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section 5.3.1.1 study procedures

Subsection Disease/Response Assessment (Radiographic Imaging) Last paragraph previously read: Scheduled tumor assessments will not be affected by delays in therapy and/or drug holidays. Subjects will continue to be monitored by the same diagnostic method throughout the study every 6 weeks after randomization, unless evidence of tumor metastases warrants otherwise. Subjects who discontinue treatment for reasons other than radiographic disease progression will continue to be followed every 6 weeks from C1D1 to determine the extent of tumor burden, until disease progression occurs.  
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 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. Section 5.3.1.1 Study Procedures Subsection MRI/CT of the Brain Last sentence previously read: MRI/CT of the brain is only required at screening and when clinically indicated (e.g., if CNS progression is suspected). Has been changed to read: MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS progression is suspected) thereafter. Section 5.3.1.1 Study Procedures Subsection Fluid Retention Questionnaire (Including Subject Daily Weight) Last paragraph, last sentence previously read: The site will advise subjects to contact the site in cases where sudden weight gain is observed for possible assessment in the clinic.  
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. Section 5.3.1.1 Study Procedures Subsection End of Treatment (EOT) Visit Add: new second sentence 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. Section 5.3.1.1 Study Procedures Subsection End of Treatment (EOT) Visit Delete: third sentence The visit should occur within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible. Section 5.3.3.2 Primary Variables Previously read: The primary endpoints are progression-free survival (PFS) determined by a Central Radiographic Assessment Committee (CRAC) and overall survival (OS).  
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.  
172
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section 5.3.3.3 secondary variables previously

The secondary variables are progression-free survival (PFS) based on investigator assessment, objective response rate (ORR) per the CRAC and investigator assessment, respectively, and 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 European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (QLQ-LC13) are also secondary endpoints in this study.  
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.
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section 5.3.3.4 exploratory variables add

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. Section 5.3.5 Pharmacokinetic Variables Previously read: Plasma concentrations of rovalpituzumab tesirine ADC as well as the timing and incidence of ATAs will be tabulated and summarized.  
Serum concentrations of rovalpituzumab tesirine ADC as well as the timing and incidence of ATAs will be tabulated and summarized.
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section 5.5.1 treatments administered

First paragraph, last sentence previously read: If the dose of dexamethasone is vomited within 15 minutes of taking the medication, the subject should retake the medication.  
If the dose of dexamethasone/placebo is vomited within 15 minutes of taking the medication, the subject should retake the medication. Section 5.5.2.1 Packaging and Labeling Subsection Rovalpituzumab Tesirine and Placebo Add: new last sentence 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.  
174  
 EudraCT 2016-003503-64 Section 5.5.2.2 Storage and Disposition of Blinded Investigational Product(s) Subsection Rovalpituzumab Tesirine/Placebo Add: new last sentence Specific storage conditions for reconstituted and diluted rovalpituzumab tesirine/placebo will be provided in a separate document outside of this protocol. Section 5.5.2.3 Preparation/Reconstitution of Dosage Form(s) Fourth sentence previously read: The rovalpituzumab tesirine drug product is dosed based on body weight. Has been changed to read: The rovalpituzumab tesirine drug product is dosed based on actual body weight. Section 5.5.2.3 Preparation/Reconstitution of Dosage Form(s) Add: new tenth sentence Specific dose preparation and documentation details will be provided to the site pharmacy in a separate document. Section 5.5.4.1 Dosing First paragraph Add: new last sentence In cases of weight gain due to fluid retention, dosing should be based on most recent prefluid retention actual weight.  
Table 5. Dose Reductions and Discontinuation for Unacceptable Toxicities Toxicity "Grade 4 LFTs or Grade 3 LFTs with concomitant Bilirubin Grade 2 or higher" previously read: Grade 4 LFTs or Grade 3 LFTs with concomitant Bilirubin Grade 2 or higher 175 Has been changed to read:
Grade 4 LFTs or Grade 3 LFTs with concomitant Bilirubin Grade 2 or higherb Table 5. Dose Reductions and Discontinuation for Unacceptable Toxicities Add: new toxicity "Grade 2 pneumonitis" and "Grade ≥ **3 pneumonitis"**  
| Grade 2 pneumonitis   | Reduce dose to 0.1 mg/kg   | Discontinue Rova-T   |
|-----------------------|----------------------------|----------------------|
| Grade ≥ 3 pneumonitis | Discontinue Rova-T         | N/A                  |  
Table 5. Dose Reductions and Discontinuation for Unacceptable Toxicities Add: new footnote "b." b. If potential DILI is suspected please follow guidelines of Section 6.1.8.3. Section 5.5.5.2 Blinding of Data for Independent Data Monitoring Committee (IDMC) Last sentence previously read: Final PFS data with interim OS data will be analyzed and reviewed by the IDMC for recommendation. Has been changed to read: For the futility analysis, OS, other efficacy and safety data will be analyzed and reviewed by the IDMC for recommendation. Section 5.5.7 Drug Accountability Fourth paragraph Add: new last sentence Rova-T is classified as a Dangerous Good/Hazardous Material according to US Department of Transportation (DOT) and International Air Transport Association (IATA).  
176 Dangerous Goods/Hazardous Materials must be packaged and shipped according to applicable regulations. Section 6.1.1.3 Adverse Events Expected Due to SCLC or Progression of SCLC Last paragraph previously read: "Disease progression" should not be captured when reporting AEs or SAEs, even if fatal, as disease progression is an efficacy endpoint for the trial. Rather, symptoms of disease progression should be reported as AEs or SAEs as appropriate.  
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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section 6.1.4 deaths second paragraph

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 AE and will not be subject to expedited reporting. These events should be captured as disease progression and recorded on the AE eCRF. After the AE reporting period, deaths attributed to progression of disease under study should not be recorded on the AE eCRF.  
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has been changed to read

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.
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section 6.1.5 adverse event collection

All adverse events reported from the time of blinded investigational product administration until 70 days following discontinuation of blinded investigational product administration will be collected, whether solicited or spontaneously reported by the subject.  
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. Section 6.1.6 Adverse Event Reporting "Primary Therapeutic Area Medical Director:" previously read:
Therapeutic Area Medical Director  
 AbbVie 200 Sidney Street Cambridge, MA 02139  
 Office: Mobile: Email:
Senior Medical Director AbbVie 1 North Waukegan Road North Chicago, IL 60064 USA
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section 6.1.6 adverse event reporting

The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with Directive 2001/20/EC. The reference document used for SUSAR reporting in the EU
countries will be the most current version of the Investigator's Brochure14 and the most current version of the Summary of Product Characteristics (SmPC).  
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.  
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Section 6.1.8.1 Management of Serosal Effusions/Serositis First paragraph, first sentence previously read: Serosal effusions (pleural or pericardial, or ascites) have been observed with rovalpituzumab tesirine and have the potential to be life-threatening (e.g., pericardial tamponade).  
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). Section 6.1.8.1 Management of Serosal Effusions/Serositis First paragraph Add: new fifth and sixth sentence 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.
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section 6.1.8.2 management of skin

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 Rova-  
 EudraCT 2016-003503-64 T/placebo to 0.1 mg/kg. Subjects with a grade 4 photosensitivity reaction must permanently discontinue Rova-T/placebo.
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section 6.1.8.2 management of skin

If clinically consistent with photosensitivity, the AE should be reported as such (using medically accurate and descriptive AE terminology), and managed as described below.  
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. Section 6.1.8.2 Management of Skin Reactions Third paragraph, first sentence previously read: Photo-documentation should be available upon request by the TA MD. Has been changed to read: Photo-documentation of skin toxicity should be available upon request by the TA MD. Section 6.1.8.4 Monitoring and Management of Edema Add: new section title and text
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6.1.8.4 monitoring and management of

The majority of the edema events with rovalpituzumab tesirine have been reported as low grade 1 or 2 (mild or moderate); however, a small number of fatal events of generalized edema have been reported with rovalpituzumab tesirine. Physical exams and monitoring of weight gain and signs or symptoms of fluid retention should be conducted during treatment. Edema events were reported during treatment and may occur up to several 181 months after last Rova-T dose. As a result subjects should be advised of signs and symptoms of fluid retention as well as monitor their weight and contact treating physician if they arise during this time. Consistent with institutional guidelines or standard practice, the use of diuretics with or without albumin may be considered in subjects with clinically significant edema and hypoalbuminemia. The selection and use of diuretics in subjects should be based on individual clinical characteristics and include monitoring of electrolyte status and signs or symptoms of intravascular volume depletion such as hypotension and impaired renal function. Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in some prior cases.  
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| Reported Term                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Grade 1                                    | Grade 2                                                                          | Grade 3   | Grade 4   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------------------------------------------|-----------|-----------|
| Generalized  edema  (Anasarca)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Noted on exam;                             | Interfering with                                                                 |           |           |
| 1+ pitting edema                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | instrumental ADLs; oral  therapy initiated | Interferes with  self care ADL;  intravenous  therapy indicated;  skin breakdown | Lifethreatening  consequences           |           |
| Definition: A disorder characterized by fluid accumulation in the tissues of the body including the skin. Edema trunk Swelling or  obscuration of  anatomic  architecture on  close inspection Readily apparent  obscuration of anatomic  architecture; obliteration  of skin folds; readily  apparent deviation from  normal anatomic contour;  limiting instrumental ADL Gross deviation  from normal  anatomic contour;  limiting self care  ADL - Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area. Edema limbs 5 - 10% inter-limb  discrepancy in  volume or  circumference at  point of greatest  visible difference;  swelling or  obscuration of  anatomic  architecture on  close inspection > 10 - 30% inter-limb  discrepancy in volume or  circumference at point of  greatest visible difference;  readily apparent  obscuration of anatomic  architecture; obliteration  of skin folds; readily  apparent deviation from  normal anatomic contour;  limiting instrumental ADL > 30% inter-limb  discrepancy in  volume; gross  deviation from  normal anatomic  contour; limiting  self care ADL - Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or  lower extremities |                                            |                                                                                  |           |           |
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section 6.1.8.5 pneumonitis add new

Pneumonitis has been infrequently reported with rovalpituzumab tesirine but has resulted in fatal outcomes. Although the causal role of rovalpituzumab tesirine could not be ruled out, the reports of pneumonitis had one or more confounders including underlying pulmonary disease/cancer, prior thoracic radiation, prior cytotoxic chemotherapy or clinical evidence suggestive of an alternative diagnosis including pneumonia. Heavily pretreated SCLC patients and patients with a history of pneumonitis may be at increased risk, and careful monitoring for signs and symptoms of pneumonitis is important. The risk of pneumonitis is increased with prior radiation to lung. In general, signs and symptoms coinciding with or preceding pneumonitis may include new or worsening cough, chest pain and/or shortness of breath, fever, and radiographic changes (reticular markings, ground glass opacities). Protocol defined disease assessments provide the opportunity for on study pulmonary monitoring with "gold standard" diagnostic method for detection of pneumonitis. The protocol allows for additional imaging per physician discretion for signs and symptoms of pulmonary toxicity. The diagnosis of drug induced pneumonitis is one of exclusion. Other etiologies including infection, which is a common cause of pulmonary infiltrates with clinical and radiographic appearance similar to drug-induced pneumonitis, need to be carefully considered and excluded before the diagnosis of drug induced pneumonitis can be established. If pneumonitis is suspected, close monitoring including additional laboratory and imaging investigation per institutional guidelines may be necessary. Systemic corticosteroids may be beneficial for rapidly progressive or more severe pneumonitis. For events of Grade 1 pneumonitis close monitoring is recommended; while dose modifications for Grade 2 and discontinuation of Rova-T for Grades 3 and 4 are required. Please see Table 5. EudraCT 2016-003503-64 Section 7.0 Protocol Deviations Contact Information previously read:
Primary Contact: Study Management Associate III AbbVie  
   
Has been changed to read:
Primary Contact: Study Project Manager II AbbVie Corporation 8401 Trans-Canada Highway Saint-Laurent, Québec H4S 1Z1 Canada  
 Fax:
Section 8.1 Statistical and Analytical Plans Second paragraph previously read:
Alternate Contact:  
  
  
North Chicago, IL 60064  
  
  
Alternate Contact: Study Project Manager I AbbVie s.r.o. METRONOM BUSINESS CENTER Bucharova 2817/13, Stodulky, 158 00 Praha 5 Czech Republic  
| Phone: Fax: Email:   |
|----------------------|  
  
Two analyses are planned for this study. The first will be performed when at least 407 progression-free survival (PFS) events, assessed by a Central Radiographic Assessment Committee (CRAC) according to RECIST v1.1, and at least 239 deaths have occurred in subjects with DLL3high. The second analysis will be performed when at least 319 deaths have occurred in subjects with DLL3high.  
The primary endpoints of OS and progress free survival (PFS) assessed by a Central Radiographic Assessment Committee (CRAC) according to RECIST v1.1 in DLL3high patients will be analyzed at the same time after observing at least 319 OS events. It is expected at approximately 420 PFS events will be observed at the time of the primary analysis.
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section 8.1 statistical and analytical

- DLL3high **Set:** It includes all randomized subjects with DLL3high. Subjects will be classified according to the treatment arm to which they are randomized regardless the actual treatment received, following intent-to-treat principle.  
The DLL3high set will be the primary analysis set for the analysis of efficacy endpoints.  
- **Randomized Set:** It includes all randomized subjects, with subjects grouped according to the treatment arm to which they are randomized regardless the actual treatment received, following intent-to-treat principle. The randomized set will be used for supportive analysis of efficacy endpoints.  
- DLL3high **Set:** It includes all randomized subjects with DLL3high ED SCLC.  
Subjects will be classified according to the treatment arm to which they are randomized regardless the actual treatment received, following intent-to-treat principle. The DLL3high set will be the analysis set for the analysis of the primary efficacy endpoints of OS and PFS. All the exploratory efficacy endpoints will be analyzed based on the DLL3high set unless the OS and PFS
based on the randomized set are statistically significant.  
- **Randomized Set:** It includes all randomized subjects, with subjects grouped according to the treatment arm to which they are randomized regardless the actual treatment received, following intent-to-treat principle. The randomized set will be the analysis set for key secondary efficacy endpoints of OS and PFS, and key secondary endpoint of EORTC QLQ-C30 physical functioning domain. All the exploratory efficacy endpoints will be analyzed based on the randomization set if the OS and PFS based on the randomization set are statistically significant.
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section 8.1.3 efficacy endpoints and

Unless specified otherwise, efficacy analyses will be performed in the DLL3high set.  
Section 8.1.4 Primary Efficacy Endpoints First paragraph previously read: Progression-free survival (PFS) and overall survival (OS) are the two primary efficacy endpoints. No order of testing of these two endpoints is specified.  
Progression-free survival (PFS) and overall survival (OS) in subjects with DLL3high ED
SCLC are the two primary efficacy endpoints.  
187
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section 8.1.4 primary efficacy endpoints

Third paragraph, second sentence previously read: The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's proportional hazards model stratified by randomization stratification factors.  
The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's proportional hazards regression model adjusting for the main-effects of the stratification factors.  
Third paragraph, last sentence previously read: Estimates of the treatment effect will be expressed as hazard ratio including 95% confidence intervals estimated through a Cox proportional-hazards analysis stratified by randomization stratification factors.  
Estimates of the treatment effect will be expressed as hazard ratio including 95% confidence intervals estimated through a Cox proportional-hazards regression model adjusting for the main-effects of the stratification factors. Section 8.1.4 Primary Efficacy Endpoints Last paragraph, third sentence previously read: The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's proportional hazards model stratified by randomization stratification factors.  
188  
The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's proportional hazards regression model adjusting for the main-effects of the stratification factors.
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section 8.1.4 primary efficacy endpoints

Estimates of the treatment effect on will be expressed as hazard ratio including 95% confidence intervals estimated through a Cox proportional-hazards analysis stratified by randomization stratification factors.  
Estimates of the treatment effect on will be expressed as hazard ratio including 95% confidence intervals estimated through Cox proportional-hazards regression models adjusting for the main-effects of the stratification factors.
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section 8.1.5 secondary efficacy endpoints

The secondary efficacy endpoints in the DLL3high set are:
- Objective response rate (ORR) per the CRAC based on RECIST v1.1 - Change in patient reported outcomes (PROs) - physical functioning domain - PFS per investigator assessment based on RECIST v1.1 - ORR per investigator assessment based on RECIST v1.1 - Clinical benefit rate (CBR) per the CRAC and investigator assessment, respectively, based on RECIST v1.1
- Duration of response (DOR) per CRAC and investigator assessment, respectively The following endpoints in the randomized set are also included in the secondary efficacy endpoints:
- OS - PFS per the CRAC based on RECIST v1.1 - ORR per the CRAC based on RECIST v1.1 Secondary time-to-event endpoints (PFS and OS) will be analyzed using the similar statistical methods described for the primary endpoints. The duration of overall response for a given subject will be defined as the number of months from the day the criteria are met for complete response (CR) or partial response (PR) by CRAC (whichever is recorded first) to the date of progressive disease or death, whichever comes first. If a subject is still responding (i.e., has not progressed nor died after CR or PR), then the subject's data will be censored at date of the last radiographic assessment by CRAC. For subjects who never experienced CR or PR, these subjects' data will not be included in the duration of response analysis. Distribution of the duration of response will be estimated for each treatment arm using Kaplan-Meier methodology. Median duration of overall response with corresponding 95% CI for each treatment arm will be provided. ORR and CBR in the treatment arm will be compared using Cochran-Mantel-Haenszel test stratified by randomization stratification factors. Rates and 95% confidence intervals will be reported for each treatment arm.
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has been changed to read

The secondary efficacy endpoints in the randomized set are:
- OS - PFS per the CRAC based on RECIST v1.1 - EORTC QLQ-C30 physical functioning domain Secondary time-to-event endpoints (PFS and OS) will be analyzed using the similar statistical methods described for the primary endpoints.
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8.1.6 exploratory efficacy endpoints

The exploratory efficacy endpoints in both DLL3high and randomization set are:
- Objective response rate (ORR) per the CRAC based on RECIST v1.1 - PFS per investigator assessment based on RECIST v1.1 - ORR per investigator assessment based on RECIST v1.1 - Clinical benefit rate (CBR) per the CRAC and investigator assessment, respectively, based on RECIST v1.1
- Duration of response (DOR) per CRAC and investigator assessment, respectively
- Change from baseline in all PRO domains (except physical functioning)
measured by EORTC QLQ-C30/LC13 and EQ-5D-5L
ORR is defined as the proportion of patients with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) by CRAC review according to RECIST v1.1. CBR is defined as the proportion of patients with a BOR of CR or PR, or SD by CRAC review according to RECIST v1.1. ORR and CBR in treatment arms will be compared using Cochran-Mantel-Haenszel test stratified by randomization stratification factors. Rates and 95% confidence intervals will be reported for each treatment arm. The duration of overall response for a given subject will be defined as the number of months from the day the criteria are met for confirmed complete response (CR) or partial response (PR) by CRAC (whichever is recorded first) to the date of progressive disease or death, whichever comes first. If a subject is still responding (i.e., has not progressed nor died after CR or PR), then the subject's data will be censored at date of the last radiographic assessment by CRAC. For subjects who never experienced CR or PR, these subjects' data will not be included in the duration of response analysis. Distribution of the duration of response will be estimated for each treatment arm using Kaplan-Meier methodology. Median duration of overall response with corresponding 95% CI for each treatment arm will be provided. Section 8.1.6 Patient Reported Outcomes (PRO) First sentence previously read: Physical functioning scale score in EORTC QLQ-C30 is the primary PRO endpoint. Has been changed to read: Physical functioning scale score in EORTC QLQ-C30 is the key secondary endpoint. Section 8.1.7 Planned Sensitivity and Subgroup Analyses Delete: first paragraph Efficacy analyses for PFS per investigator assessment and ORR per investigator assessment will be performed in the randomized set. Section 8.1.7 Planned Sensitivity and Subgroup Analyses Delete: third paragraph The physical functioning scale score (EORTC QLQ-C30) will be evaluated using an ANOVA model in the randomized set.  
192  
  
Section 8.1.7 Planned Sensitivity and Subgroup Analyses Delete: last paragraph In the DLL3high and randomized sets, CRAC assessed ORR will be compared between the 2 arms, using a chi-square test for each subgroup. Odds ratios will be presented. Section 8.1.8 Pharmacokinetic and Exposure-Response Analyses First paragraph previously read: Plasma concentrations of rovalpituzumab tesirine ADC as well as the incidence and timing of ATA formation will be tabulated and summary statistics will be computed. Plasma concentration and ATA data from this study may be combined with data from other studies and analyzed using population pharmacokinetic methodologies.  
Serum concentrations of rovalpituzumab tesirine ADC as well as the incidence and timing of ATA formation will be tabulated and summary statistics will be computed. Serum concentration and ATA data from this study may be combined with data from other studies and analyzed using population pharmacokinetic methodologies.
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section 8.3 type i error

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, overall survival (OS), ORR per CRAC, and physical functioning scale score (EORTC QLQ-C30).  
The following null hypotheses are considered for subjects with DLL3high:
H1: Rovalpituzumab tesirine arm is not superior to placebo arm in both PFS and OS.  
193 H2: Rovalpituzumab tesirine arm is not superior to placebo arm in ORR per CRAC. H3: Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning scale score (EORTC QLQ-C30). The null hypotheses will be tested in a fixed sequence of {H1, H2, H3} in order. To maintain the family-wise type I error for the study, the null hypothesis H1 will be first tested with an alpha-split approach. The hypothesis for PFS will be tested at a one-sided 0.25% level of significance and the hypothesis for OS at a one-sided 2.25% level of significance. If either PFS or OS endpoint reaches statistical significance, the study is considered positive. No further tests will be performed if H1 is not rejected. Each hypothesis of H2 and H3 will be tested in order specified above if H1 is rejected and the preceding hypothesis shows statistically significant results at the 1-sided 2.5% level of significance. Otherwise testing in the hierarchical sequence will stop. The secondary efficacy endpoints, e.g., PFS per investigator assessment, ORR per investigator assessment, CBR per CRAC, CBR per investigator assessment, DOR per CRAC, DOR per investigator assessment, and PRO evaluations in the DLL3high set will be tested at a one-sided 2.5% level of significance. Similarly, OS, PFS per CRAC, and ORR per CRAC in the randomized set will be tested at a one-sided 2.5% level.  
To meet global regulatory requirements, a multiple testing strategy will be implemented to control the family-wise type I error (alpha) to one-sided 0.025 level for comparisons of rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival
(PFS) per CRAC in DLL3high set, overall survival (OS) in DLL3high set, PFS per CRAC in randomized set, OS in randomized set, and physical functioning scale score (EORTC QLQ-C30) in 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 H01a 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. 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.  
195
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abbvie

M16-298 Protocol Amendment 4 EudraCT 2016-003503-64 Diagram of Hierarchical Testing of Primary and Secondary Endpoints is described in Figure 3.  
Figure 3.  
Diagram of Hierarchical Testing of Primary and Secondary Endpoints
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section 8.4 determination of sample

There are two primary efficacy endpoints for this study: Progression-free survival (PFS) based on the CRAC and overall survival (OS). 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. 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 arm will be around 9 months.4,5 Based on a log-rank test, at a one-sided significance level of 0.0225 and a power of 90%, a total of 319 deaths among subjects with DLL3high are needed to detect an increase of median OS to 13 months in rovalpituzumab tesirine arm, corresponding to a hazard ratio of 0.69 (i.e., a reduction in the hazard death of 31%). 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. It is projected that an observed hazard ratio of 0.795 or less, corresponding to a 2.3 months or greater improvement in median OS, would result in a statistically significant improvement in the final analysis of OS. It is assumed, taking into account the expected patient population for the study, that median progression-free survival for the placebo arm will be approximately 3 months.4,5 Treatment with rovalpituzumab tesirine is hypothesized to increase median progressionfree survival to 4.5 months (i.e., a hazard ratio of 0.667). With approximately 407 PFS
events assessed by the CRAC for subjects with DLL3high, the study provides a 90% power to detect a hazard ratio of 0.667 in PFS at a one-sided significance level of 0.0025. It is projected that an observed hazard ratio of 0.757 or less, corresponding to approximately 197 1 month or greater improvement in median PFS, would result in a statistically significant improvement in the PFS. The primary analysis of PFS will take place when at least 407 CRAC assessed PFS events and at least 239 deaths (an interim efficacy analysis of OS with approximately 75% of targeted 319 deaths) have occurred in subjects with DLL3high. When both conditions specified for the numbers of PFS and OS events are satisfied, the primary analysis of PFS and the interim efficacy analysis of OS will be performed at the same time. The final analysis of OS is projected to be approximately 31 months from first subject enrolled when approximately 319 deaths have occurred in subjects with DLL3high.  
There are two primary efficacy endpoints for this study: Progression-free survival (PFS)
based on the CRAC and overall survival (OS) in DLL3high ED SCLC patients. 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 progression-free 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 approximately 420 PFS events assessed by the CRAC for the subjects with DLL3high are needed to achieve a 91% power based on a log-rank 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.
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section 8.5 interim analysis section

An interim efficacy analysis is planned for overall survival after at least 239 deaths in subjects with DLL3high (i.e., 75% of planned deaths are observed) using a one-sided logrank test.  
The O'Brien-Fleming method will be implemented to protect the type I error rate of 0.0225 for OS. A one-sided alpha spending of 0.0084 for the interim will be allocated for declaring statistical superiority in OS at the time of the interim analysis. The final analysis of OS will be performed at a one-sided nominal alpha level of 0.01998, adjusting for the interim look at OS data. If the interim analysis of OS meets the O'Brien-Fleming boundary for statistical significance, the final OS analysis will be considered descriptive. Unblinded interim data will be analyzed and reviewed by the IDMC. The trial may be considered for early stopping for superiority and the Sponsor will be unblinded to the aggregated data by randomized treatment arms if the IDMC makes such a recommendation after consideration of the PFS and OS results, and all supportive evidence including other efficacy endpoints and safety. In the event that the IDMC recommends continuing the study due to lack of evidence for superiority, the unblinded interim results will be kept confidential to the investigators, subjects, sponsors, and personnel involved in the conduct of the study until the end of the study, since the final analyses of OS and all other endpoints will be performed in an inferentially seamless manner. Subjects already enrolled in the study will continue rovalpituzumab tesirine or placebo treatment in a blinded fashion to obtain more mature OS data for a robust characterization of treatment effect. Details for the interim efficacy analysis will be provided in the IDMC charter.
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has been changed to read

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 in the DLL3high set at futility 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. Unblinded interim data will be analyzed and reviewed by the IDMC. The trial may be considered for early stopping for futility and the Sponsor will be unblinded to the aggregated data by randomized treatment arms if the IDMC makes such a 200 recommendation after consideration of the OS results and other supportive evidence including other relevant efficacy and safety data. Details for the futility analysis will be provided in the IDMC charter. Section 8.6 Accrual/Study Duration Considerations Last sentence previously read:
It is projected that 480 subjects with DLL3high will have enrolled for the interim analysis by the time at least 407 PFS events per CRAC and at least 239 OS events should be observed in subjects with DLL3high, and subjects have completed approximately 5 months of follow-up.  
It is projected that 480 subjects with DLL3high ED SCLC will have enrolled for the primary analysis by the time approximately 420 PFS events per CRAC and at least 319 OS events should be observed in DLL3high subjects after approximately 8 - 10 months of follow-up.
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section 10.1 source documents first

The Investigator Awareness Date (SAE CRF) may serve as the source for this data point. This adverse event data point required for eCRF completion can be entered directly in the eCRF.  
The Investigator Awareness Date of SAE should be noted in the source.  
201
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section 15.0 references

Add: new Reference 19 AbbVie. Rovalpituzumab Tesirine Dear Rova-T Investigator Letter. 05 December 2018. Appendix B. List of Protocol Signatories Previously read:  
| Name   | Title   | Functional Area Clinical Clinical Clinical Pharmacokinetics Clinical Drug Supply Management Statistics Bioanalysis   |
|--------|---------|----------------------------------------------------------------------------------------------------------------------|  
Has been changed to read:  
| Name   | Title   | Functional Area Clinical Clinical Pharmacokinetics Clinical Drug Supply Management Statistics Bioanalysis   |
|--------|---------|-------------------------------------------------------------------------------------------------------------|  
EudraCT 2016-003503-64  
  
| Survival  FU  (OS)d Treatmentb PTFUc End of                                          | Weeks  (±1wk)                               |                                                                                                       |
|--------------------------------------------------------------------------------------|---------------------------------------------|-------------------------------------------------------------------------------------------------------|
| q6 Weeks  (±1wk) q6                                                                  |                                             |                                                                                                       |
| Within 7 Days  of Decision to  Discontinue  Treatment (Day 8, 15, 22,  29, 36) (±3d) | X                                           |                                                                                                       |
| Non-Treatment  Cycle Visita                                                          | Weekly                                      | Day 1 (±3d) Day  36 Day  29 Day 22  (–3d) Day  15 Day  8 Day  2 Day 1e (–3d) Day –1 Day –21 to Day –1 |
| Treatment (Each Cycle)                                                               |                                             |                                                                                                       |
| Appendix C. Study Activities                                                         | Category "Echocardiogramn" previously read: | Category Description                                                                                  |
| Screening                                                                            | Echocardiogramn X Safety  Assessments       |                                                                                                       |  
| Survival  FU  (OS)d Treatmentb PTFUc End of                                          | Weeks  (±1wk)                           |                                                                                                       |
|--------------------------------------------------------------------------------------|-----------------------------------------|-------------------------------------------------------------------------------------------------------|
| q6 Weeks  (±1wk) q6                                                                  |                                         |                                                                                                       |
| Within 7 Days  of Decision to  Discontinue  Treatment (Day 8, 15, 22,  29, 36) (±3d) | X                                       |                                                                                                       |
| Non-Treatment  Cycle Visita                                                          | Weekly                                  | Day 1 (±3d) Day  36 Day  29 Day 22  (–3d) Day  15 Day  8 Day  2 Day 1e (–3d) Day –1 Day –21 to Day –1 |
| Treatment (Each Cycle)                                                               | Echocardiogramn X X Safety  Assessments |                                                                                                       |
| Screening                                                                            |                                         |                                                                                                       |
| Has been changed to read:                                                            | Category Description                    |                                                                                                       |  
203 Appendix C. Study Activities Table note "b." previously read: End of Treatment Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.  
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. Appendix C. Study Activities Table note "e.," first sentence previously read: Cycle 1 Day 1 procedures do not need to be repeated if performed within 21 days of randomization unless clinically indicated.  
Cycle 1 Day 1 procedures, with the exception of weight, do not need to be repeated if performed within 21 days of randomization unless clinically indicated. Appendix C. Study Activities Table note "n." previously read: Echocardiogram will be performed to assess any pericardial effusion, if present, as well as cardiac function (left ventricular ejection fraction, LVEF).  
Echocardiograms are required at Screening, Day 1 of each cycle starting C2D1, and EOT. Screening echocardiogram will be performed within 7 business days of randomization to 204 assess for the presence of any pericardial effusion as well as cardiac function (left ventricular ejection fraction, LVEF). Subsequent echocardiograms should be performed within –3 business days of dosing visit to assess for the presence of any pericardial effusion. Additional echocardiogram monitoring may occur as clinically indicated during the study.
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appendix c. study activities table

Scheduled tumor assessments will not be affected by delays in therapy and/or drug holidays.  
Whenever possible, scheduled tumor assessments should not be affected by delays in therapy and/or drug holidays. 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.
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appendix c. study activities table

MRI/CT of the brain is only required at screening and when clinically indicated (e.g., if CNS progression is suspected).  
MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS progression is suspected) thereafter.  
205