1;49(6). 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan 1;45(2):228-47. 
Food and Drug Administration (FDA). FDA grants accelerated approval to lurbinectedin for 
metastatic small cell lung cancer. 2020. Accessed 29 April 2021. Available at: 
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-
lurbinectedin-metastatic-small-cell-lung-cancer.  
Food and Drug Administration (FDA). FDA Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics. 2018. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-
endpoints-approval-cancer-drugs-and-biologics.  
Fudio S. Exposure-response analyses and clinical utility index to justify the dosage of 
lurbinectedin in small-cell lung cancer. Poster session presented at: World Conference on Lung 
Cancer Singapore. 2021 Jan 28-31; Worldwide virtual event.  
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Greenwood M. The “errors of sampling” of the survivorship tables. Reports on public health and 
medical subjects. 1926. 
Heeke AL, Pishvaian MJ, Lynce F, et al. Prevalence of homologous recombination–related gene 
mutations across multiple cancer types. JCO Precis Oncol. 2018 Jul;2:1-3. 
Hesketh PJ, Bohlke K, Kris MG. Antiemetics: American Society of Clinical Oncology clinical 
practice guideline update summary. J Oncol Pract. 2017 Dec;13(12):825-30. 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. John Wiley & Sons; 
1980. 
La-Beck NM, Jean GW, Huynh C, et al. Immune checkpoint inhibitors: new insights and current 
place in cancer therapy. Pharmacotherapy. 2015 Oct;35(10):963-76. 
Longo-Muñoz F, Castellano D, Alexandre J, et al. Lurbinectedin in patients with pretreated 
neuroendocrine tumours: results from a phase II basket study. Eur J Cancer. 2022;172:340-8. 
Miller RE, Leary A, Scott CL, et al. ESMO recommendations on predictive biomarker testing for 
homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. Ann Oncol. 
2020 Dec 1;31(12):1606-22. 
National Cancer Institute (NCI). Dictionary of Genetics Terms. 2022. Accessed on 
08 September 2022. Available at: https://www.cancer.gov/publications/dictionaries/genetics-
dictionary. 
National Cancer Institute (NCI). The Cancer Genome Atlas Program. 2021. Accessed on 29 
April 2021. Available at: https://www.cancer.gov/about-nci/organization/ccg/research/structural-
genomics/tcga.  
Nuñez GS, Robles CM, Giraudon C, et al. Lurbinectedin specifically triggers the degradation of 
phosphorylated RNA polymerase II and the formation of DNA breaks in cancer cells. Mol 
Cancer Ther. 2016 Oct 1;15(10):2399-412. 
Padcev (enfortumab vedotin-ejfv) for injection, for intravenous use. US Prescribing Information. 
Astellas Pharma US. WA, US. March 2021. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761137s000lbl.pdf.  
Petrylak DP, De Wit R, Chi KN, et al. Ramucirumab plus docetaxel versus placebo plus 
docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-
based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 
18;390(10109):2266-77. 
Pharma Mar. Investigator’s Brochure. Lurbinectedin. Version 15.0. August 2022.  
Pharma Mar. Periodic benefit risk evaluation report (PBRER)/periodic safety update report 
(PSUR) for Zepzelca (lurbinectedin). February 2021. 
Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic 
urothelial carcinoma. New Engl J Med. 2020 Sep 24;383(13):1218-30.  
Radhakrishnan SK, Jette N, Lees-Miller SP. Non-homologous end joining: emerging themes and 
unanswered questions. DNA Repair (Amst). 2014 May 1;17:2-8. 
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Russo GL, Pusceddu S, Proto C, et al. Treatment of lung large cell neuroendocrine carcinoma. 
Tumour Biol. 2016 Jun;37(6):7047-57. 
Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with 
small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020 May 
1;21(5):645-54. 
Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. US Prescribing 
Information. Astellas Pharma US. NJ, US. March 2021. 
Tumini E, Herrera-Moyano E, San Martín-Alonso M, et al. The antitumor drugs trabectedin and 
lurbinectedin induce transcription-dependent replication stress and genome instability. Mol 
Cancer Res. 2019 Mar 1;17(3):773-82. 
Zepzelca (lurbinectedin) for injection, for intravenous use. US Prescribing Information. Jazz 
Pharmaceuticals Inc. CA, US. April 2022. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213702s004lbl.pdf.  
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APPENDIX 3. CLINICAL LABORATORY TESTS 
x
The tests detailed in Table 11 will be performed by the local laboratory.
x
Protocol-specific requirements for inclusion or exclusion of participants are detailed
in Section 5 of the protocol.
x
Additional tests may be performed at any time during the study as determined
necessary by the investigator or required by local regulations.
Table 11: 
Protocol-required Safety Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
Platelet Count 
White blood cell count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Red blood cell Count 
Hemoglobin 
Hematocrit 
Biochemistry-A 
Serum electrolytes 
(Na+, K+, Cl-) 
AST/ALT 
GGT 
APa 
Total bilirubin (and 
direct if total is 
> 1.5 î ULN)
LDH 
Creatinine 
CPK 
Glucose (random) 
Biochemistry-B 
Albumin 
Total proteins 
Ca++  
Mg++ 
Coagulation 
PT/INR 
PTT 
Pregnancy testing 
Highly sensitive serum or urine hCG pregnancy test (as needed for women of 
childbearing potential) 
Other Screening 
Tests 
Serologyb (HIV antibody, HBsAg, and hepatitis C virus antibody) 
Abbreviations: ALT = alanine aminotransferase; AP = alkaline phosphokinase; AST = aspartate aminotransferase; 
CPK = creatinine phosphokinase; GGT = gamma-glutamyl transferase; HBcAb = hepatitis B core antibody; HBsAg 
= hepatis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin 
time; PTT = partial thromboplastin time; ULN = upper limit of normal. 
a If alkaline phosphatase is elevated, consider fractionating. 
b All participants will be tested for HIV prior to the inclusion enrollment into the study and HIV-positive 
participants will be excluded from the study. Participants with active hepatitis B (chronic or acute; defined as 
having a positive HBsAg test result at screening) will be excluded from the study. Participants with past or 
resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA 
should be obtained in these participants prior to randomization. Participants with HCV will be excluded from the 
study; participants who test positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 
Investigators must document their review of each laboratory safety report. 
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APPENDIX 4. AES AND SAES: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
Definition of AE 
AE Definition 
x
An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of study intervention, whether or not considered related to the study
intervention.
x
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the
use of study intervention.
Events Meeting the AE Definition 
x
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those
that worsen from baseline, considered clinically significant in the medical and scientific
judgment of the investigator (ie, not related to progression of underlying disease).
x
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in
frequency and/or intensity of the condition.
x
New conditions detected or diagnosed after study intervention administration even though it
may have been present before the start of the study.
x
Signs, symptoms, or the clinical sequelae of a suspected intervention interaction.
x
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should
be reported regardless of sequelae.
Events NOT Meeting the AE Definition 
x
Any clinically significant abnormal laboratory findings or other abnormal safety assessments
that are associated with the underlying disease, unless judged by the investigator to be more
severe than expected for the participant’s condition.
x
The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition.
x
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the
procedure is the AE.
x
Situations in which an untoward medical occurrence did not occur (social and/or convenience
admission to a hospital).
x
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or
detected at the start of the study that do not worsen.
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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
x
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the
participant was at risk of death at the time of the event. It does not refer to an event, which
hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization 
x
In general, hospitalization signifies that the participant has been admitted (usually involving at
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that
would not have been appropriate in the physician’s office or outpatient setting. Complications
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization”
occurred or was necessary, the AE should be considered serious.
x
Hospitalization for elective treatment of a pre-existing condition that did not worsen from
baseline is not considered an AE.
Results in persistent or significant disability/incapacity 
x
The term disability means a substantial disruption of a person’s ability to conduct normal life
functions.
x
This definition is not intended to include experiences of relatively minor medical significance
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma
(e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not
constitute a substantial disruption.
Is a congenital anomaly/birth defect 
Other situations: 
Medical or scientific judgment should be exercised by the investigator in deciding whether SAE 
reporting is appropriate in other situations, such as significant medical events that may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other outcomes listed 
in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment for allergic 
bronchospasm, blood dyscrasias, convulsions, or development of intervention dependency or 
intervention abuse. 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
x
When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related
to the event.
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x
The investigator will then record all relevant AE/SAE information.
x
It is not acceptable for the investigator to send photocopies of the participant’s medical records
to the Sponsor in lieu of completion of the SAE required form.
x
There may be instances when copies of medical records for certain cases are requested by the
Sponsor. In this case, all participant identifiers, with the exception of the participant number,
will be redacted on the copies of the medical records before submission to the Sponsor.
x
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms,
and/or other clinical information. Whenever possible, the diagnosis (not the individual
signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity 
x
The investigator will make an assessment of intensity for each AE and SAE reported during
the study and assign it to 1 of the following categories:
o
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only
o
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).
o
Severe: severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. An AE/SAE that is assessed as severe should not be confused with a SAE.
Severe is a category utilized for rating the intensity of an event; and both AEs and
SAEs can be assessed as severe.
o
Life-threatening: life-threatening consequences; urgent intervention indicated.
o
Fatal: death related to AE
x
When the severity of an AE increases over time, the increase in the severity will be recorded as
a new AE and the original AE will stop when the new AE starts.
x
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as
described in the definition of an SAE, NOT when it is rated as severe.
x
Adverse events will be classified by the investigator using the National Cancer Institute (NCI)
common terminology criteria for adverse events (CTCAE) version 5.0. A copy of this version
can be downloaded from the cancer therapy evaluation program at http://ctep.cancer.gov. If the
CTCAE grade is not specified for a particular event or if the event term does not appear in the
CTCAE, general guidelines are provided for grading the AE in the table below.
Grade 
Symptoms 
1 
Mild, asymptomatic or mild symptoms; clinical 
or diagnostic observations only; intervention not 
indicated. 
2 
Moderate, minimal local or noninvasive 
intervention indicated; limiting, age-appropriate 
instrumental activities of daily living (ADLa) 
3 
Severe or medically significant but not 
immediately life threatening; hospitalization or 
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JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
prolongation of hospitalization indicated; 
disabling limiting self-care ADLb. 
4 
Life threatening consequences; urgent 
intervention indicated 
5 
Death related to adverse event 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothing, using the telephone, 
managing money, etc. 
b Self-care ADL refers to bathing, dressing and undressing, self-feeding, using the toilet, taking medications, 
and not bedridden. 
Note: a semicolon indicates “or” within the description of the grade. 
Assessment of Causality 
x
The investigator is obligated to assess the relationship between study intervention and each
occurrence of each AE/SAE.
x
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or
arguments to suggest a causal relationship, rather than a relationship, cannot be ruled out.
x
The investigator will use clinical judgment to determine the relationship.
x
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors,
as well as the temporal relationship of the event to study intervention administration, will be
considered and investigated.
x
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information,
for marketed products, in his/her assessment.
x
For each AE/SAE, the investigator must document in the medical notes that he/she has
reviewed the AE/SAE and has provided an assessment of causality.
x
There may be situations in which an SAE has occurred and the investigator has minimal
information to include in the initial report to the Sponsor. However, it is very important that the
investigator always make an assessment of causality for every event before the initial
transmission of the SAE data to the Sponsor.
x
The investigator may change his/her opinion of causality in light of follow-up information and
send an SAE follow-up report with the updated causality assessment.
x
The causality assessment is one of the criteria used when determining regulatory reporting
requirements.
Follow-up of AEs and SAEs 
x
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by the sponsor (or
designee) to elucidate the nature and/or causality of the AE or SAE as fully as possible. This
may include additional laboratory tests or investigations, histopathological examinations, or
consultation with other health care professionals.
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Amendment 02 
 
Follow-up of AEs and SAEs 
x
If a participant dies during participation in the study or during a recognized follow-up period,
the investigator will provide the Sponsor a copy of any post-mortem findings including
histopathology report, if performed.
x
New or updated information will be recorded in the originally submitted documents.
x
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of
the information.
Reporting of SAEs 
SAE Reporting to sponsor or designee via a Data Collection Tool 
x
SAEs must be reported to the sponsor (or designee) using an SAE Reporting system within 24
hours of first knowledge of the event by study personnel.
x
The site will enter the SAE data into the SAE reporting system as soon as it becomes available.
x
Details regarding the SAE Reporting system, instructions on completion, and contact
information can be found in the Investigator trial binder.
x
The SAE Reporting should be completed as much as possible before transmittal.
x
Contacts for SAE reporting can be found in the Investigator trial binder.
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JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE 
Definitions 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche
2. From the time of menarche until becoming post-menopausal unless permanently sterile
(see below)
x
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause.

A high FSH level in the postmenopausal range may be used to confirm a
postmenopausal state in women not using hormonal contraception or HRT.
However, in the absence of 12 months of amenorrhea, confirmation with more
than 1 FSH measurement is required.

Females on HRT and whose menopausal status is in doubt will be required to use
1 of the non-estrogen hormonal highly effective contraception methods if they
wish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of postmenopausal status before study enrollment.
x
Permanent sterilization methods (for the purpose of this study) include:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

For individuals with permanent infertility due to an alternate medical cause other
than the above (eg, Mullerian agenesis, androgen insensitivity, gonadal
dysgenesis), investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the
participant’s medical records, medical examination, or medical history interview.
x
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle
cannot be confirmed before first dose of study intervention, additional evaluation
should be considered.
Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency 
x
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc
x
Intrauterine device (IUD)
x
Intrauterine hormone-releasing system (IUS)c
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Amendment 02 
 
x
Bilateral tubal occlusion
x
Azoospermic partner (vasectomized or due to a medical cause)
x
Azoospermia is a highly effective contraceptive method provided that the partner is the sole
sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, an additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 90 days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s
review of the participant’s medical records, medical examination, or medical history interview.
Highly Effective Methodsb That Are User Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationc 
x
oral
x
intravaginal
x
transdermal
x
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc 
x
oral
x
injectable
Sexual abstinence 
x
Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the
study and the preferred and usual lifestyle of the participant.
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b )DLOXUH UDWH RI  SHU \HDU when used consistently and correctly. Typical use failure rates differ 
from those when used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance 
with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are 
limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure from friction). 
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JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
APPENDIX 6. GENETICS 
Use/Analysis of DNA 
x
Inclusion in the HRD-positive malignancies agnostic cohort requires a pre-identified
germline and/or somatic pathogenic mutation. Genetic variation may impact a
participant’s response to study intervention, susceptibility to, and severity and
progression of disease.
x
DNA samples from blood will be used for confirmation of any pre-identified
germline and/or somatic pathogenic mutations. They may also be used to develop
tests/assays including diagnostic tests related to lurbinectedin’s mechanism of action.
x
Additional analyses may be conducted if it is hypothesized that this may help further
understand the clinical data.
x
The samples may be analyzed as part of a multi-study assessment of genetic factors
involved in the response to lurbinectedin or study interventions of this class to
understand study disease or related conditions.
x
The results of genetic analyses will be reported in a separate study summary.
x
The sponsor will store the DNA samples in a secure storage space with adequate
measures to protect confidentiality.
x
The samples will be retained while research on lurbinectedin continues but no longer
than 15 years or other period as per local requirements.
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JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
APPENDIX 7. CYP3A INHIBITORS AND INDUCERS 
Table 12: 
Examples of Clinical Inhibitors for P450-mediated Metabolisms (for Concomitant Use Clinical DDI Studies 
and/or Drug Labeling) (03/06/2020) 
Endpoint 
6WURQJHVW ,QKLELWRUV  10-Fold Increase) 
Strong Inhibitors 
(<  WR  5-Fold 
Increase) 
Moderate 
Inhibitors  2 
to <5-Fold 
Increase) 
:HDN ,QKLELWRUV  1.25 to 
< 2-Fold Increase) 
Inhibitors 
CYP3A4 
boceprevir, cobicistata, danoprevir and ritonavirb, 
elvitegravir and ritonavirb, grapefruit juicec, indinavir and 
ritonavirb, itraconazolea, ketoconazole, lopinavir and 
ritonavira,b, paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir)b, posaconazole, ritonavira,b, saquinavir 
and ritonavira,b, telaprevira, tipranavir and ritonavira,b, 
telithromycin, troleandomycin, voriconazole 
Clarithromycinb, 
idelalisib, 
nefazodone, 
nelfinavira 
aprepitant, 
ciprofloxacin, 
conivaptand, 
crizotinib, 
cyclosporine, 
diltiazeme, 
dronedaronea, 
erythromycin, 
fluconazole, 
fluvoxamine, 
imatinib, 
tofisopam, 
verapamila 
chlorzoxazone, cilostazol, 
cimetidine, clotrimazole, 
fosaprepitant, istradefylline, 
ivacaftora, lomitapide, 
ranitidine, ranolazinea, 
ticagrelora 
Inducers 
Endpoint 
6WURQJ ,QGXFHUV  
Moderate 
Inducers 
 WR
<80%) 
:HDN ,QGXFHUV  WR
<50%) 
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JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
CYP3A 
apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. 
John’s wortf 
bosentan, 
efavirenz, 
etravirine, 
phenobarbital, 
primidone 
armodafinil, modafinilg, 
rufinamide 
Abbreviations: AUC = area under the concentration-time curve. 
This table is prepared to provide examples of clinical inhibitors and inducers and is not intended to be an exhaustive list. DDI data were collected based on a 
search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61]. 
a Inhibitor of P-JS GHILQHG DV WKRVH LQFUHDVLQJ $8& RI GLJR[LQ WR  1.25-fold). 
b Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used when extrapolating the observed 
effect of ritonavir alone to the effect of combination regimens on CYP3A activities. 
c The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified 
as a “strong CYP3A inhibitor” when a certain preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg, low dose, single strength). 
d The classification is based on studies conducted with intravenously administered conivaptan. 
e Diltiazem increased AUC of certain sensitive CYP3A substrates (eg, buspirone) more than 5-fold. 
f The effect of St. John’s wort varies widely and is preparation-dependent. 
g Based on effect of 200 mg/day modafinil. A higher dose (400 mg/day) modafinil had larger induction effect on CYP3A. 
Source: FDA Drug Development and Drug Interactions: Table of Substrates Inhibitors and Inducers 2020 
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Jazz Pharmaceuticals 
JZP712 
Protocol JZP712-201-02 
Amendment 02 
 
APPENDIX 8. TUMOR ASSESSMENTS GUIDELINES 
The full RECIST version 1.1 guideline is contained in the following: 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). European journal of cancer. 2009 Jan 1;45(2):228-47. 
Tumor assessments will include all known or suspected disease sites. Imaging may include chest, 
abdomen, and pelvis CT or MRI scans. Bone scans or 18-Fluorodeoxyglucose Positron Emission 
Tomography (18FDG-PET) and brain CT or MRI scans are also required at baseline (28-day 
screening period) if brain metastasis is suspected or if participants have symptoms of brain 
metastasis except in patients with lung cancer. All patients with lung cancer will require brain 
scan.  
Bone lesion(s) identified at baseline by bone scan will be further assessed by CT or MRI as per 
local practice (where bone scans are not used as a routine restaging tool) and subsequently re-
assessed by CT or MRI as per the tumor assessment schedule as an alternative to bone scans. 
Bone scans will only be repeated during study as clinically indicated (eg, participant describes 
new or worsening bone pain, or has increasing alkaline phosphatase level, or other signs and 
symptoms of new/progressing bone metastases), at the time of CR confirmation, and at every 
other tumor assessment visit (every 12 weeks) if considered local standard of care.  
MRI brain scans must be included in subsequent tumor assessments if a participant has brain 
metastases at baseline; otherwise, brain will be evaluated only when clinically indicated. 
CR and PR must be confirmed with repeat imaging performed at least 4 weeks after initial 
documentation of response. For equivocal findings of progression (eg, very small and uncertain 
new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. In the absence of clinical 
deterioration, participants with PD can remain on the current study treatment until PD is 
confirmed by subsequent scan at PI’s discretion.  
Baseline and all scans performed for treatment evaluation will be collected and stored for future 
evaluation if a cohort or cohorts for further expansion and/or regulatory submission. Measurable 
or evaluable lesions that have been previously irradiated will not be considered target lesions 
unless an increase in size has been observed following completion of radiation therapy. 
The same radiographic procedure used to assess disease sites at screening should be used 
throughout the study (eg, the same contrast protocol for CT scans). Response will be assessed by 
the investigator using RECIST v1.1 criteria. The same evaluator, if possible, should perform 
assessments to ensure internal consistency across visits. Results must be reviewed by the 
investigator before dosing at the next cycle. 
Additional radiological tumor assessments should also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration).  
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If a participant starts a new anticancer therapy before documented disease progression, then 
tumor assessments should be continued per the SoA (if feasible) until documentation of disease 
progression or death, whichever occurs first. 
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JZP712 
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Amendment 02 
 
APPENDIX 9. PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 01: 12 August 2021 
This amendment was considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The overall rationale for the changes in this protocol amendment was to include 
Agency-requested feedback. Following is a list of important changes in Amendment 01; editorial 
changes are not included in this list. 
Section # and Name 
Description of Change 
Brief Rationale 
5.1/Inclusion Criteria, 
Disease Characteristics 
for Each Cohort; 
Criterion 9a; 
Criterion10a 
Added “advanced (metastatic 
and/or unresectable)” 
To provide additional clarity that 
participants in all cohorts must have 
advanced disease 
5.1/Inclusion Criterion 
11a 
Changed “...pancreas or 
gastric/esophageal solid 
tumors” to “...pancreas, 
gastric, or esophageal solid 
tumors” 
To provide additional clarity 
5.1/Inclusion Criterion 
11b 
Changed “no more than 3 
prior lines of systemic 
therapies” to “no more than 3 
prior lines of chemotherapy” 
and updated the supporting 
text for this criterion 
To allow hormone therapies, targeted 
therapies, and/or other biological agents 
6.7/Study Intervention 
Dose Delay and 
Reduction Rules 
Deleted “and any grade 
febrile neutropenia” as a 
reason participants may 
continue with secondary 
G-CSF prophylaxis instead of
dose reduction
For alignment with the approved 
Lurbinectedin USPI 
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SAP_001.pdf: 
Jazz Pharmaceuticals, Inc. 
JZP712-201 Statistical Analysis Plan - Protocol Amendment 
2
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
DATE: 19January 2024 
STUDY DRUG: 
Lurbinectedin 
Protocol/STUDY Number:
JZP712-201 Protocol Amendment 2 (14-Oct-2022) 
STUDY TITLE: 
EMERGE-201: A phase 2, multicenter, open-label study of lurbinectedin 
efficacy and safety in participants with advanced or metastatic solid tumors 
SPONSOR: 
Jazz Pharmaceuticals 
3170 Porter Dr, Palo Alto, CA 94304 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents.
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
1.
LIST OF ABBREVIATIONS.......................................................................................7 
2.
MODIFICATION HISTORY .....................................................................................10 
3.
INTRODUCTION ......................................................................................................11 
4.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
4.1. 
Study Objectives .........................................................................................................11 
4.1.1. 
Primary Objective .......................................................................................................11 
4.1.2. 
Secondary Objectives .................................................................................................11 
4.1.3. 
 ...............................................................................................11 
4.2. 
 Study Endpoints ..........................................................................................................11 
4.2.1. 
 Primary Endpoint ........................................................................................................11 
4.2.2. 
 Secondary Endpoints ..................................................................................................11 
4.2.3. 
 
 ................................................................................................12 
5.
 STUDY DESIGN........................................................................................................12 
5.1. 
 Summary of Study Design ..........................................................................................12 
5.2. 
 Study Treatment ..........................................................................................................13 
5.3. 
 Power and Sample Size Considerations ......................................................................14 
5.4. 
 Randomization and Blinding ......................................................................................15 
5.5. 
 Interim Analysis ..........................................................................................................15 
6.
 ANALYSIS SETS .......................................................................................................16 
7.
 GENERAL ASPECTS FOR STATISTICAL ANALYSIS .........................................16 
7.1. 
 General Methods ..........................................................................................................16 
7.2. 
 Baseline, Post Baseline, and Study Day Definitions ...................................................17 
7.2.1. 
 Baseline ........................................................................................................................17 
7.2.2. 
 Post-Baseline................................................................................................................17 
7.2.3. 
 Study Day.....................................................................................................................17 
7.2.4. 
 Visit Windows .............................................................................................................18 
7.3. 
 Derived Variable Definitions .......................................................................................18 
7.3.1. 
 Treatment -Emergent Adverse Events .........................................................................18 
7.3.2. 
 Creatinine Clearance (CrCL) .......................................................................................18 
7.4. 
 Handling of Missing and Partial Data ..........................................................................18 
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7.4.1. 
 Missing Data .................................................................................................................18 
7.4.2. 
 Imputation of Non-date Missing Data ..........................................................................18 
7.4.3. 
 Incomplete and Missing AE Start Date ........................................................................19 
7.4.4. 
 Incomplete and Missing Prior and Concomitant Medication Start Date ......................19 
7.4.5. 
 Incomplete and Missing Prior and Concomitant Medication End Date .......................20 
7.5. 
 Hypotheses Testing .......................................................................................................20 
7.6. 
 Level of Significance & Multiplicity Adjustment ........................................................20 
7.7. 
 Subgroups and Subgroup Analyses ..............................................................................20 
7.8. 
 Changes to Planned Analyses .......................................................................................20 
8.
 STUDY POPULATION SUMMARIES ......................................................................20 
8.1. 
 Enrollment.....................................................................................................................20 
8.2. 
 Disposition ....................................................................................................................21 
8.3. 
 Protocol Deviations .......................................................................................................21 
8.4. 
 Demographic and Baseline Characteristics ..................................................................22 
8.5. 
 Disease Characteristics .................................................................................................23 
8.6. 
 Medical History ............................................................................................................23 
8.7. 
 Prior Anti-Cancer Therapy ...........................................................................................24 
8.7.1. 
 Prior Systemic Anti-Cancer Therapy ............................................................................24 
8.7.2. 
 Prior Anti-Cancer Radiotherapy ...................................................................................24 
8.7.3. 
 Prior Anti-cancer Procedure or Surgery .......................................................................24 
8.8. 
 Subsequent Anti-Cancer Therapy .................................................................................25 
8.9. 
 Prior and Concomitant Medications .............................................................................25 
8.10. 
 Concomitant Procedures ...............................................................................................26 
9.
 EFFICACY ...................................................................................................................26 
9.1. 
 Primary Efficacy Endpoint and Analysis ......................................................................26 
9.1.1. 
 Primary Analysis ...........................................................................................................26 
9.1.2. 
 Sensitivity Analyses ......................................................................................................27 
9.1.3. 
 Subgroup Analyses .......................................................................................................27 
9.2. 
 Secondary Efficacy Endpoints and Analyses ...............................................................27 
9.2.1. 
 Duration of Response (DOR)........................................................................................27 
9.3. 
 
 ..................................................................................................28 
9.3.1. 
 
 .......................................................................................28 
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10.
 SAFETY ........................................................................................................................28 
10.1. 
 Exposure ........................................................................................................................28 
10.1.1.  Extent of Exposure .........................................................................................................28 
10.1.2.  Treatment Compliance ...................................................................................................29 
10.2. 
 Adverse Events ..............................................................................................................29 
10.2.1.  Treatment Emergent Adverse Events (TEAEs) .............................................................29 
10.2.2.  Serious Adverse Events (SAEs).....................................................................................30 
10.2.3.  TEAEs Leading to Study Treatment Discontinuation ...................................................30 
10.2.4.  TEAEs Leading to Dose Modification ..........................................................................31 
10.2.5.  Deaths ............................................................................................................................31 
10.2.6.  Adverse Events of Special Interest ................................................................................31 
10.2.7.  Overall Summary of Adverse Events ............................................................................31 
10.3. 
 Laboratory Assessments ................................................................................................32 
10.4. 
 Vital Signs ......................................................................................................................33 
10.5. 
 ECG................................................................................................................................34 
10.6. 
 ECOG Performance Status ............................................................................................34 
10.7. 
 Physical Examination.....................................................................................................34 
10.8. 
 AAGP .............................................................................................................................35 
11.
 
 ...........................................................................35 
12.
 PHARMACODYNAMIC ANALYSES .........................................................................36 
REFERENCES ..............................................................................................................................37 
List of Tables 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Lurbinectedin Dose Reduction Levels........................................................................14 
Table 3: 
Two-sided, Exact CI of ORR Under Varying Scenarios for n = 20 ...........................14 
Table 4: 
Two-sided, Exact CI of ORR Under Varying Scenarios for n = 35 and n=100 .........15 
Table 5: 
Posterior Probability for Interim Futility Monitoring .................................................16 
Table 6: 
Protocol Specified Laboratory Tests ..........................................................................32 
List of Appendices 
Appendix 1: Schedule of activities ................................................................................................38 
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Appendix 2: NCI CTCAE Criteria v5.0 for Laboratory Parameters .............................................45 
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1. LIST OF ABBREVIATIONS
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
AAGP 
Alpha-1 Acid Glycoprotein 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BOR 
Best Overall Response 
BLLQ 
Below the Lower Limit of Quantification 
BPP 
Bayesian Posterior Probability 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CPK 
creatinine phosphokinase 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
end-of-study 
EOT 
end of treatment 
eCRF 
electronic case report form 
GGT 
Gamma-glutamyl transferase 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
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ULN 
Upper Limit of Normal 
UTD 
Unable to determine 
WHO 
World Health Organization 
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2. MODIFICATION HISTORY
Version History for SAP: 
Version 
Date 
Description 
Original 
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3. INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe in detail the statistical 
methodology and planned analyses to be conducted for Study JZP712-201 for inclusion in the 
clinical study report (CSR).  The current version of the SAP is based on Protocol Amendment 2 
dated 14-Oct-2022.  Any additional analyses or deviation from the analyses outlined in this plan 
will be documented with rationale in the final CSR.  Mock tables, listings, and figure shells will 
be provided in a separate supporting document.  
This SAP complies with the International Conference on Harmonization (ICH) Harmonized 
Tripartite Guideline Topic E9, Statistical Principles for Clinical Trials.  
All decisions regarding the final analysis of the study results, as defined in this SAP, have been 
made prior to database lock of the study data.  
4. STUDY OBJECTIVES AND ENDPOINTS
4.1. Study Objectives 
4.1.1. Primary Objective 
To evaluate the antitumor activity of lurbinectedin in the selected advanced solid tumors. 
4.1.2. Secondary Objectives 
To evaluate the overall safety profile of lurbinectedin in the selected advanced solid 
tumors. 
To assess other antitumor efficacy parameters of lurbinectedin in the selected advanced 
solid tumors. 
 
 
 
4.2.  Study Endpoints 
4.2.1.   Primary Endpoint 
Investigator-assessed objective response rate (ORR) according to RECIST v1.1. 
4.2.2.   Secondary Endpoints 
Adverse events (AEs) and serious adverse events (SAEs) as graded by NCI CTCAE 
v.5.0.
Investigator-assessed duration of response (DOR) according to RECIST v1.1. 
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5. STUDY DESIGN
5.1.  Summary of Study Design 
This is an open-label, multicenter, phase 2 study of lurbinectedin monotherapy in participants 
with advanced (metastatic and/or unresectable) solid tumors. 
The study population comprises participants in 3 cohorts with advanced (metastatic and/or 
unresectable) urothelial cancer (UC), advanced (metastatic and/or unresectable) poorly 
differentiated neuroendocrine carcinoma (PD-NEC), or homologous recombination deficient 
(HRD)-positive tumor agnostic malignancies. 
This is a signal-seeking study of lurbinectedin 3.2 mg/m2 monotherapy Q3W.  Review of the 
safety and efficacy data will be performed on an ongoing basis by the sponsor.  The sponsor may 
decide to close a cohort or cohorts due to safety concerns, lack of efficacy or any other reasons. 
A cohort or cohorts may be expanded at the spo
 discretion to greater than 20 participants if 
an efficacy signal is observed without any safety concerns. 
Beginning on Cycle 1 Day 1, participants still on study treatment will undergo tumor 
assessments per RECIST v1.1 every 6 weeks (± 7 days) through Week 36, regardless of 
treatment dose delays. After Week 36, tumor assessments will be required every 12 weeks (± 14 
days).  Participants will undergo tumor assessments until radiographic disease progression, 
withdrawal of consent, lost to follow-up, study termination by the sponsor, or death, EOT visit, 
or study termination, whichever occurs first.  After the EOT visit, all participants will be 
followed for survival by a telephone call every 3 months until at least 80% of participants in each 
cohort have died or withdraw consent or are lost to follow-up.  If a cohort closes due to futility, 
the OS follow-up for that cohort will end.  
The projected study duration for each participant will be approximately 17 months including: 
Screening Period (28 days), Intervention Period (9 months), Safety Follow-up Period (30 days), 
and OS Follow-up Period (6 months).   
An overview of the study design is illustrated in Figure 1 and details regarding study assessments 
are in Appendix 1.  
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Dose reduction levels are shown in Table 2. Up to 2 dose reductions are allowed per participant. 
Table 2: 
Lurbinectedin Dose Reduction Levels 
Dose Reduction 
Lurbinectedin Dose (mg/m2) 
1 (starting dose) 
3.2 
-1
2.6 
-2
2.0 
Participants who continue to experience treatment-related toxicity and/or frequent dose delays 
after permitted dose reductions should be discontinued from the study. However, they can 
continue receiving the study intervention if objective clinical benefit is adequately documented 
by the Investigator, and upon agreement with the Sponsor. Once the dose has been reduced for 
an individual participant, it will not be re-escalated under any circumstance. 
Study intervention will continue until confirmed disease progression, withdrawal of participant 
consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort is 
terminated by the sponsor, whichever comes first. 
5.3.  Power and Sample Size Considerations 
This is a nonrandomized multi-cohort signal finding study designed to assess the antitumor 
activity of lurbinectedin in terms of the ORR according to the RECIST v1.1 in three different 
advanced (metastatic and/or unresectable) solid tumors cohorts.  
This study includes up to a total of 60 participants in the initial assessment of efficacy in which 
each tumor cohort includes up to 20 participants.  If there is evidence of efficacy in a cohort, 
enrollment beyond 20 participants in the individual cohort may be considered. 
Each cohort will have up to 4 stages of enrollment: stage 1 at n = 12 and stage 2 at n = 20 for 
futility testing; if a cohort is expanded beyond 20 participants, the study may enroll into stage 3 
with an interim analysis to assess efficacy at n = 35, and a final stage 4 at n = 100 for the final 
analysis. 
bound of 70% confidence interval (CI) of ORR (10.5% to 33.4%) will exclude a 10% ORR 
(Table 3) and the cohort may continue.  This will provide approximately 85% confidence that the 
true ORR is > 10%, where a 10% or lower response rate is not clinically meaningful. 
Table 3: Two-sided, Exact CI of ORR Under Varying Scenarios for n = 20 
Sample 
Size 
No of 
Responders 
Observed 
ORR (%) 
70% CI of 
ORR (%) 
80% CI of 
ORR (%) 
90% CI of 
ORR (%) 
95% CI of 
ORR (%) 
20 
4 
20 
(10.5, 33.4) 
(9.0, 36.1) 
(7.1, 40.1) 
(5.7, 43.7) 
5 
25 
(14.4, 38.8) 
(12.7, 41.5) 
(10.4, 45.6) 
(8.7, 49.1) 
6 
30 
(18.5, 44.0) 
(16.6, 46.7) 
(14.0, 50.8) 
(11.9, 54.3) 
7 
35 
(22.8, 49.1) 
(20.7, 51.8) 
(17.7, 55.8) 
(15.4, 59.2) 
8 
40 
(27.2, 54.1) 
(24.9, 56.7) 
(21.7, 60.6) 
(19.1, 63.9) 
Abbreviations: ORR: Objective response rate; CI: Confidence interval. 
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 (22.9% ORR) out of 35 participants in a cohort, the lower bound of 
95% CI of ORR (10.4% to 40.1%) will exclude a 10% ORR (Table 4) and the cohort may 
continue enrollment up to a total of 100 participants. 
 the lower bound of 
95% CI of ORR (12.7% to 29.2%) will exclude a 10% ORR (Table 4). 
Table 4: Two-sided, Exact CI of ORR Under Varying Scenarios for n = 35 and n=100 
Sample Size 
No of Responders 
Observed ORR (%) 
95% CI of ORR (%) 
35 
7 
20.0 
(8.4, 36.9) 
8 
22.9 
(10.4, 40.1) 
9 
25.7 
(12.5, 43.3) 
100 
18 
18.0 
(11.0, 26.9) 
19 
19.0 
(11.8, 28.1) 
20 
20.0 
(12.7, 29.2) 
  Abbreviations: ORR: Objective response rate; CI: Confidence interval. 
5.4.  Randomization and Blinding 
Not applicable. This is a nonrandomized multi-cohort, open-label signal finding study. 
5.5.  Interim Analysis 
Review of the safety and efficacy data will be performed by the sponsor on an ongoing basis in 
this study.  
Assessment of the observed responses will be performed after enrollment of approximately 12 
and 20 efficacy-evaluable participants for treatment benefit. If no confirmed response per 
RECIST v1.1 is observed in approximately the first 12 evaluable participants of a cohort with at 
least two post-baseline evaluable tumor assessments, the recruitment of participants in that 
cohort will be stopped.  
 responses in the first 20 evaluable participants 
of a cohort, the recruitment of participants in the cohort will be stopped. There will be no pause 
in enrollment during the interim analysis of the first 12 evaluable participants of a cohort, and the 
futility boundary will be adjusted based on the actual number of participants at each stage. 
Interim futility monitoring will be implemented through the Bayesian Posterior Probability 
(BPP) approach with the prior distribution for ORR assumed to be Beta (0.5, 0.5).  Table 5 has 
the operating characteristics for futility of stopping at 12 and 20 participants.   
If no response is observed in the first 12 participants of a cohort, there is an 89% posterior 
probability that the actual response rate is 
first 20 participants of a cohort, there is a 70% posterior probability that the actual response rate 
is no more than 20%. 
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Unless otherwise specified, continuous data will be summarized using descriptive statistics 
comprising of the number of participants with data to be summarized (n), mean, standard 
deviation (SD), median, minimum (min) and maximum (max). Categorical variables will be 
tabulated by the frequency and proportion of participants falling into each category. 
All summaries, statistical analyses, data listings and figures will be completed using version 9.4 
of the Statistical Analysis System (SAS Institute, North Carolina, USA) unless otherwise noted. 
All figures will be generated with high resolution in black and white. Each summary, figure or 
data listing will include the data cutoff date in addition to the production date. 
7.2.  Baseline, Post Baseline, and Study Day Definitions 
7.2.1.  Baseline 
Baseline evaluations are defined as evaluations with a date on or prior to the date of the first dose 
of study treatment. If there are multiple valid observations in the Screening Period, then the latest 
non-missing observation on or before the first dose of study treatment will be used as the 
baseline for analyses. 
7.2.2.  Post-Baseline 
Post baseline evaluations are defined as evaluations taken after the date of the first dose of study 
treatment. 
The post-baseline period is further characterized into: 
A treatment period, which is the time period from the date of the first dose to the date of 
the last dose of study treatment 
A 30-day safety follow-up period after the last dose of study treatment 
An OS follow-up period, which is the period following the 30-day safety follow-up 
period after the last dose of study treatment until participants die or withdraw consent or 
are lost to follow-up or the cohort closes. If a participant is to permanently discontinue 
study intervention before disease progression, the participant will be followed for 
survival by telephone visits every 3 months until at least 80% of participants in each 
cohort have died, withdrawn consent, or are lost to follow-up. 
7.2.3.  Study Day 
The day of receiving the first dose of study treatment is defined as Study Day 1 or Day 1. All 
other study days will be computed relative to Day 1. Day 0 will not be used. The day before 
receiving the first dose of study treatment is Day -1 and the day after receiving the first dose of 
study treatment is Day 2. The following computation rules will be used: 
For events on or after Day 1, study day for a particular event or visit will be calculated as: 
Date event  Date Day 1 + 1. 
For events before Day 1, study day for a particular event will be calculated as: Date event 
Date Day 1. 
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7.2.4.  Visit Windows  
Analysis Visit windowing in general will not be applied. In the case of a retest (same visit 
number assigned), the latest available test results as provided in the data transfer for that 
visit/time point will be used for by-visit summaries. 
A 30-day safety follow-up period after the last dose of study treatment will be considered for 
assessing treatment-emergent adverse events (TEAEs). 
All scheduled and unscheduled visits will be included in by-participant listings. 
7.3.  Derived Variable Definitions 
7.3.1.  Treatment -Emergent Adverse Events 
Treatment-emergent adverse events are defined as AEs with an onset date on or after the date of 
the first dose of study treatment. An AE is a TEAE if it occurs up to 30 days after the last dose of 
study intervention. TEAEs can be pre-treatment AEs that worsen in CTCAE grade after the start 
of study treatment. 
7.3.2.  Creatinine Clearance (CrCL) 
The creatinine clearance will be calculated using Cockcroft-Gault formula (1976), defined as: 
for males and 
for females. Baseline weight will be used. 
7.4.  Handling of Missing and Partial Data 
7.4.1.  Missing Data 
Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument. These data will be indicated using 
plays. 
Note that if any non-date missing data is imputed, the imputed data will only be used in 
not considered to be missing data and will not be displayed as missing. 
Imputed dates will not be used to derive study day or duration. Imputed dates will be displayed 
in listings and identified as imputed. 
7.4.2.  Imputation of Non-date Missing Data 
Data used for evaluating efficacy and safety endpoints may be missing for technical reasons 
(e.g., unreadable scan, participant missed appointment). 
The primary efficacy analysis for ORR will be performed on the Efficacy-evaluable analysis set. 
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For participants without any post baseline disease assessment, the response will be imputed as 
non-responder for sensitivity analyses of ORR in the Safety analysis set.  
AEs and SAEs with missing relationship to study treatment will be considered related to study 
treatment for the purpose of analyses. 
AEs and SAEs with missing severity (CTCAE grade) will be considered missing for the purpose 
of analyses. 
7.4.3.  Incomplete and Missing AE Start Date 
The following imputation rules will be followed, when the AE start date is incomplete (e.g., only 
year is present, but month and day are missing) or completely missing: 
If year is missing (including the situation where the start date is completely missing), set 
the date to the first dose date. 
If year is present, and month and day are missing, or year and day are present, and month 
is missing,  
o
if year = year of first dose, set the date to the first dose date,
o
if year < year of first dose, set month and day to December 31st.
o
if year > year of first dose, set month and day to January 1st.
If year and month are present, and day is missing, 
o
if year = year of first dose, and
if month = month of first dose, set day to day of first dose; 
if month < month of first dose, set day to the last day of month; 
if month > month of first dose, set day to the first day of month; 
o
if year < year of first dose, set day to the last day of month;
o
if year > year of first dose, set day to the first day of month.
For all other cases that are not covered above, set the date to the first dose date. 
Imputed dates for AEs with partial dates will be used to identify treatment emergent AEs and for 
sorting in data listings. They will not be used to calculate duration of AEs. If an AE start or end 
date is completely missing, then the duration of the AE will be set to missing and the AE will be 
considered treatment emergent. 
7.4.4.  Incomplete and Missing Prior and Concomitant Medication Start Date 
The following imputation rules will be followed, when the prior and concomitant medication 
start date is incomplete (e.g., only year is present, but month and day are missing) or completely 
missing: 
If year is missing (including the situation where the start date is completely missing), do not 
impute, and the start date will be treated as missing in the analysis.  Medications with 
missing start date will be considered concomitant for the purpose of summary tables. 
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If year is present, and month and day are missing, set month and day to January 1st. 
If year and month are present, and day is missing, set day to the first day of month. 
If year and day are present, and month is missing, set month to January. 
7.4.5.  Incomplete and Missing Prior and Concomitant Medication End Date 
The following imputation rules will be followed, when the prior and concomitant medication end 
date is incomplete (e.g., only year is present, but month and day are missing) or completely 
missing: 
If it is indicated that the medication is ongoing (i.e.
this 
medication. 
If year is missing (including the situation where the end date is completely missing), do 
not impute, and the end date will be treated as missing in the analysis. 
If year is present, and month and day are missing, set month and day to December 31st. 
If year and month are present, and day is missing, set day to the last day of month. 
If year and day are present, and month is missing, set month to December. 
7.5.  Hypotheses Testing 
This nonrandomized multi-cohort signal finding study will use estimation rather than hypothesis 
testing to characterize the ORR for each cohort.  
7.6.  Level of Significance & Multiplicity Adjustment 
Not applicable. 
7.7.  Subgroups and Subgroup Analyses 
No subgroups and subgroup analyses are planned. However, the influence of baseline and 
demographic characteristics on the treatment effect may be explored via exploratory subgroup 
analyses if the number of subjects in the subgroup category is >= 5. 
7.8.  Changes to Planned Analyses 
None. 
8. STUDY POPULATION SUMMARIES
8.1.  Enrollment 
All participants who signed informed consent will be accounted in this study (Enrolled analysis 
set). 
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The number of participants screened, number of screen failures and reasons for screen failure 
(did not meet eligibility criteria, withdrew consent, adverse event, investigator discretion, lost to 
follow-up, study enrollment closed, other) will be summarized overall and by assigned cohort (as 
per IRT) and details will be included in a data listing using Enrolled analysis set.  
The number and percentage of participants included in each analysis set (Safety, Efficacy 
Evaluable, 
and reason(s) for exclusion from each analysis set will 
be summarized by assigned cohort: UC, PD-NEC, HRD-positive tumor agnostic malignancies. 
Percentages for Safety analysis set will be based on number of enrolled participants in each 
cohort. Percentages for Efficacy Evaluable
analysis sets will be 
based on number of participants in each assigned cohort in Safety analysis set. 
8.2.  Disposition 
Participant disposition will be summarized (number and percentage) overall and by assigned 
cohort for Enrolled analysis set. Participant disposition data, including study treatment 
completion, study treatment discontinuation, study completion, study withdrawal, primary reason 
for study treatment discontinuation, and primary reason for study withdrawal as provided on the 
CRF, will be listed by participant for Enrolled analysis set. Study treatment completion and study 
completion status will be assessed based on corresponding CRF pages. The number and 
percentage of participants followed-up for survival status will be summarized by assigned cohort 
and listed for Safety analysis set. 
If a participant completes the study per protocol, the last on-study date is the last visit date for 
this participant; if a participant terminates the study early, the date entered in the early 
termination folder in eCRF is the last on-study date for this participant.  
8.3. Protocol Deviations 
Protocol deviations will be categorized as important and non-important. Important protocol 
deviations will be summarized descriptively for participants with at least one important protocol 
deviation by cohort. The summary will include the following subtypes: 
Inclusion criteria not met 
Exclusion criteria not met 
Expired/compromised IP administered 
Subject dose not modified per protocol 
Incorrect dose of study treatment 
Failure to take action in response to apparent toxicity and failure to appropriately monitor 
the patient with toxicity 
Missed pregnancy test 
Failure to complete any efficacy assessments (e.g., imaging evaluations) at any timepoint 
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Failure to obtain initial informed consent, or obtaining informed consent after initiation 
of study procedures 
Use of an invalid/outdated consent form 
Prohibited medication taken or prohibited treatment given 
Falsification of source documentation 
Significant PI or staff misconduct or fraud 
Breach of confidentiality of participant/data privacy 
IRB approval lapse 
Non-compliance with protocol withdrawal criteria 
Significant, repeated protocol non-compliance that significantly impacts participant 
safety and/or the integrity of the study conduct or study data 
Every subtype will be kept in the summary even if it has 0 participants. A participant with more 
than one important protocol deviation will be counted only once in the total number of 
participants with at least one important protocol deviations. A by-participant listing of all 
protocol deviations will be provided with deviation subtype, description, and a flag for important 
protocol deviation. 
8.4.  Demographic and Baseline Characteristics 
Demographic data and other baseline characteristics will be summarized using descriptive 
statistics overall (across all cohorts) and by assigned cohort for the Safety analysis set and 
Efficacy evaluable analysis set. The denominator for percentages will be the number of 
participants in each cohort with non-missing data available for the variable of interest. All 
demographic data and other baseline characteristics will be included in by-participant data 
listings using Safety analysis set. 
The following demographic and baseline disease characteristics will be included in the 
summaries mentioned above: 
Age (years) at informed consent (as continuous variable) 
Age group at informed consent: <65 years,  65 years  
Sex at birth (male, female) 
Childbearing potential (female participants only) (yes/no) 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple, Other, or Not Reported) 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, or Not Reported) 
Weight at baseline (kg) 
Height at baseline (cm) 
Body surface area (BSA) (m2) 
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Alcohol use 
Tobacco use 
Baseline creatinine clearance (CrCL) 
Baseline ECOG performance status (0, 1) 
Baseline results for biochemistry, hematology, coagulation laboratory tests, urinalysis, vital 
signs, and ECG test results will be reported in the corresponding summary tables and listings for 
each safety endpoint.  
8.5.  Disease Characteristics 
Oncology history will be summarized descriptively by cohort using the Safety analysis set and 
for Efficacy evaluable analysis set for the following: 
Initial disease diagnosis (histopathologic diagnosis) 
Time (months) since initial disease diagnosis (histopathologic diagnosis) to first dose 
date 
Stage at diagnosis (0, 1, 2, 3, 4) 
Cancer stage at enrollment (TNM staging) (0, 1, 2, 3, 4) 
Histopathology (urothelial cancer, large cell neuroendocrine tumor of lung, HRD positive 
endometrial, HRD positive biliary tract, HRD positive breast TNBC, HRD positive 
HR+HER2-, HRD positive pancreas, HRD positive gastric/esophageal solid tumor, other) 
Mutation type (germline, somatic, unknown) for HRD-positive tumor agnostic 
malignancies cohort only 
Time since initial disease diagnosis (months) = (first dose date  date of initial disease diagnosis 
+ 1)/30.4375. Partial dates for initial disease diagnosis will not be imputed, and time since initial
diagnosis will be set to missing.
Planned summaries for prior oncology treatments including prior anti-cancer mediation, prior 
anti-cancer radiotherapy, prior anti-cancer procedure or surgery are described in Section 8.7. 
All disease characteristics will be included in by-participant data listing using Safety analysis set. 
8.6.  Medical History 
Medical conditions collected on the Medical History page of the CRF will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 25.0. Summary of medical 
history by system organ class (SOC) and preferred term (PT) will be provided using the Safety 
analysis set by cohort and across cohorts.  A participant will only be counted once within a 
particular SOC (PT) even if he/she has multiple conditions/diseases in the same SOC (PT). 
Summary results will be ordered by descending frequency of SOC and PT within each SOC. If 
the frequencies tie, an alphabetic order will be applied. 
A listing of medical history will be provided with the start date, ongoing (yes or no), and the end 
date, if not ongoing. 
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8.7.  Prior Anti-Cancer Therapy 
Prior anti-cancer therapy is defined as those taken by the participant prior to the administration 
of study treatment. Prior anti-cancer therapy, including systemic therapy, radiotherapy, and 
procedure or surgery, will be summarized descriptively by cohort for the safety analysis set. 
8.7.1.  Prior Systemic Anti-Cancer Therapy 
Prior systemic anti-cancer therapy will be coded to Anatomical Therapeutic Chemical (ATC) 
Level 4 and PT using the World Health Organization Drug Dictionary (WHODrug) version Mar 
2022. 
For prior systemic anti-cancer therapy, the following summary results will be prepared: 
Number and percentage of participants with at least one prior systemic anti-cancer 
therapy 
Number and percentage of participants with 1, 2, 3, 4, and  5 previous lines of therapy 
Number of maximum number of regimens of prior systemic anti-cancer therapy 
Time (months) from completion of the most recent prior systemic anti-cancer therapy to 
study treatment (< 3,  3 - < 6,  6 months), which is calculated as (date of first dose of 
the study treatment date of last dose of the most recent prior systemic anti-cancer 
therapy + 1)/ 30.4375. 
Characteristics of the most recent prior systemic anti-cancer therapy: type of prior 
systemic anti-cancer therapy, best response, reason therapy ended, and time (months) 
from completion of the most recent prior systemic anti-cancer therapy to 
progression/recurrence [calculated as date of progressions/recurrence date of last dose of 
the most recent prior systemic anti-cancer therapy + 1)/ 30.4375].   
All prior systemic anti-cancer therapy will be presented in a participant listing using Safety 
analysis set. Listing will include regimen number, route, start/stop date (or ongoing), best overall 
response (and date), progressive disease date, and reason therapy ended. 
8.7.2.  Prior Anti-Cancer Radiotherapy 
The number and percentage of participants with at least one prior anti-cancer radiotherapy will 
be summarized by cohort using Safety analysis set. 
All prior anti-cancer radiotherapy will be presented in participant listing using Safety analysis 
set. Listing will include treatment intent, start/stop date, and setting. 
8.7.3.  Prior Anti-cancer Procedure or Surgery 
Prior anti-cancer procedure or surgery will be coded to SOC and PT using MedDRA version 
25.0. 
The prior anti-cancer procedure or surgery will be summarized by presenting the number and 
percentage of participants by PT and SOC. Participants with the same procedure or surgery 
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reported multiple times will only be counted once for that PT or SOC. Summary results will be 
ordered by descending order of incidence of SOC and PT within each SOC.  If the frequencies 
tie, an alphabetic order will be applied. 
All prior anti-cancer procedure or surgery will be presented in a participant listing including 
intent for procedure or surgery, date, and result. 
8.8.  Subsequent Anti-Cancer Therapy 
Subsequent anti-cancer therapy is defined as an anti-cancer therapy administered after the 
discontinuation of the study treatment. Number and percentage of participants receiving 
subsequent anti-cancer therapies, where categories include subsequent systemic therapy, 
subsequent surgery for cancer treatment, and subsequent radiotherapy for cancer treatment, will 
be summarized descriptively by cohort for the Safety analysis set. Summary results will include: 
Number and percentage of participants with at least one subsequent anti-cancer therapy 
Number and percentage of participants by type of therapy 
Number and percentage of participants with 1, 2, and 
3 subsequent anti-cancer therapy 
(agents) 
Number of maximum number of regimens (agents) of subsequent systemic anti-cancer 
therapy 
All subsequent anti-cancer therapies will be presented in participant listing using Safety analysis 
set. Listing will include therapy type, regimen number, start/stop date (or ongoing), dose and 
units, progressive disease date. 
8.9.  Prior and Concomitant Medications 
Prior and concomitant medications will be coded to ATC level 4 and PT using WHODrug 
version Mar 2022. 
Medications taken prior to the first dose of study treatment and continuing beyond the first dose 
of study treatment or those medications started on or after the first dose of study treatment but 
within 30 days of last dose received (the 30-day safety window) 
Medication with start date/time being partially or completely missing will be assumed to be 
concomitant if it cannot be shown that the medication was not administered during the treatment 
period. 
The prior medications will be summarized by presenting the number and percentage of 
participants by PT and ATC level for each cohort using Safety analysis set. Participants taking 
the same medication multiple times will only be counted once for that PT or ATC level.  Each 
summary will be ordered by descending order of incidence of ATC level and PT within each 
ATC level. If the frequencies tie, an alphabetic order will be applied.  
Concomitant medications will be summarized in a similar way. 
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All prior and concomitant medications will be presented in participant listing using Safety 
analysis set. 
8.10.  Concomitant Procedures 
Medical or surgical procedures that started after the first dosing date of the study treatment and 
within 30 days of the last dose received (the 30-day safety window) 
Concomitant medical or surgical procedures will be classified using the MedDRA version 25.0. 
The concomitant medical or surgical procedures will be summarized by presenting the number 
and percentage of participants by PT and SOC. Participants having the same medical or surgical 
procedure multiple times will only be counted once for that PT or SOC. Each summary will be 
ordered by descending order of incidence of SOC and PT within each SOC.  If the frequencies 
tie, an alphabetic order will be applied. Results will be presented by cohort using Safety analysis 
set. 
All concomitant medical or surgical procedures will be presented in participant listing using 
Safety analysis set. 
9. EFFICACY
All efficacy analyses will be performed using the Efficacy-Evaluable Analysis Set, separately for 
each of the 3 cohorts, unless otherwise specified.  
Primary analysis of objective response rate (ORR) 
assessment, unless noted otherwise. 
-sided 0.05. CIs for all efficacy
endpoints will be at the two-sided 95% level. Point estimates and confidence bounds for efficacy 
endpoints will be rounded to the second decimal place. 
A by-participant listing of efficacy results will be presented for each of the cohorts including 
treatment duration, progression date, death date, and all the other efficacy endpoints. 
9.1.  Primary Efficacy Endpoint and Analysis 
9.1.1.  Primary Analysis 
The primary efficacy endpoint is the objective response rate (ORR). 
Best overall response (BOR) is defined as the best response recorded between the date of the first 
dose of study treatment and the date of objectively documented progression per RECIST v1.1, or 
the date of subsequent anticancer therapy, death due to any cause, loss to follow-up, or study 
discontinuation, whichever occurs first. Best overall response (BOR) will be determined 
programmatically in the analysis of the study results as the best timepoint response that a 
participant achieves during the study (recorded between the date of the first dose of study 
treatment and the date of objectively documented progression per RECIST v1.1), with the 
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response ranked according to the following order (from best to worst): complete response (CR) > 
partial response (PR) > stable disease (SD) > progressive disease (PD). 
The first post-baseline tumor imaging assessment should occur 6 weeks (+/- 7 days) from the 
first dosing date. A response of SD can only be made after the participant is on-study for a 
minimum of 35 days from the date of the first dose. The number and percentage of participants 
in each category of BOR (CR, PR, SD, PD, not evaluable [NE]) will be presented by each 
cohort.   
The ORR is defined as the proportion of participants whose BOR is investigator-assessed 
confirmed CR or PR using the RECIST v1.1.  The ORR will be summarized by a binomial 
response rate for each cohort and its corresponding two-sided 95% exact CIs using the Clopper 
and Pearson method (Clopper 1934).  
The calculation of the ORR and its corresponding two-sided 95% exact CIs will be carried out 
using the PROC FREQ procedure with the exact binomial option in SAS version 9.4. 
A by-participant listing of best overall response will be presented by each cohort including best 
overall response and dates of CR/PR/progression. 
9.1.2.  Sensitivity Analyses 
Not applicable. 
9.1.3.  Subgroup Analyses 
The influence of baseline and demographic characteristics on the treatment effect may be 
explored via exploratory subgroup analyses if the number of subjects in a subgroup category is 
>=5. 
9.2.  Secondary Efficacy Endpoints and Analyses 
9.2.1.  Duration of Response (DOR) 
The investigator-assessed objective response will be further characterized by the DOR. DOR will 
be evaluated for responders (confirmed CR and PR) only. 
DOR is defined as the time (months) from first confirmed response (CR or PR) to the date of the 
first documented tumor progression as determined using RECIST v1.1 criteria or death due to 
any cause, whichever occurs first.   
The following censoring rules will be applied to DOR: 
Participants who do not progress or die will be censored on the date of their last evaluable 
tumor assessment. 
Participants who started a new anticancer therapy without a prior reported progression 
will be censored on the date of their last evaluable tumor assessment on or prior to the 
initiation of first subsequent anticancer therapy. 
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Participants who are lost to follow-up or discontinued from the study without a prior 
reported progression and without start of subsequent anticancer therapy will be censored 
on the date of their last evaluable tumor assessment on or prior to the date of loss to 
follow-up or study discontinuation.  
A by-participant listing will be presented including actual cohort, best response, duration of 
response, whether the participant was censored for duration of response, and if so, the reason. 
 
 
 
 
 
 
10. SAFETY
Safety analyses will be based on the Safety Analysis Set. 
10.1.  Exposure 
10.1.1.  Extent of Exposure 
Exposure of study treatment (duration of exposure, number of cycles of treatment received, 
cumulative dose, dose intensity, and relative dose intensity) will be summarized by cohort and 
listed by participant using Safety analysis set. 
The summary results will include the following: 
Number of cycles administered per participant (median, range) 
Number and percentage of participants with 1, 2, 3, 4, 5, 
6 cycles administered 
Duration of lurbinectedin exposure (weeks), derived as [(date of last dose - date of first 
dose) + 1]/7 
Cumulative lurbinectedin dose (mg/m2), calculated as sum of the doses received from the 
first cycle until the last cycle, including the dose received in the last cycle, and corrected 
by BSA 
Intended dose intensity (mg/m2/week), calculated as the planned dose per cycle divided 
by the planned number of weeks per cycle 
Absolute dose intensity (mg/m2/week), calculated as the cumulative lurbinectedin dose 
divided by the number of weeks of treatment, where the number of weeks of treatment is 
derived as [(date of last dose - date of first dose) + 21]/7  
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Relative dose intensity (%), calculated as the ratio of absolute dose intensity divided by 
the intended dose intensity 
Number and percentage of participants with dose reduction (at least one, 1 dose 
reduction, 2 dose reductions); reasons for dose reductions will be included in by-
participant data listing only 
Number and percentage of participants with incomplete infusions (i.e., infusions noted as 
interrupted and not restarted on eCRF) at least once, 1 time, 2 times, 3 or more times) 
10.1.2.  Treatment Compliance 
Not applicable. 
10.2.  Adverse Events 
Adverse events recorded in the CRF will be coded to SOC and PT using MedDRA version 25.0. 
Unless otherwise noted, the AE summaries will be provided by SOC and PT; SOCs will be 
ordered alphabetically, with PTs within an SOC sorted in descending order of frequency. A 
participant will be counted only once at each level of summarization. If a participant has multiple 
episodes of events coded to the same preferred term, the participant will be counted just once 
while summarizing for that preferred term and at maximum severity (when applicable).  
All AE summary tables will be generated overall (across all cohorts). 
10.2.1.  Treatment Emergent Adverse Events (TEAEs) 
Treatment-emergent adverse events (TEAE) are defined as AEs with an onset date on or after the 
date of the first dose of the study treatment and within 30 days of last dose received (the 30-day 
safety window). TEAEs can be pre-treatment AEs that worsen in CTCAE grade after the start of 
study treatment. For the purpose of determining treatment-emergent, incomplete and missing AE 
start dates will be imputed as specified in Section 7.4.3. 
Treatment-
Is this 
adverse event related to study treatment [lurbinectedin
investigators do not record the relationship to lurbinectedin will be considered as related to 
lurbinectedin for summary purposes. By-participant listings for those events for which the 
investigator does not record relationship to lurbinectedin will show treatment relationship as 
missing.   
The severity of AEs will be recorded using the Common Terminology Criteria for Adverse 
Events (CTCAE), version 5.0. Adverse events are graded by the investigator as Grade 1 (mild), 
Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The severity 
summaries and listings and will be considered the least severe for the purposes of sorting for data 
presentation. 
The following summaries of TEAEs (number and percentage of participants) will be provided 
overall (across all cohorts) using Safety analysis set: 
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Summary of any TEAEs by worst CTCAE grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT 
Summary of TEAEs by PT (decreasing frequency) 
o
Any grade
o
Grade 3-4
o
Grade 3
Summary of any non-serious TEAEs by worst CTCAE grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT 
Summary of treatment-related TEAEs by worst CTCAE grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT 
Summary of treatment-related TEAEs by PT (decreasing frequency) 
A by-participant TEAE listing will be provided with participant identifier, cohort, SOC, PT, start 
date, end date, severity grade, seriousness, relationship to lurbinectedin, and outcome of the AE 
using Safety analysis set. 
10.2.2.  Serious Adverse Events (SAEs) 
reconciled with the SAE database 
before the final database lock. 
The following summaries of SAEs (number and percentage of participants) will be provided 
across the cohorts using Safety analysis set: 
Summary of SAEs by worst CTCAE grade (any grade, grade 3-4, grade 5) presented by 
SOC/PT 
Summary of treatment-related SAEs by worst CTCAE grade (any grade, grade 3-4, grade 
5) presented by SOC/PT
All analyses will be conducted from the first dosing date of study treatment to the last date of the 
30-day safety window.
A by-participant SAE listing will be provided using Safety analysis set. 
10.2.3.  TEAEs Leading to Study Treatment Discontinuation 
TEAEs leading to study treatment 
 recorded in the CRF. 
The following summaries of TEAEs leading to study treatment discontinuation (number and 
percentage of participants) will be provided across the cohorts using Safety analysis set: 
Summary of TEAEs leading to study treatment discontinuation by worst CTCAE grade 
(any grade, grade 3-4, grade 5) presented by SOC/PT 
Summary of treatment-related TEAEs leading to study treatment discontinuation by 
worst CTCAE grade (any grade, grade 3-4, grade 5) presented by SOC/PT  
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The analyses will be conducted from the first dosing date of study treatment to the last date of 
the 30-day safety window. 
All TEAEs leading to study treatment discontinuation will be included in a by-participant listing 
including but not limited to participant identifier, cohort, SOC, PT, start date, end date, severity 
grade, relationship to lurbinectedin, seriousness, and outcome of the AE using Safety analysis 
set. 
10.2.4.  TEAEs Leading to Dose Modification 
TEAEs leading to dose modification (dose delay/reduction) 
Action Taken with 
Study Treatment = Drug 
 recorded in the CRF. 
The following summaries of TEAEs leading to dose modification (number and percentage of 
participants) will be provided across the cohorts using Safety analysis set: 
Summary of TEAEs leading to dose delay/reduction by worst CTCAE grade (any grade, 
grade 3-4 presented by SOC/PT 
Summary of treatment-related TEAEs leading to dose delay/reduction by worst CTCAE 
grade (any grade, grade 3-4) presented by SOC/PT  
The analyses will be conducted from the first dosing date of study treatment to the last date of 
the 30-day safety window. 
All TEAEs leading to dose modification will be included in a by-participant listing including but 
not limited to participant identifier, cohort, SOC, PT, start date, end date, severity grade, 
relationship to lurbinectedin, seriousness, and outcome of the AE using Safety analysis set. 
10.2.5.  Deaths  
Deaths will be summarized descriptively across the cohorts: 
All deaths, reasons for death 
Deaths within 30 days of the last dose received (the 30-day safety window), reasons for 
death 
A by-participant listing of deaths will be provided for all enrolled participants population, in 
which deaths within the 30-day safety window will be flagged. 
10.2.6.  Adverse Events of Special Interest 
Not Applicable. 
10.2.7.  Overall Summary of Adverse Events 
A general summary of AEs will be provided with the number and percentage of participants in 
the Safety analysis set who experienced the following types of events across the cohorts: 
Participants with any TEAE 
Participants with any Treatment-Related TEAE 
Participants with TEAE by Worst CTCAE Grade 
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Other Screening tests 
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) 
ALT=alanine aminotransferase; AP=alkaline phosphokinase; AST=aspartate aminotransferase; CPK=creatinine 
phosphokinase; GGT=gamma-glutamyl transferase; HBcAb=hepatitis B core antibody; HBsAg=hepatis B surface 
antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
LDH=lactate dehydrogenase; PT=prothrombin time; PTT=partial thromboplastin time; ULN=upper limit of normal. 
For all hematology, coagulation and biochemistry tests, the laboratory values at baseline and 
each of the post-baseline assessments until EOT visit will be summarized and presented using 
descriptive statistics, along with the number and percentage of participants with tests not done. 
For each of the post-baseline assessments, change between baseline and that assessment in a 
specific laboratory value will be calculated as follows, 
Change in lab value = [Lab value at the post-baseline assessment]  [Lab value at baseline], 
and will be summarized and presented using descriptive statistics.  
If the laboratory value is not done or missing at either baseline or a specific post-baseline 
assessment for a participant, change between baseline and that assessment will be treated as 
unknown.  For each of the post-baseline assessments, the number and percentage of participants 
with unknown changes between baseline and that assessment will also be presented. 
The non-protocol specified tests (if any reported), and urinalysis results will not be summarized; 
they will only be included in by-participant listings. 
Data recorded by the laboratory will be converted to the International System of Units (SI) and 
summary tables will be generated using both SI and Conventional units.   
i.e., below the lower limit of
i.e., above the upper limit of quantification (ULQ), will be
converted to X for the purpose of quantitative summaries, but will be presented as recorded, i.e., 
Clinical laboratory results will be graded according to CTCAE criteria, CTCAE v5.0 criteria 
(Appendix 2).  The frequency and percentage of participants with each CTCAE grade for each 
visit during the treatment period will be described by cohort. Both the scheduled and 
unscheduled assessments will be used to identify the worst post-baseline values. 
Listings of all laboratory data with results reported using SI and Conventional units, normal 
reference ranges, and CTCAE grades (when possible) will be provided using Safety analysis set. 
Pregnancy test results and other screening tests will be included in by-participant listings only. 
10.4.  Vital Signs 
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate (beats/min), 
respiratory rate (breaths/min), body temperature (C) at baseline and each of the post-baseline 
assessments will be summarized and presented using descriptive statistics across the cohorts 
using Safety analysis set. For each of the post-baseline assessments, the change between baseline 
and that assessment in a specific vital sign will be calculated as follows:  
Change in vital sign = [post-baseline assessment]  [baseline assessment], 
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and will be summarized and presented using descriptive statistics. 
If a specific type of vital sign is not done or missing at either baseline or a specific post-baseline 
assessment for a participant, change between baseline and that assessment will be treated as 
unknown. For each of the post-baseline assessments, the number and percentage of participants 
with unknown changes between baseline and that assessment will also be presented.   
A listing of clinically significant abnormalities post baseline as judged by the investigator will be 
provided. For each participant and each vital sign, if there is at least one abnormal result, all 
results at all visits for that vital sign will be included in the listing.  
The following values will be summarized: 
Systolic pressure < 60 or > 160 mmHg 
Diastolic pressure < 50 or > 100 mmHg 
Pulse rate < 40 or > 120 beats per minute 
Respiratory rate < 10 or > 40 breaths per minute 
Temperature < 36 or > 39 degrees Centigrade 
All vital signs will be listed by participant using Safety analysis set. 
10.5.  ECG 
A single 12-lead ECG will be obtained during screening using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. A by-participant 
listing including heart rate (beats/min, PR Interval (msec), QRS duration (msec), QT interval 
(msec), QTcB (msec), QTcF (msec), ECG Interpretation and any abnormal findings will be 
prepared using Safety analysis set.  
10.6.  ECOG Performance Status 
ECOG will be assessed at screening, on Day 1 of each cycle, and at EOT. The frequency and 
percentage of participants with each ECOG score level will be summarized by visit and across 
cohorts using Safety analysis set. 
A listing of ECOG score for all participants will be provided using Safety analysis set. 
10.7.  Physical Examination 
A complete physical examination will be conducted at screening, on Day 1 of each cycle, and at 
EOT. Height will be collected at screening only. BSA will be recalculated on Day 1 of each 
treatment cycle and for any change (higher or lower) of the baseline value 10% the dose will be 
adjusted. 
A listing of physical examination data for all participants will be provided using Safety analysis 
set. Listing will include height (screening value), weight, BSA, BSA change from baseline value 
for all post-baseline visits. 
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10.8.  AAGP 
One blood sample for the evaluation of Alpha-1 Acid Glycoprotein (AAGP) will be collected at 
the end of the lurbinectedin infusion (± 5 min) on Cycle 1 Day 1 (C1D1) from all participants. 
The serum AAGP will be summarized by cohort using Safety analysis set and analyzed using 
summary statistics such as mean, SD, median, minimum, and maximum values. A by-participant 
listing of serum AAGP data will be provided for each cohort using Safety analysis set. 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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12. PHARMACODYNAMIC ANALYSES
Not applicable. 
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