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1.0 title page clinical study

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with Extensive Stage Small Cell Lung Cancer (MERU)
Incorporating Amendments 1, 2, 3 and 4 AbbVie Investigational Product:
Rovalpituzumab tesirine (Rova-T)  
Date: 05 March 2019 Development Phase: 3 Study Design: A Randomized, Double-Blind, Placebo-Controlled Phase 3  
Study of Rovalpituzumab Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with Extensive Stage Small Cell Lung Cancer (MERU)  
EudraCT Number: 2016-003503-64 Investigators: Investigator information is on file at AbbVie. Sponsor: AbbVie Inc.* Sponsor/Emergency Contact: Senior Medical Director  
AbbVie 1 North Waukegan Road North Chicago, IL 60064 USA  
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the Competent Authority.  
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory requirements, including the archiving of essential documents.  
Confidential Information No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.  
NCT03033511 1  
| AbbVie 1 North Waukegan Road North Chicago, IL 60064 USA   | Phone: Cell Phone: Fax: Email:   |
|------------------------------------------------------------|----------------------------------|
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1.1 protocol amendment summary of

| Protocol    | Date             |
|-------------|------------------|
| Original    | 13 October 2016  |
| Amendment 1 | 03 February 2017 |
| Amendment 2 | 20 April 2017    |
| Amendment 3 | 09 May 2017      |  
The purpose of this amendment is to:
- Modified Section 1.0 Sponsor/Emergency Contact Rationale: *Modification of the emergency contact for the study.*
- Update Section 1.2, Synopsis, Section 4.0, Study Objectives, Section 5.3.3.2, Section 5.3.3.3, Section 5.3.3.4, Section 8.1.4 Primary Efficacy Endpoints, Section 8.1.5 Secondary Efficacy Endpoints, Section 8.1.6 Exploratory Efficacy Endpoints to clarify the DLL3high population, secondary endpoints updated to include, OS, PFS and PRO endpoints to be tested in all randomized patient population and prioritize these ahead of other efficacy endpoints such as ORR, CBR and DOR. Exploratory endpoints were added. Rationale: This clarifies the population for primary endpoints (unchanged from prior protocol version) and allows evaluation of Rova-T efficacy on OS, PFS, and PRO in all enrolled patient population in secondary endpoint. ORR, CBR etc., are clinically less relevant than PFS, OS and PRO and thus, will be tested as exploratory endpoints.  
- Modified Section 1.2, Synopsis Study sites and Section 5.1 Overall Study Design to Approximately 300 from 275. Rationale: *The number of study sites has increased since the last amendment.*
- Update Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 1 to add the option of the subject's legally accepted representative as a person that can sign consent on the subject's behalf. Rationale: To align with the approved informed consent language.  
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- Updated Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 3 to say
'Histologically or cytologically confirmed ED SCLC (extensive stage disease at initial diagnosis) with ongoing clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line platinum-based therapy (cisplatin or carboplatin in combination with etoposide or irinotecan).' Rationale: *Clarify that intended patient population is ED SCLC as per* staging performed at the initial diagnosis and not any other time point.  
- Updated Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 5 to say
'Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle of first-line platinum-based chemotherapy.' Rationale: Clarify intended window between front-line therapy and randomization.  
- Updated Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 9f to add
'modified' to say 'Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula (Refer to Appendix E).' Rationale: Clarify required method for assessment of calculated creatinine clearance.  
- Updated Section 1.2 Synopsis, Section 5.2.2, Exclusion criteria 1 to remove
'the disease under study' and replace it with 'SCLC.'
Rationale: *Further clarify that subjects who received prior treatment for LDSCLC are excluded*
- Updated Section 1.2 Synopsis, Section 5.2.2, Exclusion criteria 2 to add
'palliative radiotherapy to a radiographically documented non-progressing lesion for symptom control.' Rationale: Clarify that palliative radiotherapy is allowed for non-progressing lesions.  
- Updated Section 1.2 Synopsis, Section 5.2.2, Exclusion criteria 4 to change the reference from Appendix E to Appendix F. Rationale: *Correcting a typo from the previous amendment.*
- Updated Section 1.2 Synopsis Statistical Methods section, Section 8.1 Statistical and Analytical Plans, Section 8.4, Section 8.5 and Section 8.6 to 3 remove the efficacy interim analysis after observing 75% of the final OS events and to add a futility analysis at 50% of the final OS events. Rationale: *Enable earlier stopping of the trial in the event of futility and* improve statistical properties at final OS.  
- LD SCLC defined in List of Abbreviations as Limited-stage disease small cell lung cancer Rationale: *Definition added to clarify the different disease states for SCLC.*
- Modified Section 3.3 Rovalpituzumab Tesirine to provide updated data.  
Rationale: *Latest data added from ongoing Rova-T studies.*
- Modified Section 3.5 Benefits and Risks to update safety language.  
Rationale: *To provide updated safety information*
- Modified Section 5.1 Overall Study Design, Footnote number 3 under Figure 1 to include the following updated language- 'Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle of first-line platinum-based chemotherapy.' Rationale: *To be consistent with the update to Inclusion Criteria 5.*
- Modified Section 5.2 Selection of Study Population to include the LD and ED
SCLC definition. Rationale: *Modified to include the definition per IASLC/VA for LD and ED* SCLC.  
- Modified Section 5.2.3.1 Prior therapy to be consistent with changes to Inclusion Criteria 3 and 5. Rationale: *To be consistent with the update to Inclusion Criteria 3 and 5.*
- Modified Section 5.2.3.2 Concomitant Therapy to add additional safety guidelines regarding sun exposure. Rationale: *To provide updated* guidelines regarding sun exposure *and to* maintain consistent with the Toxicity Management language in Section 6.1.8.2.  
- Modified Section 5.3.1.1 Study Procedures, Vital signs, to address weight increases of 5% or greater and add 'actual' prior to 'weight.' Rationale: *To ensure accurate determination of dose in the event of blinded* investigational product-related weight gain due to fluid retention 4
- Modified Section 5.3.1.1 Study Procedures, Echocardiogram, the following language has been changed: 'Echocardiograms will be performed per Appendix C, Study Activities to **rule out** pericardial effusion (**or assess**, if present), as well as **assess** cardiac function (left ventricular ejection fraction, LVEF).' Rationale: *Clarifying the purpose of on-study Echocardiograms.*
- Modified Section 5.3.1.1 Study Procedures, Disease/Response Assessment
(Radiographic Imaging), language has been added to advise sites on the need to discuss with TA MD regarding the gaps between tumor assessments and doses in certain cases of dose delays. Rationale: *Modified to address the planning of CTs in cases of treatment* delays.  
- Modified Section 5.3.1.1 Study Procedures, MRI/CT of the Brain and Footnote t under Appendix C to clarify that the MRI/CT of the brain is required at screening and when clinically indicated thereafter. Rationale: *Modified to clarify when MRI/CT of the brain is required on study.*
- Modified Section 5.3.1.1 Study Procedures, Fluid Retention Questionnaire
(Including Subject Daily Weight), the following language has been added: 'The site will advise subjects to contact the site in cases where sudden weight gain **(5% or greater)** is observed for possible assessment in the clinic.' Rationale: *Modified to clarify the definition of weight gain that requires* additional assessment by the site.  
- Modified Section 5.3.1.1 Study Procedures, End of Treatment (EOT) Visit, the following language has been added: 'The EOT procedures should be done within 7 days of documented decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.' Rationale: *Modified to fix conflicted language in the protocol.*
- Modified Section 5.3.3.2 Primary Variables to add '…determined by a Central Radiographic Assessment Committee (CRAC) **per RECIST v. 1.1** and overall survival (OS) in DLL3high **population.'**
Rationale: To clarify the version of RECIST used for this study and to clarify that the DLL3high subjects are analyzed.  
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- Modified Section 5.5.1 Treatment Administration to add 'placebo' after
'dexamethasone' in the last sentence of the first paragraph Rationale: *Modified to be consistent with the rest of the paragraph.*
- Modified Section 5.5.2.1 Packing and Labeling, Rovalpituzumab Tesirine and Placebo to include updated Hazardous Drug packing and shipping standards. Rationale: Added to clarify packaging and shipping requirements as per applicable regulations.  
- Modified Section 5.5.2.2 Storage and Disposition of Blinded Investigational Product(s) and Section 5.5.2.3 Preparation/Reconstitution of Dosage Form(s) to note specific instructions for reconstituted and diluted IP will be found in an outside document. Rationale: Site awareness for a separate document that contains additional information on IP storage and disposition.  
- Modified Section 5.5.4.1 Dosing to add fluid retention weight gain guidance.  
Rationale: *To instruct sites on cases of weight gain due to fluid retention.*
- Modified Table 5 to include:  
| Grade 2 pneumonitis   | Reduce dose to 0.1 mg/kg   | Discontinue Rova-T   |
|-----------------------|----------------------------|----------------------|
| Grade ≥ 3 pneumonitis | Discontinue Rova-T         | N/A                  |
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- addition of footnote b.

Rationale: Update dose modification guidelines to align with safety profile for Rova-T as described in the IB v.7.  
- Modified Section 5.5.5.2 Blinding of Data for Independent Data Monitoring Committee (IDMC) to update the change from an interim analysis to a futility analysis. Rationale: *To align with the updated statistical plan.*
- Modified Section 5.5.7 Drug Accountability to update classification of Rova-T
as a dangerous good/hazardous material. Rationale: *Added to clarify classification as well as packaging and shipping* requirements as per applicable regulations.  
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- Modified Section 6.1.1.3 to update guidance on capturing disease progression and fatal events for AEs and SAEs in the CRF. Rationale: *To clarify on AE/SAE reporting regarding events due to disease* progression.  
- Modified Section 6.1.4 Deaths to add language about capturing these events in the CRF. Rationale: To provide guidance on capturing deaths during AE/SAE reporting period in EDC.  
- Modified Section 6.1.5 Adverse Event Collection Period, to say 'All adverse events reported from the time of blinded investigational product administration until 70 days following **the last dose** of blinded investigational product will be collected, whether solicited or spontaneously reported by the subject.' Rationale: *To clarify AE collection period from last dose of blinded IP.*
- Modified Section 6.1.6 Adverse Event Reporting to update the emergency contact for the study and add updated language regarding SUSARs and guidelines for the Reference Safety Information (RSI). Rationale: Modification of the emergency contact for the study and current information regarding SUSAR reporting.  
- Modified Section 6.1.8 Toxicity Management to add additional safety guidance on serosal effusions, skin reactions, edema, and pneumonitis. Rationale: Provide additional guidance to investigators and subjects for awareness and guidance to align with IBv7.  
- Updated Section 7.0 Protocol Deviations-Primary and Alternate contact information. Rationale: *To provide sites with current AbbVie contact information.*
- Modified Section 8.1.3 Efficacy Endpoints and Analyses to delete the first sentence. Rationale: *Align with updated analysis plan as outlined above.*
- Updated Section 8.1.7 to Patient Reported Outcomes (PRO) and add the following language, 'Physical functioning scale score in EORTC QLQ-C30 is the **key secondary** endpoint.' Rationale: Align with updated analysis plan as outlined above.  
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- Changed Section Planned Sensitivity and Subgroup Analysis to 8.1.8 and delete the first, third and last sentence of the section. Rationale: *Align with updated analysis plan as outlined above.*
- Changed Section Pharmacokinetic and Exposure-Response Analyses to 8.1.9.  
Modified Synopsis Section 1.2 Criteria for Evaluation, Pharmacokinetic, Section 5.3.5 Pharmacokinetic Variables and Section 8.1.9 Pharmacokinetic and Exposure-Response Analyses to change 'plasma' to 'serum.' Rationale*: To update numbering in the section of the protocol and align with* the lab manual.  
- Modified Section 8.3 Type I Error Adjustment Procedure for Multiple Testing to include the DLL3high set, update the null hypotheses and level of significance. Figure 3 was also added. This is outlined above in the Synopsis section. Rationale: *Align with updated analysis plan as outlined above.*
- Modified Section 10.1 Source Documents to clarify that the Investigator Awareness date of a SAE should be noted in the source, not the EDC. Rationale: *This data point cannot be captured in the EDC.*
- Added the following addition to References, '19. AbbVie. Rovalpituzumab Tesirine Dear Rova-T Investigator Letter. 05 December 2018.' Rationale: *Added reference due to new safety data.*
- Modified Appendix B: List of Protocol Signatories Rationale: *Updated new team members since last amendment.*
- Modified Appendix C: Echocardiogram. Now a required assessment listed under Screening. Rationale: *To provide a bigger window for sites to complete the assessment.*
- Modified Footnote b under Appendix C to say, 'End of Treatment Visit procedures should be done within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.' Rationale: Updated to be consistent with EOT treatment language.  
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- Modified Footnote e under Appendix C to add the following language,
'Cycle 1 Day 1 procedures, **with the exception of weight**.' Rationale: Updated to clarify when weight should be done to be used for dosing decisions.  
- Modified Footnote n under Appendix C to clarify when Echocardiograms are required throughout the study and in relation to pericardial effusion assessments. Rationale: *To allow for a larger window for the assessment to be completed.*
- Modified Footnote q under Appendix C to advise sites on the need to contact TA MD for the gaps in tumor assessments. Rationale: *Updated to indicate when the TA MD should be consulted.*
- Make administrative changes of typographical errors, minor language and word revision as needed throughout the document. Rationale: *Clarifies and ensures consistency throughout.*
An itemized list of all changes made to this protocol under this amendment can be found in Appendix K.  
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1.2 synopsis

| AbbVie Inc.                                                                                                                                                                                                | Protocol Number: M16-298                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|
| Name of Study Drug: rovalpituzumab tesirine                                                                                                                                                                | Phase of Development: 3                  |
| (Rova-T) Name of Active Ingredient: rovalpituzumab                                                                                                                                                         | Date of Protocol Synopsis: 05 March 2019 |
| tesirine Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab  Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with |                                          |  
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with Extensive Stage Small Cell Lung Cancer (MERU)  
Objectives: Primary  
- To evaluate if rovalpituzumab tesirine improves progression-free survival, assessed by a Central  
Radiographic Assessment Committee (CRAC) according to RECIST v1.1, and overall survival  
in subjects with extensive-stage small cell lung cancer (ED SCLC) tumors with a high level of  
DLL3 expression (DLL3high) who have ongoing clinical benefit (SD, PR, or CR) following  
first-line platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or etoposide) compared to placebo.  
Secondary  
- To evaluate if rovalpituzumab tesirine improves progression-free survival by CRAC and overall  
survival in all randomized subjects compared to placebo.  
- To assess change in patient reported outcomes (PRO) with physical functioning as measured by  
the EORTC QLQ-C30 questionnaire in all randomized subjects compared to placebo.  
Exploratory  
- To evaluate rovalpituzumab tesirine anti-tumor activity by determining objective response rate  
(ORR), clinical benefit rate (CBR), and duration of responses (DOR) by CRAC and Investigator  
assessment in DLL3high and in all randomized subjects.  
- To evaluate if rovalpituzumab tesirine improves progression-free survival by Investigator  
assessment compared to placebo in DLL3high and in all randomized subjects.  
- To assess change from baseline in all patient reported outcomes (PRO) domains (except physical  
functioning) measured by EORTC QLQ-C30/LC13 and EQ-5D-5L.  
- To characterize the pharmacokinetics and incidence of anti-therapeutic antibodies (ATAs)  
against rovalpituzumab tesirine.  
- To evaluate pharmacodynamic and predictive biomarkers in blood and tumor for association  
with sensitivity, efficacy and safety.  
- To explore DLL3 expression in circulating tumor cells (CTCs) for association with efficacy.  
Investigators: Multicenter, International Study Sites: Approximately 300  
Study Population: Subjects with extensive-stage Small Cell Lung Cancer (ED SCLC) with ongoing clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line platinum-based chemotherapy (cisplatin or carboplatin in combination with etoposide or irinotecan).  
10 Number of Subjects to be Enrolled: Up to approximately 740 SCLC subjects, to obtain approximately 480 subjects with DLL3high expression in tumor (DLL3high). DLL3high is defined as ≥ 75% tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC Assay.
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methodology

This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and multicenter study.  
ED SCLC subjects who meet all the inclusion criteria and none of the exclusion criteria, and demonstrate ongoing clinical benefit (SD, PR, or CR) at the completion of 4 cycles of first-line platinum-based chemotherapy (such benefit must be ongoing at the last re-staging assessment prior to randomization), will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg rovalpituzumab tesirine or placebo, and will receive their assigned therapy on Day 1 of each 6-week cycle, omitting every third cycle. Upon completion of first-line chemotherapy, eligible subjects must be offered prophylactic cranial irradiation (PCI), if offering this procedure is not contradictory to country or institutional guidelines. Subjects receiving PCI must complete it prior to randomization into the study. Subjects will also receive 8 mg orally (PO) of dexamethasone or placebo twice daily on Day –1, Day 1, and Day 2 of each 6-week cycle, omitting every third cycle. Randomization will be stratified by RECIST v1.1 response after completion of first-line platinum-based chemotherapy at screening assessment (SD vs. PR/CR), DLL3 expression, (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of central nervous system (CNS) metastases (Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI.  
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs first.  
Diagnosis and Main Criteria for Inclusion/Exclusion:
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main inclusion

1. Subject or the subject's legally acceptable representative must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures and should be willing and able to comply with parameters as outlined in the protocol.  
2. Subject must be ≥ 18 years of age.  
3. Histologically or cytologically confirmed ED SCLC (extensive stage disease at initial diagnosis),
with ongoing clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line platinum-based therapy (cisplatin or carboplatin in combination with etoposide or irinotecan).  
4. Subjects with a history of CNS metastases prior to the initiation of first-line platinum-based chemotherapy must have received definitive local treatment and have documentation of stable or improved CNS disease status based on brain imaging within 28 days prior to randomization, off or on a stable dose of corticosteroids.  
5. Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle of first-line platinum-based chemotherapy 6. Availability of archived or representative tumor material for assessment of DLL3 expression.  
7. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.  
8. Recovery to ≤ Grade 1 of any clinically significant toxicity (excluding alopecia) prior to randomization.  
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diagnosis and main criteria for

9. Subject must have adequate bone marrow, renal and hepatic function as follows:
a. Absolute neutrophil count (ANC) ≥ 1,000/μL
b. Platelet count ≥ 75,000/μL
c. Hemoglobin ≥ 8.0 g/dL
d. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN
(≤ 5× ULN if evidence of hepatic involvement by malignant disease)
f. Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula (Refer to Appendix E).  
g. Albumin ≥ 3g/dL
10. If female, subject must be either postmenopausal as defined as:
- Age > 55 years with no menses for 12 or more months without an alternative medical cause. - Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L.  
OR
- Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).  
OR a Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control, starting at randomization through at least 6 months after the last dose of blinded investigational product.  
If the male subject is sexually active, he must agree, from randomization through at least 6 months after the last dose of blinded investigational product, to practice the protocol specified contraception.  
11. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and a negative urine pregnancy test at randomization.  
Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined in the protocol) at Screening do not require pregnancy testing.
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main exclusion

1. Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint inhibitors, other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, T-cell or other cell-based or biologic therapies, or any other anti-cancer therapy than that described in Inclusion Criteria 3 - 5 for SCLC.  
2. Any disease-directed radiotherapy (except, PCI, palliative radiotherapy to a radiographically documented non-progressing lesion for symptom control, or pre-planned radiotherapy for CNS metastases present prior to start of first-line therapy and non-progressing) after last dose of first-line chemotherapy.  
3. Any significant medical condition including any suggested by screening laboratory findings that in the opinion of the Investigator or Sponsor may place the subject at undue risk from the study.  
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eudract 2016-003503-64

Diagnosis and Main Criteria for Inclusion/Exclusion (Continued): Main Exclusion (Continued):  
4. Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac  
symptoms consistent with New York Heart Association (NYHA) Class III - IV heart failure (refer to Appendix F) within 6 months prior to randomization.  
5. Documented history of capillary leak syndrome.  
6. Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization or earlier history of  
recurrent Grade 2 or higher effusions with ongoing requirement for pericardiocentesis or thoracentesis.  
7. Serious infection within 2 weeks prior to randomization, including any Grade 3 or higher (per NCI  
CTCAE version 4.0) viral, bacterial, or fungal infection.  
8. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study  
or for approximately 6 months after the last dose of blinded investigational product.  
9. Male subject who is considering fathering a child or donating sperm during the study or for  
approximately 6 months after the last dose of blinded investigational product.  
10. Systemic therapy with corticosteroids at > 10 mg/day prednisone or equivalent within 1 week prior to  
randomization.  
11. Subject has a history of active malignancies other than SCLC within the past 2 years prior to study  
entry, with the exception of in situ cancer which was curatively treated.  
12. Any prior exposure to a pyrrolobenzodiazepine (PBD-based)-or indolinobenzodiazepine-based drug,  
prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity or other contraindications to rovalpituzumab tesirine or excipient contained in the drug formulation.  
13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells. Investigational Products: Rovalpituzumab tesirine or Placebo  
Dexamethasone or Placebo  
Doses: Rovalpituzumab tesirine/Placebo: 0.3 mg/kg, Day 1 of each 6-week  
cycle, omitting every third cycle.  
Dexamethasone/Placebo 8 mg orally (PO) twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle.  
Mode of Administration: Rovalpituzumab tesirine/Placebo: Intravenous  
Dexamethasone/Placebo: Oral  
Duration of Treatment: Subjects will receive rovalpituzumab tesirine/placebo in combination with dexamethasone/placebo on Day 1 of a 6-week cycle, omitting every third cycle until disease progression.  
Criteria for Evaluation:  
Efficacy: Efficacy assessments will consist of evaluations for tumor progression using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be based on a Central Radiographic Assessment Committee (CRAC) review of medical images, as outlined in the Schedule of Assessments. Additionally, efficacy will be assessed by overall survival.  
Pharmacokinetic: Serum concentrations of rovalpituzumab tesirine ADC and the presence of antitherapeutic antibodies (ATA) will be determined.  
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criteria for evaluation (continued)

Biomarkers: Pharmacodynamic and predictive biomarker assessments will include analyses of tumor material and circulating tumor cells for DLL3 expression, blood samples for inflammatory, tumor, and soluble markers. Samples may also be used for other nucleic acid or protein based exploratory biomarkers to understand the sensitivity or resistance to rovalpituzumab tesirine and biology of SCLC. Safety: Safety assessments include physical exam, vital signs, body weight, ECOG score, clinical adverse events, laboratory tests (hematology, serum chemistries, urinalysis, and coagulation), ECGs, echocardiogram, fluid retention questionnaire, radiographic images review for fluid retention, and monitoring of concomitant medications.
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patient reported outcome (pro)

Changes in the patient reported outcomes (PROs) EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L from baseline will be assessed.
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statistical methods efficacy

Progression-free survival (PFS) per CRAC and overall survival (OS) in patients with DLL3high ED SCLC
are the two primary efficacy endpoints. To meet global regulatory requirements, a multiple testing strategy will be implemented to control the family-wise type I error (alpha) for comparisons of rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival (PFS) per CRAC in DLL3high patients, overall survival (OS) in DLL3high patients, PFS per CRAC in randomized patients, OS in randomized patients, and physical functioning scale score (EORTC QLQ-C30) in the randomized set. The following null hypotheses are considered:
Two hypotheses in H01 are H01a and H01b.  
H01a: Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in DLL3high set. H01b: Rovalpituzumab tesirine arm is not superior to placebo arm in OS in DLL3high set.  
H02: Rovalpituzumab tesirine arm is not superior to placebo arm in OS in randomized set. H03: Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in randomized set.  
H04: Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning scale score
(EORTC QLQ-C30) in randomized set.  
The null hypotheses will be tested in a fixed sequence of {H01a, H01b, H02, H03, and H04} in order. To maintain the family-wise type I error for the study, the null hypotheses in H01 (H01a and H01b) will be first tested with an alpha-split approach. The one-sided alpha of 0.25% and 2.25% will be assigned for PFS
and OS hypothesis in H01, respectively. Out of one-sided alpha of 2.25% allocated to OS hypothesis
(H01b), the one-sided alpha of 10–6 will be spent for the early look at the OS data for futility analysis. If the hypothesis for PFS in H01 (H01a) is rejected the one-sided alpha of 0.25% will be recycled to the OS hypothesis in H01 (H01b). Hence, the hypothesis for OS in H01 (H01b) will be tested either at a one-sided 2.4999% or one-sided 2.2499% level of significance depending on the PFS hypothesis in H01 a is rejected or not.  
If either PFS or OS endpoint reaches statistical significance, the study is considered positive. No further tests will be performed if the OS endpoint in DLL3high population (H01b) does not reach statistical significance.  
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statistical methods (continued)

The hypothesis in H02 will be tested if the hypothesis in H01b is rejected. If the hypothesis in H02 is rejected, then, either (i) H03 and H04 will be tested sequentially if the PFS endpoint in DLL3high subjects (H01a) is also rejected or (ii) only H04 will be tested if the PFS endpoint in DLL3high subjects (H01a) is not rejected.  
Futility Analysis:
Unblinded interim data will be analyzed and reviewed by the IDMC. A futility analysis will be conducted when approximately 160 deaths in subjects with DLL3high ED SCLC (approximately 50% of the planned deaths) are observed. The trial may be stopped for futility if the estimated Overall Survival Cox HR of Rova-T to Placebo at this analysis exceeds 0.9. The one-sided alpha of 10–6 will be spent for the early look at the efficacy data for futility analysis.
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sample size

There are two primary efficacy endpoints for this study: Progression-free survival (PFS) based on the CRAC and overall survival (OS) in subjects with DLL3high ED SCLC. To maintain the overall 1-sided type I error at a 2.5% for this study, the type I error will be split, assigning 0.25% to progression-free survival and the remaining 2.25% to overall survival. However, the OS endpoint will be tested at a one-sided 2.2499% significance level as a one-sided alpha of 10–6 will be spent for the early look at the OS data for futility analysis. The sample size of the study is primarily determined by the analysis of OS. It is assumed, taking into account the expected patient population for the study, that median overall survival in the placebo and rovalpituzumab tesirine arm will be around 9 months and 13 months, respectively. The increase of median OS in rovalpituzumab tesirine arm corresponds to a hazard ratio of 0.69, i.e., a reduction in the hazard of death by 31%. With all these assumptions, a total of 319 deaths among subjects with DLL3high are needed to achieve a 90% power based on a log-rank test at a one-sided significance level of 0.022499. Assuming a 19-month accrual period and the last enrolled subject followed for 12 months, at least 480 subjects with DLL3high are expected to be randomized (240 subjects in each arm). A total of 740 subjects regardless of DLL3 expression level (including 480 subjects with DLL3high) will enroll in the study, assuming an approximate prevalence of 65% for subjects with DLL3high. For one-sided significance level of 0.022499, it is projected that an observed hazard ratio of 0.799 or less, corresponding to a 2.3 months or greater improvement in median OS, would result in a statistically significant improvement in the primary analysis of OS.  
The primary endpoints of OS and PFS in DLL3high patients will be analyzed at the same time after observing at-least 319 OS event. It is expected at approximately 420 PFS events will be observed at the time of the primary analysis.  
It is assumed, taking into account the expected patient population for the study, that median progressionfree survival for the placebo and rovalpituzumab tesirine arm will be approximately 3 months and 4.5 months, respectively. The increase of median progression-free survival in rovalpituzumab tesirine arm corresponds to a hazard ratio of 0.667. With all these assumptions, a total of 420 PFS events assessed by the CRAC for the subjects with DLL3high are needed to achieve a 91% power based on a logrank test at a one-sided significance level of 0.0025. It is projected that an observed hazard ratio of 0.760 or less, corresponding to approximately 1 month or greater improvement in median PFS, would result in a statistically significant improvement in the PFS.  
15
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eudract 2016-003503-64 statistical methods (continued)

Individual concentrations of rovalpituzumab tesirine ADC will be tabulated and summarized for subjects treated with the active regimen and summary statistics provided. The incidence of ATA will be summarized.  
Biomarkers:
Biomarkers will be measured at baseline and post-treatment and analyses performed to identify markers associated with rovalpituzumab tesirine response, pharmacodynamics, PK, or safety.  
Safety:
The safety of rovalpituzumab tesirine will be assessed by evaluating the study drug exposure, adverse events, all deaths, as well as changes in laboratory determinations and vital sign parameters.  
16  
| 1.3               | List of Abbreviations and Definition of Terms                                                                                 |    |
|-------------------|-------------------------------------------------------------------------------------------------------------------------------|----|
| Abbreviations ADC | Antibody-drug conjugate                                                                                                       |    |
| AE                | Adverse event                                                                                                                 |    |
| ALT               | Alanine aminotransferase                                                                                                      |    |
| ANA               | Anti-nuclear antibodies                                                                                                       |    |
| ANC               | Absolute neutrophil count                                                                                                     |    |
| aPTT              | Activated partial thromboplastin time                                                                                         |    |
| ASCL1             | Achaete-scute homolog 1                                                                                                       |    |
| ASRO              | American Society for Radiation Oncology                                                                                       |    |
| AST               | Aspartate aminotransferase                                                                                                    |    |
| AT                | Aminotransferase                                                                                                              |    |
| ATA               | Anti-therapeutic antibody                                                                                                     |    |
| ATC               | Anatomical therapeutic chemical (codes)                                                                                       |    |
| β-hCG             | Beta-human chorionic gonadotropin                                                                                             |    |
| BUN               | Blood urea nitrogen                                                                                                           |    |
| CBR               | Clinical benefit rate                                                                                                         |    |
| CDSM              | Clinical Drug Supply Management                                                                                               |    |
| CFR               | Code of Federal Regulations                                                                                                   |    |
| CNS               | Central nervous system                                                                                                        |    |
| CR                | Complete response                                                                                                             |    |
| CRAC              | Central Radiographic Assessment Committee                                                                                     |    |
| CRP               | C-reactive protein                                                                                                            |    |
| CSC               | Cancer stem cell                                                                                                              |    |
| CT                | Computerized tomography                                                                                                       |    |
| CTC               | Circulating tumor cell                                                                                                        |    |
| CTCAE             | Common Terminology Criteria for Adverse Events                                                                                |    |
| ctDNA             | Circulating Tumor DNA                                                                                                         |    |
| CYP3A4            | Cytochrome P450 3A4                                                                                                           |    |
| DILI              | Drug-induced liver injury                                                                                                     |    |
| DLL3              | Delta-like protein 3                                                                                                          |    |
| DLL3high          | DLL3 high expression in tumor defined as ≥ 75% tumor cells staining  positive according to the VENTANA DLL3 (SP347) IHC Assay | 17 |
untitled h1
eudract 2016-003503-64

| EudraCT 2016-003503-64   |                                                            |    |
|--------------------------|------------------------------------------------------------|----|
| DNA                      | Deoxyribonucleic acid                                      |    |
| DOR                      | Duration of response                                       |    |
| ECG                      | Electrocardiogram                                          |    |
| ECOG                     | Eastern Cooperative Oncology Group                         |    |
| eCRF                     | electronic Case Report Form                                |    |
| EDC                      | Electronic data capture                                    |    |
| ED SCLC                  | Extensive-stage disease small cell lung cancer             |    |
| EFNS                     | European Federation of Neurological Societies              |    |
| EGF                      | Epidermal growth factor                                    |    |
| EORTC                    | European Organization for Research and Treatment of Cancer |    |
| EOT                      | End of Treatment                                           |    |
| EQ-5D-5L                 | EuroQoL Five Dimensions Questionnaire                      |    |
| ESMO                     | European Society for Medical Oncology                      |    |
| ESR                      | Erythrocyte sedimentation rate                             |    |
| EU                       | European Union                                             |    |
| FDA                      | US Food and Drug Administration                            |    |
| FSH                      | Follicle-stimulating hormone                               |    |
| GCP                      | Good Clinical Practice                                     |    |
| Gy                       | Gray                                                       |    |
| HDPE                     | High-density polyethylene                                  |    |
| HIPAA                    | Health Insurance Portability and Accountability Act        |    |
| HR                       | Hazard ratio                                               |    |
| ICF                      | Informed consent form                                      |    |
| ICH                      | International Council for Harmonisation                    |    |
| IDMC                     | Independent Data Monitoring Committee                      |    |
| IEC                      | Independent Ethics Committee                               |    |
| IHC                      | Immunohistochemistry                                       |    |
| IL                       | Interleukin                                                |    |
| IMP                      | Investigational Medicinal Product                          |    |
| INR                      | International normalized ratio                             |    |
| IRB                      | Institutional Review Board                                 |    |
| IRT                      | Interactive response technology                            |    |
| IUD                      | Intrauterine device                                        |    |
| IV                       | Intravenous(ly)                                            | 18 |  
| JSMO    | Japanese Society of Medical Oncology         |    |
|---------|----------------------------------------------|----|
| LCNEC   | Large cell neuroendocrine cancer             |    |
| LDH     | Lactate dehydrogenase                        |    |
| LD SCLC | Limited-stage disease small cell lung cancer |    |
| LFT     | Liver function test                          |    |
| LVEF    | Left ventricular ejection fraction           |    |
| MedDRA  | Medical Dictionary for Regulatory Activities |    |
| MRI     | Magnetic resonance imaging                   |    |
| MTD     | Maximum tolerated dose                       |    |
| nAb     | Neutralizing antibodies                      |    |
| NASH    | Non-alcoholic steatohepatitis                |    |
| NCCN    | National Comprehensive Cancer Network        |    |
| NCI     | National Cancer Institute                    |    |
| NEUROD1 | Neurogenic differentiation 1                 |    |
| NSAID   | Non-steroidal anti-inflammatory drug         |    |
| NSE     | Neuron-specific enolase                      |    |
| NYHA    | New York Heart Association                   |    |
| ORR     | Objective response rate                      |    |
| OS      | Overall survival                             |    |
| PBD     | Pyrrolobenzodiazepine                        |    |
| PCI     | Prophylactic cranial irradiation             |    |
| PD      | Progressive disease                          |    |
| PDX     | Patient-derived xenografts                   |    |
| PET     | Positron emission tomography                 |    |
| PFS     | Progression-free survival                    |    |
| PK      | Pharmacokinetics                             |    |
| PO      | Per os (by mouth)                            |    |
| PR      | Partial response                             |    |
| PRO     | Patient reported outcome                     |    |
| PT      | Prothrombin time                             |    |
| PTFU    | Post-treatment follow up                     |    |
| q6wk    | Every 6 weeks                                |    |
| RECIST  | Response Evaluation Criteria in Solid Tumors |    |
| RF      | Rheumatoid factor                            | 19 |  
| Rova-T   | Rovalpituzumab tesirine                         |
|----------|-------------------------------------------------|
| RPTD     | Recommended Phase 2 dose                        |
| SAE      | Serious adverse event                           |
| SAP      | Statistical analysis plan                       |
| SC-DR002 | DNA cross-linking agent also known as D6.5      |
| SC16     | Humanized DLL3-specific IgG1 antibody           |
| SCLC     | Small cell lung cancer                          |
| SD       | Stable disease                                  |
| SIADH    | Syndrome of Inappropriate Anti-Diuretic Hormone |
| SMPC     | Summary of product characteristics              |
| SPF      | Sun protection factor                           |
| SUSAR    | Suspected Unexpected Serious Adverse Reactions  |
| TBL      | Total bilirubin                                 |
| TEAE     | Treatment-emergent adverse event                |
| TIC      | Tumor-initiating cells                          |
| TNM      | Tumor, node, metastases                         |
| TTP      | Time to progression                             |
| ULN      | Upper limit of normal                           |
| VA       | Veterans Administration                         |
| VEGF     | Vascular endothelial growth factor              |
| WHODRUG  | World Health Organization Drug (Dictionary)     |
| WOCBP    | Women of childbearing potential                 |  
| 2.0       | Table of Contents                                                                          |
|-----------|--------------------------------------------------------------------------------------------|
| 1.0       | Title Page 1                                                                               |
| 1.1       | Protocol Amendment: Summary of Changes 2                                                   |
| 1.2       | Synopsis 10                                                                                |
| 1.3       | List of Abbreviations and Definition of Terms 17                                           |
| 2.0       | Table of Contents 21                                                                       |
| 3.0       | Introduction 26                                                                            |
| 3.1       | Small Cell Lung Cancer 26                                                                  |
| 3.2       | Delta-Like Protein 3 26                                                                    |
| 3.3       | Rovalpituzumab Tesirine 27                                                                 |
| 3.4       | Differences Statement 29                                                                   |
| 3.5       | Benefits and Risks 29                                                                      |
| 4.0       | Study Objectives 30                                                                        |
| 5.0       | Investigational Plan 32                                                                    |
| 5.1       | Overall Study Design and Plan: Description 32                                              |
| 5.2       | Selection of Study Population 33                                                           |
| 5.2.1     | Inclusion Criteria 34                                                                      |
| 5.2.2     | Exclusion Criteria 36                                                                      |
| 5.2.3     | Prior and Concomitant Therapy 38                                                           |
| 5.2.3.1   | Prior Therapy 38                                                                           |
| 5.2.3.2   | Concomitant Therapy 39                                                                     |
| 5.2.3.2.1 | Allowed Concomitant Therapy 39                                                             |
| 5.2.3.3   | Prohibited Therapy 41                                                                      |
| 5.2.4     | Contraception Recommendations 41                                                           |
| 5.3       | Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic and  Safety Assessments/Variables 42 |
| 5.3.1     | Efficacy and Safety Measurements Assessed and Flow Chart 42                                |
| 5.3.1.1   | Study Procedures 43                                                                        |
| 5.3.1.2   | Collection and Handling of Biomarker and Optional Exploratory  Research Samples 55         |
| 5.3.2     | Drug Concentration Measurements 58                                                         |
| 5.3.2.1   | Collection of Samples for Analysis 5821                                                    | EudraCT 2016-003503-64  
| EudraCT 2016-003503-64   |                                                                       |
|--------------------------|-----------------------------------------------------------------------|
| 5.3.2.2                  | Handling/Processing of Samples 58                                     |
| 5.3.2.3                  | Disposition of Samples 58                                             |
| 5.3.2.4                  | Measurement Methods 59                                                |
| 5.3.3                    | Efficacy Variables 59                                                 |
| 5.3.3.1                  | Definition of Disease Progression 59                                  |
| 5.3.3.2                  | Primary Variables 59                                                  |
| 5.3.3.3                  | Secondary Variables 60                                                |
| 5.3.3.4                  | Exploratory Variables 60                                              |
| 5.3.4                    | Safety Variables 60                                                   |
| 5.3.5                    | Pharmacokinetic Variables 61                                          |
| 5.3.6                    | Biomarker and/or Optional Exploratory Research Variables 61           |
| 5.4                      | Removal of Subjects from Therapy or Assessment 62                     |
| 5.4.1                    | Discontinuation of Individual Subjects 63                             |
| 5.4.2                    | Discontinuation of Entire Study 64                                    |
| 5.5                      | Treatments 64                                                         |
| 5.5.1                    | Treatments Administered 64                                            |
| 5.5.2                    | Identity of Investigational Product(s) 65                             |
| 5.5.2.1                  | Packaging and Labeling 65                                             |
| 5.5.2.2                  | Storage and Disposition of Blinded Investigational Product(s) 66      |
| 5.5.2.3                  | Preparation/Reconstitution of Dosage Form(s) 67                       |
| 5.5.3                    | Method of Assigning Subjects to Treatment Arms 67                     |
| 5.5.4                    | Selection and Timing of Dose for Each Subject 68                      |
| 5.5.4.1                  | Dosing 68                                                             |
| 5.5.4.2                  | Dose Modifications 68                                                 |
| 5.5.4.2.1                | Dose Treatment Delays due to Toxicity or Progression 68               |
| 5.5.4.2.2                | Dose Reduction Guidelines 69                                          |
| 5.5.5                    | Blinding 72                                                           |
| 5.5.5.1                  | Blinding of Investigational Product 72                                |
| 5.5.5.2                  | Blinding of Data for Independent Data Monitoring Committee  (IDMC) 72 |
| 5.5.6                    | Treatment Compliance 72                                               |
| 5.5.7                    | Drug Accountability 73                                                |
| 5.6                      | Discussion and Justification of Study Design 7422                     | EudraCT 2016-003503-64  
| EudraCT 2016-003503-64   |                                                               |
|--------------------------|---------------------------------------------------------------|
| 5.6.1                    | Discussion of Study Design and Choice of Control Groups 74    |
| 5.6.2                    | Appropriateness of Measurements 74                            |
| 5.6.3                    | Suitability of Subject Population 75                          |
| 5.6.4                    | Selection of Doses in the Study 75                            |
| 6.0                      | Complaints 75                                                 |
| 6.1                      | Medical Complaints 76                                         |
| 6.1.1                    | Definitions 76                                                |
| 6.1.1.1                  | Adverse Event 76                                              |
| 6.1.1.2                  | Serious Adverse Events 77                                     |
| 6.1.1.3                  | Adverse Events Expected Due to SCLC or Progression of SCLC 78 |
| 6.1.2                    | Adverse Event Severity 79                                     |
| 6.1.3                    | Relationship to Study Drug 79                                 |
| 6.1.4                    | Deaths 80                                                     |
| 6.1.5                    | Adverse Event Collection Period 81                            |
| 6.1.6                    | Adverse Event Reporting 82                                    |
| 6.1.7                    | Pregnancy 84                                                  |
| 6.1.8                    | Toxicity Management 84                                        |
| 6.1.8.1                  | Management of Serosal Effusions/Serositis 85                  |
| 6.1.8.2                  | Management of Skin Reactions 85                               |
| 6.1.8.3                  | Management of Potential Drug-Induced Liver Injury 87          |
| 6.1.8.4                  | Monitoring and Management of Edema 89                         |
| 6.1.8.5                  | Pneumonitis 91                                                |
| 6.2                      | Product Complaint 92                                          |
| 6.2.1                    | Definition 92                                                 |
| 6.2.2                    | Reporting 92                                                  |
| 7.0                      | Protocol Deviations 93                                        |
| 8.0                      | Statistical Methods and Determination of Sample  Size 94      |
| 8.1                      | Statistical and Analytical Plans 94                           |
| 8.1.1                    | Disposition of Study Subjects 95                              |
| 8.1.2                    | Demographics and Baseline Characteristics 95                  |
| 8.1.3                    | Efficacy Endpoints and Analyses 95                            |
| 8.1.4                    | Primary Efficacy Endpoints 9623                               | EudraCT 2016-003503-64  
| EudraCT 2016-003503-64   |                                                                             |
|--------------------------|-----------------------------------------------------------------------------|
| 8.1.5                    | Secondary Efficacy Endpoints 97                                             |
| 8.1.6                    | Exploratory Efficacy Endpoints 97                                           |
| 8.1.7                    | Patient Reported Outcomes (PRO) 98                                          |
| 8.1.8                    | Planned Sensitivity and Subgroup Analyses 99                                |
| 8.1.9                    | Pharmacokinetic and Exposure-Response Analyses 99                           |
| 8.2                      | Safety Analyses 100                                                         |
| 8.2.1                    | Treatment-Emergent Adverse Events (TEAEs) 100                               |
| 8.2.2                    | Clinical Laboratory Evaluation 101                                          |
| 8.2.3                    | Vital Signs 101                                                             |
| 8.2.4                    | ECOG Performance Status 101                                                 |
| 8.2.5                    | Electrocardiogram 101                                                       |
| 8.2.6                    | Concomitant Medications 101                                                 |
| 8.3                      | Type I Error Adjustment Procedure for Multiple Testing 101                  |
| 8.4                      | Determination of Sample Size 105                                            |
| 8.5                      | Futility Analysis 106                                                       |
| 8.6                      | Accrual/Study Duration Considerations 106                                   |
| 8.7                      | Randomization Methods 107                                                   |
| 9.0                      | Ethics 107                                                                  |
| 9.1                      | Independent Ethics Committee (IEC) or Institutional Review  Board (IRB) 107 |
| 9.2                      | Ethical Conduct of the Study 108                                            |
| 9.3                      | Subject Information and Consent 108                                         |
| 9.3.1                    | Informed Consent Form and Explanatory Material 109                          |
| 9.3.2                    | Revision of the Consent Form and Explanatory Material 109                   |
| 10.0                     | Source Documents and Case Report Form  Completion 110                       |
| 10.1                     | Source Documents 110                                                        |
| 10.2                     | Case Report Forms 110                                                       |
| 11.0                     | Data Quality Assurance 112                                                  |
| 12.0                     | Use of Information 112                                                      |
| 13.0                     | Completion of the Study 113                                                 |
| 14.0                     | Investigator's Agreement 114                                                |
| 15.0                     | Reference List 11524                                                        |
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list of tables

| Table 1.   | Examples of Strong CYP3A4 Inhibitors 41                            |
|------------|--------------------------------------------------------------------|
| Table 2.   | Clinical Laboratory Tests 49                                       |
| Table 3.   | Identity of Investigational Products 65                            |
| Table 4.   | Dose Reductions for Blinded Investigational Product (IP) 70        |
| Table 5.   | Dose Reductions and Discontinuation for Unacceptable Toxicities 71 |
| Table 6.   | Recommended Management of Photosensitivity 87                      |
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list of figures

| Figure 1.   | Study Schema 33                                                         |
|-------------|-------------------------------------------------------------------------|
| Figure 2.   | Adverse Event Collection 81                                             |
| Figure 3.   | Diagram of Hierarchical Testing of Primary and Secondary  Endpoints 104 |
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list of appendices

25  
| Appendix A.   | Responsibilities of the Clinical Investigator 117                                    |
|---------------|--------------------------------------------------------------------------------------|
| Appendix B.   | List of Protocol Signatories 119                                                     |
| Appendix C.   | Study Activities 120                                                                 |
| Appendix D.   | Performance Status Scales Conversion 127                                             |
| Appendix E.   | Calculated Creatinine Clearance Using Modified Cockcroft-Gault  Equation 128         |
| Appendix F.   | New York Heart Association Classification 129                                        |
| Appendix G.   | Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1  for Tumor Response 130 |
| Appendix H.   | CTCAE v 4.0 Grading of Relevant AEs 137                                              |
| Appendix I.   | Fluid Retention Questionnaire 142                                                    |
| Appendix J.   | Adverse Events Expected Due to SCLC or Progression of SCLC 144                       |
| Appendix K.   | Protocol Amendment: List of Changes 146                                              |
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3.0 introduction 3.1 small cell

Small cell lung cancer (SCLC) is an important unmet medical need, representing 15 –
20% of the 220,000 annual new cases of lung cancer.1,2 SCLC arises from epithelial cells with neuroendocrine differentiation. Historically, SCLC has been staged using the Veterans Administration (VA) staging system as limited versus extensive stage disease, the former being defined as disease limited to the chest that can be encompassed by a radiation field while the latter includes all other cases. Approximately one-third of newly diagnosed patients will have limited stage disease while the rest will be extensive. Systemic chemotherapy remains the cornerstone of therapy for all stages of SCLC. Standard initial chemotherapy for all patients with a suitable performance status consists of a platinum salt (carboplatin or cisplatin) in combination with a second agent, usually etoposide or irinotecan. For patients with limited stage disease, concurrent or sequential involved-field thoracic radiotherapy is indicated. Response rates to initial therapy are high, ranging from 70 - 90% for limited stage and 60 - 70% for extensive stage; however, responses are typically not durable and recurrence rates are high in the limited stage disease and nearly universal in the extensive stage disease, leading to median survivals of 14 - 20 months and 9 - 11 months, respectively.3 Extensive stage disease subjects achieving SD or better during first-line platinum-based therapy have median progression-free survival (PFS) of approximately 2.1 - 2.3 months and median OS of approximately 6.9 - 8.9 months from the completion of first-line therapy.4,5 Exploration of clinical benefit maintenance strategies in extensive disease SCLC with the goal of prolonging PFS and OS after completion of first-line standard therapies is therefore warranted. Delta-like protein 3 (DLL3) is an atypical, inhibitory ligand of the Notch receptor family, discovered by AbbVie Stemcentrx scientists as a novel therapeutic target in SCLC and 26 other high-grade neuroendocrine carcinomas. It was identified by whole transcriptome sequencing of tumor initiating cells (TICs) isolated from SCLC and large cell neuroendocrine cancer (LCNEC) patient-derived xenografts (PDXs), and found to be expressed in the majority of SCLC and LCNEC tumors, but with no detectable protein expression in normal tissues or non-neuroendocrine tumor types.6 DLL3 has been implicated in the regulation of cell fate decisions during development, and likely acts as an oncogene in high-grade neuroendocrine tumors where it is a downstream transcriptional target of the achaete-scute homolog 1 (ASCL1) transcription factor in SCLC tumor cells, and acts to inhibit the Notch receptor pathway, thereby facilitating neuroendocrine tumorigenesis.6-8
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3.3 rovalpituzumab tesirine

Rovalpituzumab tesirine (SC16LD6.5) is a DLL3-targeted antibody-drug conjugate (ADC) consisting of the humanized DLL3-specific IgG1 monoclonal antibody SC16; the DNA cross-linking agent SC-DR002 (D6.5); and a protease-cleavable linker that covalently links SC DR002 to SC16. The primary mechanism of rovalpituzumab tesirine is binding of the ADC to DLL3 on target-expressing cells, followed by internalization of the ADC-DLL3 complex and release of SC-DR002 via proteolytic cleavage in late endosomes. Interstrand crosslinks of cellular DNA induced by intercalated SC-DR002 leads to cellular cytotoxicity. In the Phase 1 first in human study of rovalpituzumab tesirine (Study SCRX16-001), the best overall response (confirmed) for all SCLC subjects (dose escalation, retreatment, and maintenance cohorts) was retrospectively assessed by the Independent Review Committee (IRC) by RECIST v1.1 criteria. The ORR (confirmed) was 16% (95% CI: 7.35, 27.42), with 12% achieving PR. The clinical benefit rate (CBR) was 59% (95% CI: 44.93, 71.40). The median duration of response by the IRC was 1.7 months (95% CI: 0.03, 3.06). The median progression-free survival by the IRC was 3.0 months (95% CI: 2.56, 3.84), with a probability of progression-free survival at 12 weeks of 52% (95% CI: 39, 63). The median overall survival was 4.3 months (95% CI: 3.22, 5.65). The probability of overall survival at 12 weeks was 69% (95% CI: 52, 81). In DLL3-positive (≥ 1%
27 tumor cells staining positive for DLL3 with murine anti-DLL3 antibody assay) subjects, the ORR was 23% (95% CI: 10.42, 40.14), and the CBR was 77% (95% CI: 59.86, 89.58). A slightly higher ORR (27%) and CBR (87%) were observed in DLL3-high (≥ 50% tumor cells staining positive for DLL3 with murine anti-DLL3 antibody assay) subjects. In the Phase 2 Study SCRX001-002 (TRINITY) in patients with SCLC recurrent after at least two systemic chemotherapy regimens, rovalpituzumab tesirine dosed at 0.3 mg/kg every 6 weeks for two cycles (with an option for additional two cycles upon progression occurring ≥ 12 weeks after the second dose) resulted in the following:
- In DLL3high (Ӌ 75% tumor cells staining positive for DLL3 with VENTANA
Rabbit IHC (SP347) DLL3 assay) subjects, ORR of 14% per IRC assessment, median OS of 5.7 months and median PFS of 3.8 months
- In DLL3high subjects, the clinical benefit rate was 74% with a median duration of clinical benefit of 3.0 months per IRC assessment Additionally, DLL3 positive (≥ 25% tumor cells staining positive for DLL3 with VENTANA Rabbit IHC (SP347) DLL3 assay) and DLL3high groups had comparable response rates given highly overlapping populations where approximately 85% of DLL3 positive subjects were also DLL3high.  
In December 2018, enrollment in Study M16-289 TAHOE ("A Randomized, Open-Label, Multicenter, Phase 3 Study of Rovalpituzumab Tesirine Compared with Topotecan for Subjects with Advanced or Metastatic DLL3high Small Cell Lung Cancer (SCLC) who have First Disease Progression During or Following Front-Line Platinum-Based Chemotherapy") was discontinued at the recommendation of the Independent Data Monitoring Committee (IDMC) after review of available efficacy data which demonstrated shorter overall survival in the rovalpituzumab tesirine arm compared with the topotecan control arm. At the time enrollment was halted, 444 DLL3high (≥ 75%
tumor cells staining positive for DLL3 with VENTANA Rabbit IHC (SP347) DLL3 assay) subjects had enrolled on the trial. The IDMC recommended that investigators and 28 subjects make individual decisions as to whether or not to continue treatment based on patient level response. The results of the TAHOE study did not adversely impact the safety profile for rovalpituzumab tesirine.19
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3.4 differences statement

This is the first randomized, double-blind, multicenter, Phase 3 study comparing rovalpituzumab tesirine versus placebo as maintenance therapy following first-line platinum-based therapy in subjects with extensive-stage SCLC.
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3.5 benefits and risks

Although response rates to first-line platinum-based chemotherapy in ED SCLC are high, SCLC nearly invariably recurs, which may be attributed to the relative resistance of cancer stem cells (CSCs)/TICs to conventional chemotherapy. Rovalpituzumab tesirine has been found to reduce the frequency of TICs in low passage SCLC patient-derived xenograft models significantly more than platinum-based SOC therapy.6 By targeting this resistant, residual cell population, rovalpituzumab tesirine has a unique mechanistic rationale for benefit in post-chemotherapy maintenance setting. Rovalpituzumab tesirine had shown promising clinical activity in subjects with recurrent/relapsed SCLC (Section 3.3), and it is likely that the observed benefit will translate into maintenance setting. This study will assess the efficacy, tolerability, and safety of rovalpituzumab in subjects with extensive-stage SCLC who have ongoing clinical benefit (SD, PR, or CR) following first-line platinum-based chemotherapy (cisplatin or carboplatin in combination with etoposide or irinotecan). As of 30 June 2018, 1246 subjects have received study medication in the rovalpituzumab tesirine clinical program; an estimated 1039 subjects (with SCLC or other DLL3expressing solid tumors) have received at least 1 dose of rovalpituzumab tesirine at doses ranging from 0.05 mg/kg to 0.8 mg/kg on a q3w schedule and 0.3 mg/kg to 0.4 mg/kg on a q6w schedule.  
29 Among subjects with SCLC treated with rovalpituzumab tesirine 0.3 mg/kg q6w, 96.8% of subjects reported at least 1 adverse event. The most frequently reported adverse events among subjects with SCLC treated with rovalpituzumab tesirine 0.3 mg/kg q6w were decreased appetite (28.0%), photosensitivity reaction (27.7%), oedema peripheral (27.2%), dyspnoea (26.6%), and nausea (25.6%). Important identified risks following treatment with rovalpituzumab tesirine include: pleural effusions (33.9%), pericardial effusions (16.7%), generalized edema (2.7%) and photosensitivity reactions (27.7%). Important potential risks following treatment with rovalpituzumab tesirine include pneumonitis (1%). The following adverse events of special interest have also been identified: cutaneous reactions (48.7%), thrombocytopenia and hemorrhage events (28%), edema (33.8%), hypoalbuminemia (16.2%), hepatotoxicity (19.3%), nephrotoxicity (5.9%), anemia (19.7%), neutropenia (9.2%) and infusion related reaction (0.2%). In addition, preclinical toxicology studies conducted in the rat and the cynomolgus monkey have identified bone marrow, lung, and kidney as potential sources of clinical adverse events (AEs) (AbbVie Investigator Brochure v7). Accordingly, safety assessments will include regular assessments at protocol-specified time points of routine physical examination, laboratory and imaging tests including CT/MRI assessments and echocardiograms, a fluid retention questionnaire, and daily weights (Section 5.3.1.1). The timing and frequency of these assessments are designed so that potential rovalpituzumab tesirine-related toxicities are identified prior to additional drug doses, limiting the risk of toxicity exacerbation. The dose delay/reduction/discontinuation protocol guidelines provide additional level of risk mitigation for subjects enrolled in this study. It is thus considered that the study has acceptable benefit/risk profile for subjects with ED SCLC and stable disease or better following completion of four cycles of platinum-based standard front line treatment, taking into account short progression-free and overall survival of these subjects.4
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4.0 study objectives

The primary objective of this study is to evaluate if rovalpituzumab tesirine improves progression-free survival, assessed by CRAC, and overall survival in subjects with 30 extensive-stage SCLC tumors with a high level of DLL3 expression (DLL3high) who have ongoing clinical benefit (SD, PR, or CR) following the completion of 4 cycles of first-line, platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or etoposide) compared to placebo. The secondary objectives are:
- To evaluate if rovalpituzumab tesirine improves progression-free survival by CRAC and overall survival in all randomized subjects compared to placebo.  
- To assess change in patient reported outcomes (PRO) with physical functioning as measured by the EORTC QLQ-C30questionnaire in all randomized subjects compared to placebo.
The exploratory objectives are:
- To evaluate rovalpituzumab tesirine anti-tumor activity by determining objective response rate (ORR), clinical benefit rate (CBR), and duration of responses (DOR) by CRAC and investigator assessment in DLL3high and in all randomized subjects.  
- To evaluate if rovalpituzumab tesirine improves progression-free survival by investigator assessment compared to placebo in DLL3high and in all randomized subjects.  
- To assess change from baseline in all patient reported outcomes (PRO)
domains (except physical functioning) measured by EORTC QLQ-C30/LC13 and EQ-5D-5L.  
- To characterize the pharmacokinetics and incidence of anti-therapeutic antibodies (ATAs) against rovalpituzumab tesirine.
- To evaluate pharmacodynamic and predictive biomarkers in blood and tumor for association with sensitivity, efficacy and safety.  
- To explore the DLL3 expression in circulating tumor cells (CTCs) for association with efficacy.
31
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5.0 investigational plan 5.1 overall

The study is designed to enroll approximately 740 SCLC subjects to obtain approximately 480 subjects with DLL3high expression in tumor (DLL3high) and to meet scientific and regulatory objectives without enrolling an undue number of subjects in alignment with ethical considerations. DLL3high is defined as ≥ 75% tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC Assay. This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and multicenter study. Approximately 300 clinical sites will participate. Eligible subjects will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg rovalpituzumab tesirine or placebo, and will receive their assigned therapy on Day 1 of each 6-week cycle, omitting every third cycle. Subjects will also receive 8 mg orally (PO) of dexamethasone or placebo twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6-week cycle, omitting every third cycle. Subjects will be stratified by RECIST v1.1 response after completion of first-line platinum-based chemotherapy at screening assessment (SD vs. PR/CR), DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of central nervous system (CNS) metastases (Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI. Survival Follow-up will continue until the endpoint of death, the subject becomes lost to follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs first. A schematic of the study is provided in Figure 1, Study Schema.  
32  
  
Arrowheads = blinded investigational product administration; CR = complete response; OS = overall survival; PR = partial response; PTFU = post-treatment follow-up; SD = stable disease 1. Upon completion of first-line platinum-based chemotherapy, eligible subjects must be offered prophylactic cranial irradiation (PCI), if offering this procedure is not contradictory to country or institutional guidelines. Subjects receiving PCI must complete it prior to randomization into the study.  
2. Collection of tumor material for DLL3 testing will be provided any time after the signing of the informed consent and prior to randomization.  
3. Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle of first-line platinum-based chemotherapy.  
On study disease assessments, for the purposes of efficacy assessments will be performed by a Central Radiographic Assessment Committee (CRAC) blinded to study treatment information and independent of Investigators and personnel who are involved in conducting the study (Section 5.3.1.1).
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5.2 selection of study population

Current standard of care after first-line platinum-based chemotherapy consists primarily of observation until disease progression, at which time second line chemotherapy, such as with topotecan, may be instituted. No therapy is approved for use or routinely used as maintenance or consolidation after first-line platinum-based chemotherapy in extensive stage SCLC. Rovalpituzumab tesirine may be beneficial in this setting, but no prior studies have formally explored its potential. Therefore, this study will involve a comparison of rovalpituzumab tesirine against placebo. For the purposes of study eligibility, limited stage disease SCLC (LD-SCLC) is defined as a disease confined to the hemithorax of origin, with or without the involvement of regional lymph nodes, including ipsilateral and contralateral hilar, ipsilateral and contralateral mediastinal, and ipsilateral supraclavicular nodes. Extensive stage disease SCLC (ED-SCLC) is defined as all other SCLC. Subjects must meet all of the inclusion and none of the exclusion criteria to be eligible for this study. Eligibility criteria may not be waived by the Investigator and are subject to review in the event of a Good Clinical Practice (GCP) audit and/or regulatory authority inspection.
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5.2.1 inclusion criteria

1. Subject or the subject's legally acceptable representative must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures and should be willing and able to comply with parameters as outlined in the protocol.  
2. Subject must be ≥ 18 years of age. 3. Histologically or cytologically confirmed ED SCLC (extensive stage disease at initial diagnosis), with ongoing clinical benefit (SD, PR, or CR per RECIST v.1.1)
following completion of 4 cycles of first-line platinum-based therapy (cisplatin or carboplatin in combination with etoposide or irinotecan).  
4. Subjects with a history of CNS metastases prior to the initiation of first-line platinum-based therapy must have received definitive local treatment and have documentation of stable or improved CNS disease status based on brain imaging within 28 days prior to randomization, off or on a stable dose of corticosteroids.  
5. Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle of first-line platinum-based chemotherapy.  
34 6. Availability of archived or representative tumor material for assessment of DLL3 expression.  
7. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (Refer to Appendix D).  
8. Recovery to ≤ Grade 1 of any clinically significant toxicity (excluding alopecia)
prior to randomization.  
9. Subject must have adequate bone marrow, renal and hepatic function as follows:
a. Absolute neutrophil count (ANC) ≥ 1,000/μL b. Platelet count ≥ 75,000/μL c. Hemoglobin ≥ 8.0 g/dL d. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤ 3 × ULN (≤ 5 × ULN if evidence of hepatic involvement by malignant disease)
f. Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula (Refer to Appendix E)
g. Albumin ≥ 3 g/dL
10. If female, subject must be either postmenopausal as defined as:
- Age > 55 years with no menses for 12 or more months without an alternative medical cause.  
- Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L. OR
- Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).  
35 OR a Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control (Section 5.2.4), starting at randomization through at least 6 months after the last dose of blinded investigational product. If the male subject is sexually active, he must agree, from randomization through at least 6 months after the last dose of blinded investigational product, to practice the protocol specified contraception (Section 5.2.4).  
11. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and a negative urine pregnancy test at randomization. Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined in Section 5.2.4) at Screening do not require pregnancy testing.
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rationale for inclusion criteria

1 In accordance with Harmonized Good Clinical Practice (GCP) 2 - 7 To select and/or collect data on the subject population 8 - 9 For the safety of the subjects 10 - 11 The impact of rovalpituzumab tesirine on pregnancy in humans is unknown
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5.2.2 exclusion criteria

A subject will not be eligible for study participation if he/she meets any of the following criteria:
1. Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint inhibitors, other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, T-cell or other cell-based or biologic therapies, or any other anti-cancer therapy than that described in Inclusion Criteria 3 - 5 for SCLC.  
36 2. Any disease-directed radiotherapy (except PCI, palliative radiotherapy to a radiographically documented non-progressing lesion for symptom control, or preplanned radiotherapy for CNS metastases present prior to start of first-line therapy and non-progressing) after last dose of first-line chemotherapy.  
3. Any significant medical condition including any suggested by screening laboratory findings that in the opinion of the Investigator or Sponsor may place the subject at undue risk from the study.  
4. Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III - IV heart failure (refer to Appendix F) within 6 months prior to randomization.  
5. Documented history of capillary leak syndrome. 6. Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization or earlier history of recurrent Grade 2 or higher effusions with ongoing requirement for pericardiocentesis or thoracentesis.  
7. Serious infection within 2 weeks prior to randomization, including any Grade 3 or higher (per NCI CTCAE version 4.0)11 viral, bacterial, or fungal infection.  
8. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study or for approximately 6 months after the last dose of blinded investigational product.  
9. Male subject who is considering fathering a child or donating sperm during the study or for approximately 6 months after the last dose of blinded investigational product.  
10. Systemic therapy with corticosteroids at > 10 mg/day prednisone or equivalent within 1 week prior to randomization.  
11. Subject has a history of active malignancies other than SCLC within the past 2 years prior to study entry, with the exception of in situ cancer which was curatively treated.  
37 12. Any prior exposure to a pyrrolobenzodiazepine (PBD-based) or indolinobenzodiazepine-based drug, prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity or other contraindications to rovalpituzumab tesirine or excipient contained in the drug formulation.  
13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
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rationale for exclusion criteria

1, 10 - 13 To select the appropriate subject population 2 - 7 For the safety of the subjects 8 - 9 The impact of rovalpituzumab tesirine on pregnancy in humans is unknown
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5.2.3 prior and concomitant therapy

Any concomitant medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal supplements) that the subject is receiving at the time of study drug administration or receives during the study through the safety reporting period (Section 6.1.5), must be recorded along with the reason for use, date(s) of administration including start and end dates, and dosage information including dose, route and frequency. Any concomitant therapy given for a protocol-related AE should be recorded from the time of informed consent. The AbbVie TA MD should be contacted if there are any questions regarding concomitant or prior therapies.
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5.2.3.1 prior therapy

Subjects will have received first-line platinum-based chemotherapy consisting of 4 cycles of treatment with combination of either cisplatin or carboplatin with etoposide or 38 irinotecan; administration of Day 1 of the last cycle of first-line chemotherapy must be at least 3 weeks but no more than 9 weeks prior to randomization. Subjects previously treated for LD-SCLC are not eligible. Subjects with central nervous system (CNS) metastases present prior to the initiation of first-line chemotherapy will have completed definitive local treatment (e.g., surgery or radiotherapy). Upon completion of first-line chemotherapy, subjects without a history of CNS metastases must have been offered prophylactic cranial irradiation (PCI), if offering this procedure is not contradictory to country or institutional guidelines. Subjects receiving PCI must complete it prior to randomization into the study. PCI regimen must be consistent with those endorsed by the National Comprehensive Cancer Network (NCCN) or European Society for Medical Oncology (ESMO).
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5.2.3.2 concomitant therapy

All subjects enrolled will receive premedication consisting of dexamethasone/placebo. Refer to Section 5.5.1, Treatments Administered for details. There are no other required concomitant therapies. However, due to the potential for rovalpituzumab tesirine-related skin photosensitivity, patients should be advised to avoid direct and indirect sun exposure as much as possible from Cycle 1 Day 1 until 30 days after the final dose. When sun exposure is unavoidable, patients should wear protective clothing and sunglasses, and use a broad-spectrum sunscreen and lip balm (SPF 30 or greater). Thirty-one to ninety days after last dose of Rova-T/placebo, the patient may resume outdoor activities with appropriate sun protection including broad brimmed hat, protective clothing and sunscreen SPF 30 or higher.
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5.2.3.2.1 allowed concomitant therapy

Standard supportive care for drug-related toxicity is permitted, including growth factors and blood product transfusions per local institutional standards. Other standard supportive care for symptom control or drug-related toxicity is allowed, such as analgesics, anti-emetics, electrolyte replacement, and hydration. Bone modifying agents 39
(e.g., bisphosphonates, denosumab) for bone metastases are also permitted per local institutional standards. Other prescribed medications for non-neoplastic conditions are allowed, as well as vitamins and nutritional supplements. Concomitant prednisone (or equivalent) may be used at a dose of ≤ 10 mg/day. The use of intermittent high-dose corticosteroid treatment to prevent or manage infusion reactions, serosal effusions (see Section 6.1.8.1), or other non-cancer-related symptoms including premedication for known hypersensitivity reactions to contrast for scans is allowed. Routine prophylaxis with vaccines is permitted; however, vaccines used should not contain live micro-organisms. If the subject is taking chronic suppressive anti-infectives (antiviral, antifungal, or antibacterial), appropriate investigation must be completed prior to randomization, and documentation must exclude active infection. After exclusion of active infection, otherwise eligible subjects should complete or continue suppressive anti-infectives as prescribed. If a subject requires palliative radiation during the study (e.g., symptomatic worsening of a bone lesion) diagnostic imaging has to be performed to assess for radiographic progression prior to radiation, and documentation of non-progressive status by radiography will be captured in the eCRF. Any cancer-directed therapy a subject receives due to disease improvement should be discussed with the TA MD in advance, if possible. In the event of isolated CNS-only progression during study treatment, blinded investigational product may be withheld while local treatment is administered (e.g., radiotherapy) in accordance with institutional practice. Blinded investigational product may be restarted 1 week after the completion of local CNS disease-directed therapy.  
40
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5.2.3.3 prohibited therapy

Subjects may not receive other investigational drugs, immunosuppressive medications, radiotherapy, or systemic anti-neoplastic therapy during the study, other than as allowed in Section 5.2.3.2 and Section 5.2.3.2.1. Additionally, strong inhibitors of cytochrome P450 3A4 (CYP3A4) should be avoided (refer to Table 1).  
| Enzyme/Transporter     | Strong Inhibitor Examples10                                                                                                                                                                                                                                                                                                                                                                                                       |
|------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CYP3A4                 | boceprevir, clarithromycin, cobicistat, conivaptan,  danoprevir and ritonavir, diltiazem, elvitegravir  and ritonavir, idelalisib, indinavir and ritonavir,  itraconazole, ketoconazole, lopinavir and ritonavir,  nefazodone, nelfinavir paritaprevir and ritonavir  and (ombitasvir and/or dasabuvir), posaconazole,  ritonavir, saquinavir and ritonavir, telaprevir,  tipranavir and ritonavir, troleandomycin,  voriconazole |
| (CYP) Cytochrome P450. |                                                                                                                                                                                                                                                                                                                                                                                                                                   |
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5.2.4 contraception recommendations

If female, subject must be either postmenopausal or permanently surgically sterile (refer to inclusion criteria for definitions of both) OR a Woman of Childbearing Potential (WOCBP), practicing at least one of the following methods of birth control, on randomization (or earlier) through at least 6 months after the last dose of blinded investigational product.  
- Combined (estrogen and progestogen containing) hormonal contraception
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 1 month prior to randomization.  
- Progestogen-only hormonal contraception (oral, injectable, implantable)
associated with inhibition of ovulation, initiated at least 1 month prior to randomization.  
41
- Bilateral tubal occlusion/ligation. - Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a hysterosalpingogram confirms success of the procedure.  
- Vasectomized partner(s), provided the vasectomized partner has received medical assessment of the surgical success and is the sole sexual partner of the WOCBP trial participant.  
- Intrauterine device (IUD). - Intrauterine hormone-releasing system (IUS). - True abstinence: Refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable).  
If required per local practices, male or female condom with or without spermicide OR cap, diaphragm or sponge with spermicide should be used in addition to one of the birth control methods listed above (excluding true abstinence). Male subjects who are sexually active with a WOCBP, even if the male subject has undergone successful vasectomy, must agree from randomization through at least 6 months after the last dose of blinded investigational product to use condoms and his female partner(s) must use at least one of the contraceptive measures (as defined in the protocol for female study subjects of childbearing potential).  
Male subject agrees not to donate sperm from randomization through at least 6 months after the last dose of blinded investigational product.
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5.3 efficacy pharmacokinetic biomarker pharmacogenetic

Study procedures described are listed in the following section of this protocol and are summarized in tabular format in Appendix C, Study Activities.  
42
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5.3.1.1 study procedures

Unless otherwise stated, the baseline measurement for any given variable will be defined as the last value obtained for the variable prior to the first dose of blinded investigational product. Screening procedures must be performed within 21 days prior to randomization, with the exception of radiographic assessments (CT scan or MRI including the head, chest, and abdomen) which may be performed within 28 days prior to randomization. The collection of tumor material for DLL3 testing will be provided any time after the signing of the informed consent and prior to randomization. Randomization may occur within 3 days prior to C1D1. Subsequent study procedures should be performed within 3 days prior to the scheduled treatment visits, within a ±3 day window during the non-treatment visits, and within a ±1 week window during the post-treatment follow up, and survival follow up phase unless otherwise indicated. The results of all screening and evaluations at the time of randomization must be within clinically acceptable limits, upon review by the investigator, before a subject can be randomized. Subjects will not be randomized in the study if laboratory or other screening results are unacceptable. Subjects are allowed to rescreen and have laboratory samples redrawn to meet eligibility within the same 21 day screening window. Subjects who meet the inclusion criteria and do not meet any of the exclusion criteria may be randomized.
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informed consent

Signed informed consent will be obtained from the subject before any study-specific procedures are undertaken or before any prohibited medications are withheld from the subject in order to participate in this study. Informed consent may be obtained before the 21-day screening window. For the optional tumor biopsy procedure at time of disease progression an optional tumor material biopsy procedure informed consent should be 43 completed. Details about how informed consent will be obtained and documented are provided in Section 9.3. Subjects will be considered screen failures if the informed consent has been signed and a study-specific procedure has been performed (e.g., central laboratories drawn), but subject does not randomize into the study. The reason for screen failure will be documented in the source and will be captured in the eCRF.
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tumor material at screening

For all subjects, archived or fresh tumor material must be submitted to the AbbVie designated central IHC laboratory for determination of DLL3 expression prior to randomization, as per Appendix C, Study Activities. Tumor material testing for DLL3 status may occur at any time after initial diagnosis for subjects who provide consent. These subjects must be registered in IRT. Eligibility will depend on the fulfillment of all other inclusion and exclusion criteria and the trial status (whether the study is still open for accrual). For purposes of the study, "unknown" status is possible if all available samples were tested and failed due to unforeseen technical or logistical reasons; subject with no tumor sample will not be eligible for the trial or subject with sample not fulfilling sponsor's specifications (different method of tissue fixation, known necrotic, too few cells etc.) will not be eligible.
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medical and surgical history (including

The following will be collected during the Screening Visit:
- Medical history, including demographics and documentation of any clinically significant medical condition and/or surgical history
- History of tobacco and alcohol use:
44
- **current smoker** [subject who has > 100 smoking events in their lifetime and has smoked within the last 12 months]
- **past smoker** [subject who has > 100 smoking events in their lifetime and has not smoked in past 12 months]
- **never smoked** [subject with ≤ 100 smoking events in lifetime]
- Detailed oncology history including:
- Histology
- Date of initial cancer diagnosis - TNM Stage at diagnosis, if available - Veterans Administration (VA) Stage at diagnosis - Sites of metastases
- Absence of active CNS metastases will be confirmed by MRI or CT of the brain
- Mutational status, if performed or applicable - Any surgical procedures - Treatments administered (including dates and type of modality)
- Detailed prior and concomitant medication usage including dates of usage and dosing information for all medications and supplements taken Any changes observed from the Screening assessments (prior to dosing) will be recorded in the subject's medical history. At each visit, including the End of Treatment Visit, the subject's medical history will be reviewed and any changes from baseline will be recorded on the adverse event eCRF. All medication (prescription or over-the-counter, including vitamins and/or herbal supplements) will be recorded from the first study drug administration through the 70 days following the last dose of blinded investigational product.
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physical examination

A physical examination will be performed per Appendix C, Study Activities. If the Screening assessment is performed within 21 days of C1D1, it is not required to be repeated on C1D1 unless clinically indicated. Clinically significant changes from baseline will be documented in the source documentation and eCRFs as adverse events. Height will be measured at the Screening visit only. For height assessments, the subject should not wear shoes. Investigators will assess subjects for pleural and pericardial effusion prior to dosing of blinded investigational product on Day 1 of each cycle. Physical exam will include cardiac, pulmonary (including cardiopulmonary exam for serosal effusions), evaluation of extremities for peripheral edema, neurological (sensory, motor, cranial nerves), head and neck, lymphatic, hepatobiliary, gastrointestinal, genitourinary, and skin evaluation per local standard of care.
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vital signs

Vital signs will be performed per Appendix C, Study Activities. Vital signs include actual weight, sitting blood pressure, heart rate and body temperature. If possible, blood pressure and heart rate measurements should not immediately follow scheduled blood collections. Actual weight will be collected in the clinic prior to dosing at each cycle and the recorded weight will be utilized for dosing calculations. For weight assessments, the subject should not wear shoes. In the event of a 5% or greater increase in weight within 2 consecutive visits or compared to baseline which ever has the shorter interval, a prompt workup for fluid retention (e.g., edema, effusions, etc.) should be conducted. If weight gain is due to proven or suspected fluid retention related to study drug, and dosing is not prohibited per Section 5.5.4, dose should be calculated based on actual weight before the event of fluid retention. Vital signs should be collected prior to the infusion.
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12-lead electrocardiogram (ecg)

A resting 12-lead ECG will be performed per Appendix C, Study Activities. ECGs consist of a single 12-lead study performed within a 5-minute window after at least 5 minutes of quiet rest in a supine position. Additional ECG monitoring may occur as clinically indicated during the study. A qualified physician will determine whether any findings outside of normal physiological variation are clinically significant (in consultation with a cardiologist if necessary). The physician will document whether findings are clinically significant (CS) or not clinically significant (NCS) on the tracing and sign and date the tracing. The original annotated ECG tracing containing the physician's assessment will be retained in the subject's records at the study site.
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echocardiogram

Echocardiograms will be performed per Appendix C, Study Activities to rule out pericardial effusion (or assess, if present), as well as assess cardiac function (left ventricular ejection fraction, LVEF).
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ecog performance status

The ECOG performance status will be documented according to Appendix C, Study Activities. Refer to Appendix D, Performance Status Scales Conversion for details.  
If the Screening assessment is performed within 21 days of C1D1, it is not required to be repeated on C1D1 unless clinically indicated.
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documentation of non-childbearing status and

For each female subject, the Investigator will document non-childbearing status (surgically sterile or post-menopausal for at least 1 year) or potential childbearing status.  
47 Should a female study subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating Investigator immediately (Section 6.1.6). For female subjects of childbearing potential, the laboratory will perform pregnancy testing according to Appendix C, Study Activities. A serum pregnancy test will be performed at Screening and the results must be available prior to the administration of the first dose of blinded investigational product on C1D1. Subjects with borderline pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result. Urine pregnancy tests will be performed at Day 1 of each cycle, the Non-Treatment cycle, End of Treatment Visit, and PTFU until 6 months after the last dose of blinded investigational product. Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined in Section 5.2.4) at Screening do not require pregnancy testing. Postmenopausal female subjects ≤ 55 years of age must have an FSH level > 40 IU/L and will have FSH performed at Screening and assessed by the Investigator.
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clinical laboratory tests

Samples for chemistry, hematology, coagulation, and urinalysis will be collected per Appendix C, Study Activities. Specific laboratory assessments are outlined in Table 2, Clinical Laboratory Tests. If the Screening assessment is performed within 7 days of C1D1, it is not required to be repeated on C1D1 unless clinically indicated. Starting at Cycle 2, lab assessments may be performed 3 days prior to Day 1 visits. All laboratory samples will be assessed using a certified central laboratory and these data will be used for all data analysis. The central laboratory will provide instructions regarding the collection, processing, and shipping of samples. All laboratory samples will be shipped to the central laboratory. A qualified (e.g., certification or accreditation) local laboratory may be used to perform laboratory analyses for treatment decisions as per standard of care.  
48 Qualified medical staff at the site will review, initial and date all local and central laboratory results. Any laboratory value outside the reference range that is considered clinically significant by the Investigator will be followed as appropriate. Clinically significant laboratory values will be recorded as adverse events if they meet the criteria as specified in Section 6.1.1.  
| Hematology                                                                                                                                                                                                                                                                                                                    | Clinical Chemistry                                                                                                                                                                                                                                                                                                                    | Urinalysis (Dipstick)                                                                                                                                                                                                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Hematocrit Hemoglobin Red blood cell (RBC) count White blood cell (WBC) count Neutrophils  Bands (if indicated) Lymphocytes Monocytes Basophils (if indicated) Eosinophils (if indicated)  Platelet count (estimate not acceptable) Mean corpuscular volume Mean corpuscular hemoglobin  concentration RBC distribution width | Blood urea nitrogen (BUN) Serum creatinine Total bilirubin Serum glutamic-pyruvic transaminase (SGPT/ALT) Serum glutamic-oxaloacetic transaminase (SGOT/AST) Alkaline phosphatase Sodium Potassium Calcium Inorganic phosphorus Uric acid Total protein Glucose Albumin Magnesium Chloride Amylase Lipase Lactate dehydrogenase (LDH) | Specific gravity Ketones pH Protein Blood Glucose Urobilinogen Bilirubin Leukocyte esterase Serum Pregnancy Test Beta-Human Chorionic  Gonadotropin (β-hCG) (if applicable) Follicle-stimulating hormone  (FSH) (if applicable) |
| Coagulation Activated Partial Thromboplastin Time (aPTT) Prothrombin time (PT) International Normalized Ratio (INR)                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                 |
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table 2. clinical laboratory tests

Treatment response will be assessed by radiographic tumor evaluation per RECIST v1.1 at protocol-specified time points as outlined in the Appendix C, Study Activities.  
Diagnostic quality, spiral CT scan with contrast is recommended for all anatomic areas except brain (MRI is recommended for brain imaging); other CT methods or MRI for respective anatomic areas may be used if performed consistently throughout the study for each individual subject and only under the circumstances described in Appendix G. Scans of the chest and abdomen must be obtained; scans of the neck and pelvis must also be obtained if there is documented or suspected involvement in these regions. Screening radiographic assessment must include brain MRI/CT. Diagnostic/baseline pre-first-line scans through screening scans will be reviewed by the investigator to determine disease response status per RECIST v1.1 for eligibility and stratification. On study disease response will be determined by the Investigator at each assessment according to RECIST v1.1 (Appendix G, Response Evaluation Criteria for Solid Tumors
(RECIST) v 1.1)12 and independently reviewed by Central Radiographic Assessment Committee (described below). Disease/Response Assessment may be performed within 7 days prior to the Day 1 visit. Effusion (pleural, pericardial, etc.) assessments will be performed by a radiologist at each on-study radiographic assessment and any new findings communicated to the Investigator prior to the next dose of blinded investigational product. Effusions should contribute to disease status assessment per RECIST v 1.1 only if confirmed malignant by cytology or otherwise clearly disease-related; if disease progression is suspected solely based on the appearance of new or increase of existing effusions, confirmation of malignant nature of such effusions is strongly recommended due to known adverse event profile of rovalpituzumab tesirine. If collected, effusion fluid must be tested for cytology if disease progression due to appearance/worsening of effusion is suspected. Isolated CNS-only progression will not require removal of the subject from therapy. Refer to Section 5.2.3.2.1, Allowed Concomitant Therapy for details associated with CNS only progression. The EOT assessment may be omitted if the previous assessment was performed within the preceding 6 weeks. Scheduled tumor assessments should not be affected by delays in therapy and/or drug holidays. Subjects will continue to be monitored by the same diagnostic method 50 throughout the study every 6 weeks after randomization, unless evidence of tumor progression warrants otherwise. In some cases, mandatory dose delays due to toxicity will lead to a gap between tumor assessment and dosing. In cases where this gap exceeds 1 week, the TAMD should be contacted for guidance. Subjects who discontinue treatment for reasons other than radiographic disease progression will continue to be followed every 6 weeks from randomization to determine the extent of tumor burden, until disease progression occurs.
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mri/ct of the brain

MRI of the brain will be performed at protocol-specified time points as outlined in Appendix C, Study Activities. Brain MRI may be substituted by CT with intravenous contrast at the discretion of the Investigator. MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS progression is suspected) thereafter.
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central radiographic assessment committee (crac)

In addition to being reviewed by the investigator and/or site staff, radiological scans will be assessed by a Central Radiographic Assessment Committee (CRAC), as outlined in the Appendix C, Study Activities. Sites will collect the appropriate scans and ship by courier or submit electronically to the central facility at each subject's disease assessment. If, in addition to protocol-specified disease assessment modalities other modalities were used to assess disease (e.g., FDG-PET, X-ray), imaging should also be transferred to the central facility. The EOT assessment may be omitted if the previous assessment was performed within the preceding 6 weeks. Subject treatment management will be based on review by the local investigator and/or site staff. The investigator should treat according to clinical judgment and the CRAC will make the definitive decision on tumor response or progression in regards to the PFS endpoint.  
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randomization and subject number assignment

An Interactive Response Technology system (IRT) will be utilized to register subjects. Subjects who complete all Screening procedures and meet the eligibility criteria will proceed to randomization. Refer to Section 5.5.3 for details associated with subject assignment to treatment arms.
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health resource utilization

Health Resource Utilization will be documented at each clinic visit per Appendix C, Study Activities. Information regarding hospitalizations, emergency room visits, and physician office visits will be collected since the last study visit.
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patient reported outcomes (pro)

Health-related quality of life and symptom assessments will be performed per Appendix C, Study Assessments using the EORTC QLQ-C30, the EORTC QLQ-LC13, and the European Quality of Life-5 Dimensions (EQ-5D-5L). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
(EORTC QLQ-C30)13 is used as general cancer-specific instrument. The EORTC QLQ-C30 has 30 items and 5 functional domain scales: Physical, Role, Emotional, Social, and Cognitive; two items evaluate global quality of life. The EORTC QLQ-C30 core questionnaire can be supplemented by the additional lung module EORTC QLQ-LC13, resulting in a 43-item disease and cancer site-specific quality of life and symptom questionnaire. The EORTC QLQ-LC13 module items evaluate symptoms such as cough, haemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or feet, hair loss, and pain. The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) is a generic preference instrument that has been validated in numerous populations. The EQ-5D-5L is composed of 5 questions and a visual analog scale (VAS) assessing overall health that can be converted into a single health status or "utility" score for use in an economic evaluation to adjust life-years gained by the subject's health-related quality of life.  
52
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fluid retention questionnaire (including subject

Throughout the treatment period as outlined in the Appendix C, Study Activities, subjects will be asked about the development of any new or worsening peripheral edema or dyspnea (Appendix I, Fluid Retention Questionnaire). The assessments on Days 8, 15, 29, and 36 may take place by phone, with the site contacting the subject and reviewing the questionnaire. Starting on Day 1 through the EOT visit, subjects will maintain a diary of daily weights (captured on the Fluid Retention Questionnaire). Subjects should be instructed to use a consistent device throughout the study. The site will advise subjects to contact the site in cases where sudden weight gain (5% or greater) is observed for possible assessment in the clinic.
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non-treatment cycle visit

In order to establish 12 weeks of non-treatment after two dosing cycles, every third cycle of treatment should be omitted and a clinic visit conducted, as outlined in Appendix C, Study Activities. The visit should be performed after the Disease Response/Assessment has been conducted and reviewed by the Investigator. The subject should continue to complete the Fluid Retention Questionnaire, including conducting daily weight assessments, and the site should contact the subject weekly during this 42 day nontreatment cycle to review the questionnaire and assess for any adverse events or changes in concomitant medications. The following cycle of treatment may be resumed 42 days ± 3d if the subject has not met any reason for study treatment discontinuation as outlined in Section 5.4.
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end of treatment (eot) visit

The visit at which an investigator identifies disease progression or a subject meets other criteria for study treatment discontinuation will be considered the End of Treatment Visit. The EOT procedures should be done within 7 days of documented decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible. The 53 EOT visit is the last visit during the treatment phase before subjects begin the Post Treatment Follow Up and/or Survival Follow Up phase. The reason(s) for the discontinuation from study treatment will be recorded and assessments will be performed per Appendix C, Study Activities. Disease/Response Assessment, CT/MRI of the brain (if applicable), and submission of scans to the CRAC, may be omitted if performed within the last 6 weeks.
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post-treatment follow up

For all subjects who discontinue study treatment for reasons other than disease progression, the first follow-up visit will occur at 6 weeks (± 1 week) after the last Disease Response/Assessment, then every 6 weeks (± 1 week) until disease progression or initiation of new anti-cancer therapy, whichever occurs first. Refer to Appendix C, Study Activities for details of required assessments. At disease progression, an optional collection of fresh tumor material may be conducted (Section 5.3.1.2, Collection and Handling of Biomarker and Optional Exploratory Research has details regarding Tumor Material at Time of Disease Progression).
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survival follow up (os)

After disease progression or if subjects stop treatment and decline further study radiographic assessments prior to the endpoint of disease progression, subjects will be followed for subsequent anti-cancer therapies (dates and responses), as well as survival status, every 6 weeks* (± 1 week) until the endpoint of death, the subject becomes lost to follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs first (*or as requested by AbbVie to support data analysis). If the subject withdraws from study follow-up, the study staff may use a public information source (such as county records) to obtain information about survival status only, as appropriate per local regulations. Refer to Appendix C, Study Activities for details of required assessments.  
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5.3.1.2 collection and handling of

Blood, tumor material, and serosal fluid will be collected as noted in Appendix C, Study Activities and may be utilized to evaluate known and/or novel markers (nucleic acids, peptides/proteins and/or metabolites) of disease status, related conditions or to evaluate the association with pharmacokinetics, safety or efficacy. Samples will also be utilized for the development of Companion Diagnostics in conjunction with rovalpituzumab tesirine clinical development. The biomarker rationale is discussed in the Biomarker Research Variables Section (Section 5.3.6). All biomarker samples should be labeled and shipped as outlined in the study-specific laboratory manual. AbbVie (or people or companies working with AbbVie) will store the samples in a secure storage space with adequate measures to protect confidentiality. The samples may be retained while research on rovalpituzumab tesirine (or drugs of this class) or this disease and related conditions continues, but for no longer than 20 years after study completion, or per local requirement.
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tumor material at screening

For all subjects, tumor material representative of the qualifying malignancy must be submitted to a central laboratory for determination of DLL3 expression. An archived tumor specimen or fresh tumor material (obtained via on-study biopsy procedure if archival tumor specimen is unavailable) may be used for DLL3 expression evaluation by methods such as but not necessarily limited to immunohistochemistry (IHC). Additional analyses, such as routine hematoxylin and eosin for morphology, IHC for confirmation of diagnosis (e.g., for synaptophysin, chromogranin-A, or CD56), or scoring of immune infiltrates (e.g., IHC for CD3+, CD4+, CD8+, and Foxp3+ cells) may be performed.  
55 Material may also be utilized for exploratory biomarkers research of drug sensitivity, resistance, or disease biology.
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blood (plasma) for inflammatory markers

At the indicated times noted in Appendix C, Study Activities, blood will be collected, processed to plasma for testing of inflammatory markers including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), rheumatoid factor (RF), and ctDNA. On Day 1 (–3 day window is permitted) of each cycle, the collection will be pre-infusion. A sample will also be collected at the EOT or at the time of disease progression.
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blood (serum) for tumor and

At the indicated times noted in Appendix C, Study Activities, blood will be collected, processed as serum for possible testing of tumor-specific biomarkers that may reflect disease burden such as but not necessarily limited to neuron-specific enolase (NSE) and biomarkers that may be related to the pharmacodynamics effects of rovalpituzumab tesirine such as but not necessarily limited to soluble DLL3, circulating chemokines, or cytokines such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), interleukin (IL)-6, or IL-8. Other biomarkers based on emerging science may also be assessed. On Day 1 (–3 day window is permitted) of each cycle, the collection will be pre-infusion. A sample will also be collected at the EOT or at the time of disease progression.
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blood for circulating tumor cells

At the indicated times noted in Appendix C, Study Activities, blood samples will be collected for assessment and characterization of circulating tumor cells (CTCs) as a possible reflection of disease burden and DLL3 expression to study association with efficacy. Whole blood sample will be collected for CTC analysis at pre-dose on Cycle 1 Day 1 (–3 days window is permitted) and EOT only at specific sites based on feasibility.  
56
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serosal fluid

Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) will be procured for possible PK, pharmacodynamic, and/or biomarker testing. See the laboratory manual for additional details.
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pharmacogenetic samples

A whole blood sample for DNA isolation will be collected on Cycle 1 Day 1 (preinfusion) and End of Treatment Visit from each subject. Pharmacogenetic collection should occur unless precluded by local or national regulations or policies. Samples will be shipped frozen to AbbVie or a designated laboratory for DNA extraction and long-term storage. Instructions for the preparation and shipment of the pharmacogenetic exploratory research samples will be provided in a laboratory manual.
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optional exploratory research samples

Subjects will have the option to provide samples for exploratory research. Subjects may still participate in the main study even if they decide not to participate in this optional exploratory research. AbbVie (or people or companies working with AbbVie) will store the exploratory research samples in a secure storage space with adequate measures to protect confidentiality. The samples will be retained while research on rovalpituzumab tesirine (or drugs of this class) or this disease and related conditions continues, but for no longer than 20 years after study completion. The procedure for obtaining and documenting informed consent for exploratory research samples is discussed in Section 9.3.
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tumor material at the time

An optional tumor material collection by biopsy procedure may be obtained at the time of disease progression, from subjects who consent to undergo biopsy procedure to better 57 understand mechanisms of resistance and expression of DLL3. Other nucleic acid or protein based biomarkers related to the response to rovalpituzumab tesirine and SCLC biology may be assessed. Samples will be shipped to AbbVie or a designated laboratory for long-term storage. Instructions for the preparation and shipment of the biomarker exploratory research samples will be provided in a laboratory manual.
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5.3.2 drug concentration measurements 5.3.2.1

Approximately 6 mL of blood will be collected by venipuncture for pharmacokinetic (PK), Anti-therapeutic antibody (ATA), and neutralizing antibodies (nAb) testing as indicated in Appendix C, Study Activities. Two samples will be collected at each treatment cycle. The pre-infusion sample will be collected prior to dosing on Day 1 (–3 days window is allowed) and the second sample will be collected within 60 minutes post-infusion. Only one collection will be required at the Non-Treatment Cycle visit and EOT visit. Blood will be processed to serum and three aliquots generated, each containing approximately 0.8 mL of serum. The date and time of each sample collected will be recorded to the nearest minute.
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5.3.2.2 handling/processing of samples

Specific instructions for collection of blood/serum samples and subsequent preparation and storage of the samples for the assays will be provided by the central laboratory, AbbVie, or its designee.
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5.3.2.3 disposition of samples

The frozen serum samples for the rovalpituzumab tesirine ADC, rovalpituzumab tesirine ADC ATA, and neutralizing antibodies (nAb) assays will be packed in dry ice sufficient to last during transportation and shipped from the study site to the central laboratory.  
58 An inventory of the included samples will accompany the package and an electronic copy of the manifests (including subject number, study day, the time of sample collection and barcode) will be sent to the contact person at gprd_lupet@abbvie.com.
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5.3.2.4 measurement methods

Serum concentrations of rovalpituzumab tesirine ADC and relative titers of rovalpituzumab tesirine ADC ATA will be determined using validated methods. Any additional related analytes may be analyzed using non-validated methods. Serum samples collected for the PK, ATA and nAb analysis may be used for future assay development or validation activities. Rovalpituzumab tesirine ADC nAb samples upon request may be used for the analysis of neutralizing anti-drug antibodies in a validated assay.
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5.3.3 efficacy variables 5.3.3.1 definition

Disease progression will be defined as radiographic progression of disease by RECIST version 1.1. Refer to Appendix G, Response Evaluation Criteria for Solid Tumors
(RECIST) version 1.1 for Tumor Response.12 Effusions (pleural, pericardial, etc.) will contribute to disease response assessment only if confirmed malignant by cytology or otherwise clearly disease-related; if disease progression is suspected solely based on the appearance of new or increase of existing effusions, confirmation of malignant nature of such effusions is strongly recommended prior to making the decision on treatment discontinuation due to known adverse event profile of rovalpituzumab tesirine. If collected, effusion fluid must be tested centrally and/or locally for cytology if disease progression due to appearance/worsening of effusion is suspected.
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5.3.3.2 primary variables

The primary endpoints are progression-free survival (PFS) determined by a Central Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall survival
(OS) in DLL3high population.  
59
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5.3.3.3 secondary variables 5.3.3.4 exploratory

The secondary variables are progression-free survival (PFS) determined by a Central Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall survival (OS) in randomized set population. Change in patient reported outcome (PRO) with physical functioning as measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) in randomized set population is also a secondary endpoint in this study. The exploratory variables are progression-free survival (PFS) based on investigator assessment, objective response rate (ORR) per the CRAC and investigator assessment, respectively, clinical benefit rate (CBR) per the CRAC and investigator assessment, respectively, and the duration of response (DOR) per the CRAC and investigator assessment, respectively. Response assessment will be based on RECIST v1.1. Changes in patient reported outcomes (PROs) as measured by EQ-5D-5L and all other PRO domains (except for physical functioning) as measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (QLQ-LC13) are also exploratory endpoints in this study. AbbVie will assess adverse events, laboratory data, ECGs and vital signs throughout the study. Adverse events intensity and laboratory evaluation changes will be assessed by utilizing NCI CTCAE Version 4.0.11 During the conduct of the study, the AbbVie medical and safety team will be monitoring blinded, subject laboratory results and serious adverse event data as they are reported. Safety endpoints will be summarized using data from the Safety set. Safety analyses will involve examination of the incidence, severity, and type of treatment-emergent adverse events (TEAEs) reported, changes in vital signs and laboratory test results from baseline (the assessment prior to first dose) to specified time points throughout the study.  
60
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5.3.5 pharmacokinetic variables

Serum concentrations of rovalpituzumab tesirine ADC as well as the timing and incidence of ATAs will be tabulated and summarized.
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5.3.6 biomarker and/or optional exploratory

Blood, serosal fluid, and tumor material samples will be collected to conduct analyses to investigate biomarkers. The types of biomarkers to be analyzed may include, but are not limited to, nucleic acids, proteins, lipids or metabolites. Tumor specimen and CTCs will be tested for DLL3 expression and analyses will be performed to correlate the expression levels to rovalpituzumab tesirine response. Enumeration of CTCs, soluble DLL3 in plasma, or markers that are related to the disease or to drug response will be measured at baseline and post-treatment. The information learned from analyzing these samples may be used to investigate factors influencing response to treatment, pharmacodynamics, PK, safety, scientific questions related to SCLC, and/or in the development of new therapies and diagnostic tests. The results of biomarker testing may not be included with the study summary. Whole blood for pharmacogenetic analysis may include but not be limited to DLL3, ASCL1, or NEUROD1.
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exploratory research variables

Optional samples may be collected to conduct exploratory investigations into known and novel biomarkers. The types of biomarkers to be analyzed may include, but are not limited to, nucleic acids, proteins, lipids or metabolites. The samples may be analyzed as part of a multi-study assessment of factors influencing the subjects' response to the blinded investigational product (or drugs of the same or similar class) or the development and progression of the subjects' disease or related conditions. The samples may also be 61 used to develop new diagnostic tests, therapies, research methods or technologies. The results from these analyses are exploratory in nature and may not be included with the study report. In the event a subject withdraws consent to participate from the study, stored biomarker samples will continue to be used for research and analysis. In the event that a subject would like to withdraw consent for research of samples, the subject may request for samples to be withdrawn. Once AbbVie receives the request, remaining samples will be destroyed. If the subject changes his/her consent, and the samples have already been tested, those results will still remain part of the overall research data.
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5.4 removal of subjects from

Each subject has the right to withdraw from study treatment at any time. In addition, the Investigator may discontinue a subject from the study treatment at any time for any reason if the Investigator considers it necessary. Each subject will be withdrawn from the study or study treatment (as applicable) per Section 5.4.1 if any of the following occur:
- The subject has radiographic progression according to RECIST v1.1 (with the exception of CNS-only progression).  
- The subject requires cancer-directed radiotherapy or surgery related to clinical disease progression, or alternate anti-cancer agents during the study period.  
(Refer to Section 5.2.3.2.1, Allowed Concomitant Therapy for exceptions from this criterion).  
- The subject experiences treatment toxicity which, in the Investigator's opinion, prohibits further therapy or the Investigator believes it is otherwise in the best interest of the subject.  
- Subject is pregnant or begins breastfeeding during the treatment portion of the study.  
- The subject decides to withdraw consent for any reason. - Any other medical reason that AbbVie or the study Investigator deems appropriate.  
- Significant non-compliance to the protocol.  
62 Discontinued subjects will not be replaced.
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5.4.1 discontinuation of individual subjects

When subject discontinuation from study treatment (without reaching a protocol-defined endpoint) is planned, the Investigator is to notify the AbbVie Therapeutic Area Medical Director (TA MD) or the clinical team representative (Section 7.0) via telephone as soon as possible (provided, in each case, subject care and safety are not compromised). If not notified prior to discontinuation, the AbbVie TA MD may contact the site to discuss the reason for withdrawal from the study. The visit at which an investigator identifies disease progression or a subject meets other criteria for study treatment discontinuation will be considered the End of Treatment Visit. The reason(s) for the discontinuation from study treatment will be recorded and assessments will be performed per Appendix C, Study Activities. It is preferable that End of Treatment Visit procedures be conducted prior to the initiation of another anti-cancer therapy. However, these procedures should not interfere with the initiation of any new treatments or therapeutic modalities that the Investigator feels are necessary to treat the subject's condition. If a subject is discontinued with an ongoing adverse event or an unresolved clinically significant laboratory result, the site will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory results or adverse event is achieved. Subjects no longer undergoing clinical assessments will have survival information collected at every 6 weeks (± 1 week) until the endpoint of death, the subject becomes lost to follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs first. In the event that a positive result is obtained on a pregnancy test for a subject during the study, the administration of blinded investigational product to that subject must be 63 discontinued immediately. The site must report the positive pregnancy test result by completing the appropriate eCRF within 24 hours of becoming aware of the pregnancy.
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5.4.2 discontinuation of entire study

AbbVie may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause provided that written notice is submitted in advance of the intended termination. The investigator may also terminate the study at his/her site for reasonable cause, after providing written notice to AbbVie in advance of the intended termination. Advance notice is not required by either party if the study is stopped due to safety concerns. If AbbVie terminates the study for safety reasons, AbbVie will notify the investigator and provide written instructions for study termination.
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5.5 treatments 5.5.1 treatments administered

Rovalpituzumab tesirine, the investigational agent under study in this protocol, is an ADC. All subjects randomized will receive premedication consisting of dexamethasone/placebo orally (PO) at 8 mg twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each cycle in which rovalpituzumab tesirine/placebo is administered. Dexamethasone/placebo dosing should occur such that there are approximately 12-hours (i.e., 10 - 14 hours) between AM and PM doses. The first dose of the dexamethasone/placebo on the day of dosing should be at least 30 minutes but no more than 4 hours prior to the rovalpituzumab tesirine/placebo infusion. If the dose of dexamethasone/placebo is vomited within 15 minutes of taking the medication, the subject should retake the medication. In the event that a subject arrives for rovalpituzumab tesirine/placebo administration on Day 1, but has not taken any or all required dexamethasone/placebo doses on Day –1 and/or Day 1, rovalpituzumab tesirine/placebo administration may not proceed, and rovalpituzumab tesirine/placebo will be held until the required dexamethasone/placebo dosing has occurred.  
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5.5.2 identity of investigational product(s)

| Placebo for       |                                                                                                |                          |      |      |
|-------------------|------------------------------------------------------------------------------------------------|--------------------------|------|------|
| Rovalpituzumab    | Placebo for                                                                                    |                          |      |      |
| Tesirine          | Dexamethasone*                                                                                 | Dexamethasone            |      |      |
| Dosage Form       | Powder for  solution for                                                                       |                          |      |      |
| infusion in vials |                                                                                                |                          |      |      |
| Investigational   | Rovalpituzumab                                                                                 |                          |      |      |
| Product           | Tesirine                                                                                       | Powder for  solution for |      |      |
| infusion in vials | Capsules                                                                                       | Placebo capsules         |      |      |
| Strength          | 10 mg/ml when  reconstituted with  3.2 ml of sterile  water for injection                      | N/A                      | 8 mg | N/A  |
| Route of          | Intravenous                                                                                    | Intravenous              | Oral | Oral |
| Administration    |                                                                                                |                          |      |      |
| *                 | Commercially-available Dexamethasone tablets are over-encapsulated to maintain study blinding. |                          |      |      |  
AbbVie will supply rovalpituzumab tesirine/placebo and dexamethasone/placebo. Each site will be responsible for maintaining drug accountability records, including product description, manufacturer, and lot numbers for all investigational products dispensed by the site.
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5.5.2.1 packaging and labeling rovalpituzumab

Vials of rovalpituzumab tesirine/placebo will be packaged in cartons. Each vial and carton will be labeled per country requirements. Labels must remain affixed to the vial and carton. Rova-T drug product is classified as a Dangerous Goods/Hazardous Material and is packaged and shipped by AbbVie according to US Department of Transportation (DOT) and International Air Transport Association (IATA) certified regulations.
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dexamethasone and placebo

Dexamethasone/placebo will be packaged in high-density polyethylene (HDPE) bottles according to the study needs. The bottles will be labeled per country requirements. Labels must remain affixed to the containers.
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5.5.2.2 storage and disposition of

For all storage areas and refrigerators, temperature logs will be maintained to document proper storage conditions. The temperature must be recorded on the temperature logs to verify proper function on each business day. Temperature excursions must be reported to AbbVie immediately. Sites should use the AbbVie Temperature Excursion Management System (ATEMS) module via IRT, if available, or fax copies of the temperature log indicating the extent of the excursion (time, duration of the temperature excursion, min/max values and study drugs affected) to AbbVie Clinical Drug Supply Management (CDSM) including the Storage Temperature Excursion Reporting Form. In case of a temperature excursion, study medication should be quarantined and not dispensed until AbbVie CDSM or ATEMS deems the medication as acceptable. The investigational products are for investigational use only and are to be used only within the context of this study. The study drug supplied for this study must be maintained under adequate security and stored under the conditions specified on the label until dispensed for subject use or returned to the destruction facility.
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rovalpituzumab tesirine/placebo

Rovalpituzumab tesirine/placebo must be stored refrigerated at 2° to 8°C (36° to 46°F), protected from light, and must not be frozen. Specific storage conditions for reconstituted and diluted rovalpituzumab tesirine/placebo will be provided in a separate document outside of this protocol.
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dexamethasone/placebo

Dexamethasone/placebo should be stored at 15° to 25°C (59° to 77°F) and protected from light. For Australia, dexamethasone/placebo should be stored below 25°C and protected from light.
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5.5.2.3 preparation/reconstitution of dosage form(s)

Both rovalpituzumab tesirine and matching placebo will be supplied as a lyophilized powder in a vial. Each vial of rovalpituzumab tesirine or placebo will be reconstituted with 3.2 mL of sterile water for injection. When reconstituted, vial of rovalpituzumab tesirine will contain 10 mg/mL (30 mg total per vial). The rovalpituzumab tesirine drug product is dosed based on actual body weight. The contents of two or more vials of reconstituted drug product may be required to accomplish the desired dose. The total volume administered treatment arm will be dependent upon the assigned dose. The rovalpituzumab tesirine drug product and placebo solution(s) will be administered via intravenous (IV) infusion. Rovalpituzumab tesirine drug product and placebo solution(s) will be added to 50 mL or 100 mL of 0.9% normal saline with an infusion over 30 minutes (20 - 45 minute infusion window). The rate should be adjusted based on patient tolerability. Specific dose preparation and documentation details will be provided to the site pharmacy in a separate document. A complete description of the chemistry and formulation may be found in the Investigator's Brochure.14
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5.5.3 method of assigning subjects

All subjects in the study will be randomized using an IRT system. Before the study is initiated, directions for the IRT will be provided to each site. The site will contact the IRT to obtain a Screening (subject) number once the subject has signed the informed consent and a study-specific procedure has been performed (i.e., central laboratory samples drawn). Once the screening number is assigned, if the subject is not randomized into the study, the reason for screen failure will be documented in the source document and in the eCRF. For others, the site will access the system and a unique randomization number will be provided.  
67 The IRT will randomize subjects in a 1:1 ratio, with one-half of the subjects being randomized to the rovalpituzumab tesirine treatment arm and the other one-half to the placebo arm. The stratification factors used for the randomization should be the last values on or prior to the date of randomization.
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5.5.4 selection and timing of

Dosing is based on actual body weight of the subject to the nearest kilogram, assessed in the clinic prior to dosing at each cycle, and administered according to the calculated dose.  
In cases of weight gain due to fluid retention, dosing should be based on most recent prefluid retention actual weight.  
Subjects must meet all of the following criteria on each dosing day before receiving blinded investigational product:
- Absolute neutrophil count (ANC) ≥ 1,000/μL - Platelet count ≥ 75,000/μL - Resolution of blinded investigational product-related AEs, including findings indicative of pleural or pericardial effusions, and clinically-significant laboratory abnormalities to Grade 0 or 1 (excluding ANC and alopecia), or to baseline grade.
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5.5.4.2 dose modifications 5.5.4.2.1 dose

Subjects who experience blinded investigational product-related toxicity during a cycle must have recovered as specified above before the next cycle may proceed. Any dose modifications except those indicated as mandatory below (including dose delay, reduction, resumption, and discontinuation) are to be performed at the discretion of the Investigator. Further guidelines suggesting dose modifications based on prior studies of rovalpituzumab tesirine are provided in Section 5.5.4.2.2, Dose Reduction Guidelines.  
68  
  
In cases of treatment delays of > 28 days, the TA MD should be contacted regarding the subject's continuation of treatment. In the event of isolated CNS-only progression during study treatment, blinded investigational product will be withheld while local treatment is administered (e.g., radiotherapy) in accordance with institutional practice. Blinded investigational product may be restarted 1 week after the completion of local CNS disease-directed therapy. If more than 6 weeks have elapsed since the previous radiographic tumor assessment, the subject must undergo a radiographic tumor assessment to evaluate extracranial disease status prior to resuming blinded treatment. If additional sites of PD are present, the subject will be required to discontinue blinded investigational product.
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5.5.4.2.2 dose reduction guidelines

Blinded investigational product dose reductions and discontinuation of blinded investigational product for specific toxicities should occur as outlined in Table 4, Dose Reductions for Blinded Investigational Product (IP) and Table 5, Dose Reductions and Discontinuation for Unacceptable Toxicities. Dose reductions for unacceptable toxicities described in Table 5 are mandatory. Reduced dose levels are described in (Table 4). Generally, if unacceptable toxicity recurs after two dose reductions, treatment will be discontinued (for further details, refer to Table 5). If the blinded investigational product dose is reduced, no re-escalation will be allowed. If different unacceptable toxicities occur in sequential treatment cycles (e.g., Grade 3 LFT after the first dose and Grade 3 thrombocytopenia lasting more than 7 days after the second dose), dose reduction will proceed to the next lower dose level. If different unacceptable toxicities occur within one cycle, maximum specified dose reduction will be implemented. Dose reductions and discontinuation are not planned for dexamethasone/placebo. If full dose of dexamethasone/placebo cannot be administered due to an AE, the blinded infusion should be delayed until dexamethasone/placebo can be administered. Exceptions to the dose modification guidelines should be discussed with the TA MD prior to implementation.  
69 EudraCT 2016-003503-64 Details of toxicity management are further outlined in Section 6.1.8, Toxicity Management. Table 4. Dose Reductions for Blinded Investigational Product (IP)  
| First Dose Reduction   | Second Dose Reduction   |               |
|------------------------|-------------------------|---------------|
| Starting Dose          | (Reduce Dose)           | (Reduce Dose) |
| 0.3 mg/kg              | 0.2 mg/kg               | 0.1 mg/kg     |  
70 EudraCT 2016-003503-64
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table 5. dose reductions and

| Toxicitya                                                                                                                                                             | First Occurrence                                                                                                                                          | Second Occurrence        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|
| Grade 3 thrombocytopenia lasting more than                                                                                                                            | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| 7 days Grade 4 thrombocytopenia/Grade 3  thrombocytopenia with bleeding/Need for  platelet transfusion                                                                | Reduce dose to 0.1.mg/kg                                                                                                                                  | Discontinue Blinded IP   |
| Grade 4 neutropenia lasting more than 7 days                                                                                                                          | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| Grade 3 febrile neutropenia                                                                                                                                           | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| Grade 4 febrile neutropenia                                                                                                                                           | Reduce dose to 0.1.mg/kg                                                                                                                                  | Discontinue Blinded IP   |
| Grade 3 Liver Function Tests (LFTs)                                                                                                                                   | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| Grade 4 LFTs or Grade 3 LFTs with                                                                                                                                     | Reduce dose to 0.1.mg/kg                                                                                                                                  | Discontinue Blinded IP   |
| concomitant Bilirubin Grade 2 or higherb Potential DILI (Drug-induced liver injury)                                                                                   | See Section 6.1.8.3                                                                                                                                       | See Section 6.1.8.3      |
| Grade 3 or 4 hypoalbuminemia                                                                                                                                          | Reduce dose to 0.1 mg/kg                                                                                                                                  | Discontinue Blinded IP   |
| Any other Grade 3 or 4 laboratory  abnormality considered clinically significant  and treatment-related                                                               | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| Grade 2 serosal effusions or edema                                                                                                                                    | Reduce to 0.2 mg/kg                                                                                                                                       | Reduce to 0.1 mg/kg      |
| Grade 3 serosal effusions or edema or                                                                                                                                 | Reduce dose to 0.1.mg/kg                                                                                                                                  | Discontinue Blinded IP   |
| Grade 2 capillary leak syndrome Grade 4 serosal effusions or edema or                                                                                                 | Discontinue Blinded IP                                                                                                                                    | N/A                      |
| Grade ≥ 3 capillary leak syndrome Grade 3 photosensitivity reaction                                                                                                   | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| See Section 6.1.8.2                                                                                                                                                   | See Section 6.1.8.2                                                                                                                                       |                          |
| Grade 4 photosensitivity reaction                                                                                                                                     | Discontinue Blinded IP                                                                                                                                    | N/A                      |
| Grade 2 pneumonitis                                                                                                                                                   | Reduce dose to 0.1 mg/kg                                                                                                                                  | Discontinue Rova-T       |
| Grade ≥ 3 pneumonitis                                                                                                                                                 | Discontinue Rova-T                                                                                                                                        | N/A                      |
| Any other Grade 3 or Grade 4 non-laboratory  treatment-related toxicity with the exception  of fatigue, asthenia, nausea, or other  manageable constitutional symptom | Reduce dose to 0.2 mg/kg                                                                                                                                  | Reduce dose to 0.1 mg/kg |
| a.                                                                                                                                                                    | Refer to Appendix H, CTCAE v 4.0 Grading of Relevant AEs for definitions of NCI-CTCAE severity grades and  for definition of serosal effusions and edema. |                          |
| b.                                                                                                                                                                    | If potential DILI is suspected please follow guidelines of Section 6.1.8.3.                                                                               |                          |  
71
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5.5.5 blinding 5.5.5.1 blinding of

AbbVie, the Investigator, the study site personnel, and subject will remain blinded to each subject's treatment with rovalpituzumab tesirine or placebo and dexamethasone or placebo and throughout the course of the study. The IRT system will provide access to blinded subject treatment information during the study. AbbVie must then be notified within 24 hours of the blind being broken. The date and reason that the blind was broken must be recorded in the source documentation and eCRF, as applicable. An Independent Data Monitoring Committee (IDMC) will be formed and constituted according to appropriate regulatory guidelines. The IDMC will review the unblinded data from the study with respect to subject accrual, pretreatment characteristics of accrued subjects, the frequency and severity of toxicities and morbidity, and provide recommendations according to the charter. Detailed information regarding the composition of the committee and procedures including frequency of meetings and scope of reviews will be documented in a separate charter. For the futility analysis, OS, other efficacy and safety data will be analyzed and reviewed by the IDMC for recommendation.  
The investigator or his/her designated and qualified representatives will administer/dispense blinded investigational product only to subjects randomized in the study in accordance with the protocol. The blinded investigational product must not be used for reasons other than that described in the protocol. Blinded investigational product administration must be performed by study site staff and documented in source documents and the eCRF.  
72
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5.5.7 drug accountability

The site will record the dose of rovalpituzimab tesirine/placebo and dexamethasone/placebo given to each subject in the source documents and on the eCRF. Upon receipt of a shipment of rovalpituzimab tesirine/placebo and dexamethasone/placebo, the representative at each site will (1) open and inspect the shipment; (2) verify that the rovalpituzimab tesirine/placebo has been received intact, in the correct amounts and at the correct address; (3) sign and date the Proof of Receipt (POR) or similar documentation accompanying the shipment; (4) register the shipment as received via the IRT. All blinded investigational products must be retained in the designated secure area under proper storage conditions. This will be documented by signing and dating the Proof of Receipt (POR) or similar document or via direct recording in the IRT. An overall accountability of the blinded investigational product will be performed and verified by the site monitor throughout the study and at the study site closeout visit. An accurate running inventory of rovalpituzimab tesirine/placebo and dexamethasone/placebo will be maintained utilizing the IRT drug accountability module and, if required, according to your institutional policy and will include the lot number, POR number(s), the bottle/kit numbers, and the date blinded investigational product was dispensed for each subject. Upon completion or termination of the study, all original bottles/cartons containing unused rovalpituzimab tesirine/placebo and dexamethasone/placebo (empty containers will be defaced and discarded on site) will be returned to the Destruction Facility according to AbbVie's instructions, or if pre-arranged between the sponsor and site, destruction of used and unused bottles will be performed at the site. Rova-T is classified as a Dangerous Good/Hazardous Material according to US Department of Transportation (DOT) and International Air Transport Association (IATA). Dangerous Goods/Hazardous Materials must be packaged and shipped according to applicable regulations.  
73 The study Investigator or his/her designated representative agrees not to supply study medication to any persons not enrolled in the study or not named as a sub-investigator listed on the FDA 1572 or Investigator Information and Agreement (IIA) form.
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5.6 discussion and justification of

Phase 1 data described in Section 3.0 and proposed mechanism of action suggest that rovalpituzumab tesirine may improve outcome of SCLC patients by extending clinical benefit following first-line platinum-based chemotherapy. This randomized, doubleblind, placebo controlled phase 3 study will evaluate the effect of rovalpituzumab tesirine as maintenance therapy following first-line platinum-based chemotherapy of extensive stage SCLC. Primary endpoints of PFS and OS are well established in solid tumor trials and in SCLC specifically. A randomized, double-blind, placebo controlled study such as described here is optimal for assessing the treatment effect of rovalpituzumab tesirine versus current standard, best supportive care to a current standard treatment (placebo is required to allow for blinding).
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5.6.2 appropriateness of measurements

The safety measures that will be used in this trial are considered standard procedures for evaluating the potential adverse effects of study medications. Adverse events and, when applicable, clinical laboratory data will be graded using NCI CTCAE, version 4.0.11 Response will be assessed according to RECIST v1.1,12 which includes standard criteria for evaluating response in solid tumors. The intervals of evaluation in this protocol are appropriate for disease management. Standard tests will be performed to detect the possible presence of specific antibodies to blinded investigational product. Pharmacokinetic assessments for drug activity are also common in clinical studies.  
74
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5.6.3 suitability of subject population

Although response rates to first-line chemotherapy remain high with platinum-based regimens, time to disease recurrence is short in extensive-stage SCLC. Rovalpituzumab tesirine has demonstrated anti-tumor activity in relapsed/refractory SCLC population. Exploring rovalpituzumab tesirine in ED SCLC subjects with stable disease or objective response following first-line chemotherapy is acceptable considering observed activity/toxicity profile of rovalpituzumab tesirine, and that the standard approach in this setting is no treatment until progression. In a recent Phase 1 study (SCRX16-001) with rovalpituzumab tesirine, the maximum tolerated dose (MTD) was established at 0.4 mg/kg every 3 weeks based on the incidence of Cycle 1 toxicities, while the recommended Phase 2 dose (RPTD) in SCLC was chosen as 0.3 mg/kg every 6 weeks for a total of two doses with the allowance to retreat at the same dose level and schedule upon progression. The RPTD is based on the toxicity and efficacy profile during multiple cycles dosing (AbbVie Stemcentrx data on file). This experience included multiple doses of rovalpituzumab tesirine at a) 0.2 mg/kg every 6 weeks, b) 0.3 mg/kg every 6 weeks or c) 0.3 mg/kg every 6 weeks for a total of two doses and then at 0.1 mg/kg every 6 weeks thereafter. Based on the totality of the experience with rovalpituzumab tesirine and taking into consideration its pharmacokinetic characteristics, dosing of 0.3 mg/kg q6wk for 2 cycles, omitting every third cycle will be used in this study. This study will not exceed a maximum dose of 1.5 mg/kg at each dose. A complaint is any written, electronic, or oral communication that alleges deficiencies related to the physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or performance of a product/device after it is released for distribution.  
75 The investigational product in this study is defined as rovalpituzumab tesirine or placebo and dexamethasone or placebo. Complaints associated with any component of this investigational product must be reported to the Sponsor (Section 6.2.2). For AEs, please refer to Sections 6.1.1 through 6.1.6. For product complaints, please refer to Section 6.2.
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6.1 medical complaints

The investigator will monitor each subject for clinical and laboratory evidence of adverse events on a routine basis throughout the study. The investigator will assess and record any adverse event in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the adverse event to blinded investigational product, and any action(s) taken. For serious adverse events considered as having "no reasonable possibility" of being associated with blinded investigational product, the investigator will provide an Other cause of the event. For adverse events to be considered intermittent, the events must be of similar nature and severity. Adverse events, whether in response to a query, observed by site personnel, or reported spontaneously by the subject will be recorded. All adverse events will be followed to a satisfactory conclusion.
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6.1.1 definitions 6.1.1.1 adverse event

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the event is considered causally related to the use of the product. Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered an adverse event.  
76 Worsening in severity of a reported adverse event should be reported as a new adverse event. Laboratory abnormalities and changes in vital signs are considered to be adverse events only if they result in discontinuation from the study, necessitate therapeutic medical intervention, meets protocol specific criteria (see Section 6.1.8 regarding toxicity management) and/or if the investigator considers them to be adverse events. An elective surgery/procedure scheduled to occur during a study will not be considered an adverse event if the surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been pre planned prior to study entry. However, if the pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition for which the elective surgery/procedure is being done will be considered an adverse event. All protocol-related AEs must be collected from the signing of the study specific informed consent until study drug administration. In addition, adverse events with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 70 days have elapsed following discontinuation of study drug administration will be considered as treatment-emergent adverse events.
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6.1.1.2 serious adverse events

If an adverse event meets any of the following criteria, it is to be reported to AbbVie as an SAE within 24 hours of the site being made aware of the SAE:  
| Death of Subject                                     | An event that results in the death of a subject.                                                                                                                                                                                                |
|------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Life-Threatening                                     | An event that, in the opinion of the investigator, would have  resulted in immediate fatality if medical intervention had not  been taken. This does not include an event that would have  been fatal if it had occurred in a more severe form. |
| Hospitalization or  Prolongation of  Hospitalization | An event that results in an admission to the hospital for any  length of time or prolongs the subject's hospital stay. This  does not include an emergency room visit or admission to an 77                                                     |  
| outpatient facility or hospitalization for respite care.                                           |                                                                                                                                                                                                                                                                                                                                   |
|----------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Congenital Anomaly                                                                                 | An anomaly detected at or after birth, or any anomaly that  results in fetal loss.                                                                                                                                                                                                                                                |
| Persistent or  Significant  Disability/Incapacity                                                  | An event that results in a condition that substantially interferes  with the activities of daily living of a study subject. Disability  is not intended to include experiences of relatively minor  medical significance such as headache, nausea, vomiting,  diarrhea, influenza, and accidental trauma (e.g., sprained  ankle). |
| Important Medical  Event Requiring  Medical or Surgical  Intervention to  Prevent Serious  Outcome | An important medical event that may not be immediately lifethreatening or result in death or hospitalization, but based on  medical judgment may jeopardize the subject and may require  medical or surgical intervention to prevent any of the  outcomes listed above (i.e., death of subject, life-threatening,  hospitalization, prolongation of hospitalization, congenital  anomaly, or persistent or significant disability/incapacity).  Additionally, any elective or spontaneous abortion or stillbirth  is considered an important medical event. Examples of such  events include allergic bronchospasm requiring intensive  treatment in an emergency room or at home, blood dyscrasias  or convulsions that do not result in inpatient hospitalization, or  the development of drug dependency or drug abuse.                                                                                                                                                                                                                                                                                                                                   |  
For serious adverse events with the outcome of death, the date and cause of death will be recorded on the appropriate case report form.
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6.1.1.3 adverse events expected due

Adverse events that may be expected from primary SCLC lesions, compression of adjacent thoracic structures or distant metastases are presented in Appendix J, Adverse Events Expected Due to SCLC or Progression of SCLC of the protocol. These adverse events may occur alone or in various combinations and are considered expected adverse events in SCLC subjects.  
78 Although exempted from expedited reporting to Health Authorities and Institutional Review Boards (IRBs) as individual cases, these SAEs must be reported to the Sponsor within 24 hours of the site being made aware of the SAE. AEs or SAEs should not be reported as "Disease progression," even if fatal, as PD is an efficacy endpoint for the study. Rather, report the specific disease (clinical) manifestation of the progression (eg, 'malignant pleural effusion,' 'spinal bone metastases,' 'lymphadenopathy,' 'brain metastases') or if not possible, report "malignant neoplasm progression" as the AE or SAE as appropriate.
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6.1.2 adverse event severity

The investigator will rate the severity of each adverse event according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE
Version 4.0).11 If a reported adverse event **increases** in severity, the initial adverse event should be given an outcome date and a new adverse event reported on a different date from the end date of the previous adverse event to reflect the change in severity. For all reported serious adverse events that increase in severity, the supplemental eCRFs also need to be updated to reflect the change in severity. When CTCAE criteria cannot be used, the event should be graded as defined below:  
| Grade 1   | The adverse event is transient and easily tolerated by the subject (mild).                                                                      |
|-----------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2   | The adverse event causes the subject discomfort and interrupts the  subject's usual activities (moderate).                                      |
| Grade 3/4 | The adverse event causes considerable interference with the subject's  usual activities and may be incapacitating or life-threatening (severe). |
| Grade 5   | The adverse event resulted in death of the subject (severe).                                                                                    |
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6.1.3 relationship to study drug

The investigator will use the following definitions to assess the relationship of the adverse event to the use of blinded investigational products:
79  
| Reasonable    | After consideration of factors including timing of the event,                                                                                                |
|---------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Possibility   | biologic plausibility, clinical judgment, and potential alternative  causes, there is sufficient evidence (information) to suggest a  causal relationship.   |
| No Reasonable | After consideration of factors including timing of the event,                                                                                                |
| Possibility   | biologic plausibility, clinical judgment, and potential alternative  causes, there is insufficient evidence (information) to suggest a  causal relationship. |  
For causality assessments, events assessed as having a reasonable possibility of being related to the study drug will be considered "associated." Events assessed as having no reasonable possibility of being related to study drug will be considered "not associated." In addition, when the investigator has not reported causality or deemed it not assessable, AbbVie will consider the event associated. If an investigator's opinion of no reasonable possibility of being related to study drug is given, an Other cause of event must be provided by the investigator for the serious adverse event.
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6.1.4 deaths

For SAEs with the outcome of death, the date and cause of death will be recorded on the appropriate case report form. Deaths that occur during the protocol specified AE reporting period (Section 6.1.6) that are more likely related to disease progression will therefore be considered as an expected SAE and will not be subject to expedited reporting. These events should be recorded on the AE eCRF as described in Section 6.1.1.3. After the AE reporting period, deaths attributed to progression of disease under study should not be recorded on the AE eCRF. Death should be considered an outcome and not a distinct event. The event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept on the AE eCRF. Generally, only one such event should be reported. The term "sudden death" should only be used for the occurrence of an abrupt and unexpected death due to presumed cardiac causes in a patient with or without pre-existing heart disease, within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was last seen alive and stable. If the cause of death is unknown and cannot be ascertained at the time of reporting, "unexplained death" should be recorded on the AE eCRF. If the cause of death later becomes available (e.g., after autopsy), "unexplained death" should be replaced by the established cause of death.
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6.1.5 adverse event collection period

All adverse events reported from the time of blinded investigational product administration until 70 days following the last dose of blinded investigational product will be collected, whether solicited or spontaneously reported by the subject. In addition, protocol-related serious adverse events and non-serious adverse events will be collected from the time the subject signed the study-specific informed consent, only if considered by the Investigator to be causally related to study-required procedures. Adverse event information will be collected as shown in Figure 2.  
  
* Only if considered by the Investigator to be causally related to study-required procedures.  
81
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6.1.6 adverse event reporting

In the event of a serious adverse event, whether associated with blinded investigational product or not, the Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the serious adverse event by entering the serious adverse event data into the electronic data capture (EDC) system. Serious adverse events that occur prior to the site having access to the RAVE® system, or if RAVE is not operable, should be documented on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical Pharmacovigilance within 24 hours of the site being made aware of the serious adverse event.  
  
For safety concerns, contact the Oncology Safety Management Team at:
Oncology Safety Team  
  
AbbVie 1 North Waukegan Road North Chicago, IL 60064 Office:  
  
  
Email:
82 For any subject safety concerns, please contact the physician listed below:  
 Primary Therapeutic Area Medical Director:  
 AbbVie 1 North Waukegan Road North Chicago, IL 60064 USA  
  
In emergency situations involving study subjects when the primary Therapeutic Area Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline where your call will be re-directed to a designated backup AbbVie TA MD:
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phone

AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with global and local guidelines and Appendix A of the Investigator Brochure will serve as the Reference Safety Information (RSI). The RSI in effect at the start of a DSUR reporting period serves as the RSI during the reporting period. For follow-up reports, the RSI in place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to assess expectedness. In Japan, the principal investigator will provide documentation of all serious adverse events to the Director of the investigative site and the Sponsor.  
83
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6.1.7 pregnancy

Pregnancy in a study subject must be reported to AbbVie within 24 hours of the investigative site becoming aware of the pregnancy. Subjects who become pregnant during the study must be discontinued (Section 5.4). All subjects should be informed that contraceptive measures (refer to Section 5.2.4, Contraception Recommendations and Pregnancy Testing for the details on contraception) should be taken throughout the study and for at least 6 months after the last dose of study drug. Male subjects should be informed that contraceptive measures should be taken by their female partner. Information regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will be collected. In the event of a pregnancy occurring in the partner of an enrolled subject, written informed consent for release of medical information from the partner must be obtained prior to the collection of any pregnancy-specific information, and the pregnancy will be followed to outcome. Pregnancy in a study subject is not considered an adverse event. The medical outcome for either mother or infant, meeting any serious criteria including an elective or spontaneous abortion is considered a serious adverse event and must be reported to AbbVie within 24 hours of the site becoming aware of the event.
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6.1.8 toxicity management

Subjects will be monitored continuously for toxicity while on study treatment. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.11 If a subject has an AE possibly related to blinded investigational product administration, then dose interruptions/holds with possible modifications as described below may be implemented. Adjustments to these guidelines may occur based on the clinical judgment of the investigator with notification to the TA MD. Dose modifications for toxicities as described in Section 5.5.4.2.2 are mandatory.  
84
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6.1.8.1 management of serosal effusions/serositis

Serosal effusions (pleural or pericardial, or ascites) have been observed with rovalpituzumab tesirine and have the potential to be life-threatening (e.g., cardiac tamponade). Therefore, development of any of these events or worsening from baseline warrants prompt evaluation by the Investigator or designee. Alternative causes such as infection, congestive heart failure, or disease progression, should be ruled out. When appropriate, a unifying diagnosis should be reported, e.g., "heart failure," not the signs and symptoms "pleural effusion" and "edema limbs." Effusion events were reported during treatment and may occur up to several months after last Rova-T dose. As a result, subjects should be advised of signs and symptoms of fluid retention and contact treating physician if they arise during this time. When considered clinically significant (e.g., Grade 2 or higher and considered related to blinded investigational product):
- Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in some prior cases. The Investigator should consider a tapering regimen, such as dexamethasone up to 8 mg orally twice a day for 5 days, followed by 4 mg orally twice a day for 5 days, then 2 mg orally twice a day for 5 days. Alternatively, nonsteroidal therapies for serositis may be considered, such as non-steroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen 400 - 600 mg orally three to four times daily) or colchicine
(e.g., 0.6 mg orally two to three times daily) given for 1 - 2 weeks.  
- Until clinical experience suggests otherwise, guidance for dose delay and/or reduction, as well as criteria for ongoing dosing, should follow Section 5.5.4.2.
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6.1.8.2 management of skin reactions

All cutaneous reactions which develop during treatment warrant prompt evaluation. Skin toxicity with rovalpituzumab tesirine may consist of photosensitivity but possibly other reactions such as palmar-plantar erythrodysesthesia or erythema multiforme. As such, 85  
  
development of a cutaneous reaction during treatment warrants prompt evaluation by the Investigator or designee. Photosensitivity reactions may occur hours to days after sun exposure. Patients should be advised to avoid direct and indirect sun exposure as much as possible from Cycle 1 Day 1 until 30 days after the final dose. When sun exposure is unavoidable, patients should wear protective clothing and sunglasses, and use a broad-spectrum sunscreen and lip balm (SPF 30 or greater). Thirty-one to ninety days after last dose of Rova-T/placebo, the patient may resume outdoor activities with appropriate sun protection including broad brimmed hat, protective clothing and sunscreen SPF 30 or higher. Subjects with a grade 3 photosensitivity reaction should dose reduce Rova-T/placebo to 0.2 mg/kg after the first occurrence and following a second grade 3 photosensitivity reaction, reduce RovaT/placebo to 0.1 mg/kg. Subjects with a grade 4 photosensitivity reaction must permanently discontinue Rova-T/placebo. If clinically consistent with photosensitivity, the AE should be reported as such (using medically accurate and descriptive AE terminology), and managed as described in Table 6. Photo-documentation of skin toxicity should be available upon request by the TA MD. The investigative site will take measures to protect the identity of the patient. These measures include taking the photograph very close to the affected skin region to exclude facial features, or if facial features cannot be excluded due to the location of the skin reaction, covering identifying features (such as the eyes) with a black rectangle. Formal evaluation by a dermatologist, including possible skin biopsy to rule out alternative etiologies such as erythema multiforme, which may warrant discontinuation of blinded investigational product, and to facilitate the most appropriate terminology for AE reporting. All events of cutaneous toxicity should be monitored until resolution or return to baseline. Recommendations for management of photosensitivity reactions are outlined in Table 6.  
86  
| CTCAE v4.0                    | Treatment Recommendations                                                                                                                                                   | Dose Modifications                                                                                     |             |
|-------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|-------------|
| Grade 1                       | Painless erythema and                                                                                                                                                       | Low-potency topical steroid (face)                                                                     |             |
| erythema covering < 10% BSA   | High-potency topical steroid  (body)                                                                                                                                        | -                                                                                                      |             |
| Grade 2                       | Tender erythema covering 10 -                                                                                                                                               | Low-potency topical steroid (face)                                                                     |             |
| 30% BSA                       | High-potency topical steroid  (body) Nonsteroidal anti-inflammatory  agents orally as needed                                                                                | -                                                                                                      |             |
| Grade 3                       | Erythema covering > 30%  BSA and erythema with  blistering; photosensitivity;  oral corticosteroid therapy  indicated; pain control  indicated (e.g., narcotics or  NSAIDs) | Low-potency topical steroid (face)  High-potency topical steroid  (body) Prednisone 0.5 mg/kg × 7 days | Reduce dose |
| Grade 4                       | Life-threatening consequences;                                                                                                                                              | Low-potency topical steroid (face)                                                                     |             |
| urgent intervention indicated | High-potency topical steroid  (body) Prednisone 0.5 mg/kg × 7 days  Hospitalization                                                                                         | Discontinue                                                                                            |             |  
In order to simplify the collection of detailed Safety Data associated with dermatological issues, prior to the verification of a specific diagnosis the general term of "Skin Toxicity" should be recorded on the Adverse Event eCRF and the corresponding details should be captured on the Skin Toxicity Supplemental eCRF (as outlined in the form). Once a final dermatological diagnosis is verified, the AE eCRF should be updated to reflect the specific diagnosis.
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6.1.8.3 management of potential drug-induced

Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs.  
87 A potential DILI is defined as:
- ALT or AST elevation > 3 times (3×) upper limit of normal (ULN) and - Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) and
- No other immediately apparent possible causes of aminotransferase (AT)
elevation and hyperbilirubinemia including but not limited to viral hepatitis, pre-existing chronic or acute liver disease or tumor(s), or the administration of other drug(s) known to be hepatotoxic In general, an increase of AT to > 3 × ULN should be followed by repeat testing within 48 - 72 hours of all four of the usual measures (ALT, AST, alkaline phosphatase, and total bilirubin) to confirm the abnormalities and to determine if they are increasing or decreasing. An inquiry regarding symptoms should also be made (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash). Subjects may be retested locally, but normal laboratory ranges should be recorded and results made available to the Investigator immediately. All data must be recorded in the CRF. If symptoms persist or repeat testing shows AT > 3 × ULN for subjects with normal baseline measures or 2-fold increases above baseline values for subjects with elevated values before drug exposure, close observation should be initiated. If close monitoring is not possible, blinded investigational product should be discontinued. Close observation includes:
- Repeating liver enzyme and serum bilirubin tests two or three times weekly.  
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has been discontinued and the subject is asymptomatic.  
- Obtaining a more detailed history of symptoms and prior or concurrent diseases
- Obtaining a history of concomitant drug use (including nonprescription medications and herbal and dietary supplement preparations), alcohol use, recreational drug use, and special diets
- Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and biliary tract disease
- Obtaining a history of exposure to environmental chemical agents - Obtaining additional tests to evaluate liver function, as appropriate
(e.g., international normalized ratio [INR], direct bilirubin)
- Considering gastroenterology or hepatology consultations Blinded investigational product will be discontinued if potential DILI is suspected and:
- ALT or AST > 8 × ULN - ALT or AST > 5 × ULN for more than 2 weeks - ALT or AST > 3 × ULN and (TBL > 2× ULN or INR > 1.5) - ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia All subjects showing possible DILI should be followed until all abnormalities return to normal or to the baseline state. Any hepatic related adverse event should be recorded and the Hepatic Adverse Event eCRF triggered from the Adverse Event page.