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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 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.  
89 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.  
| 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 |                                            |                                                                                  |           |           |  
Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in some prior cases.
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6.1.8.5 pneumonitis

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.  
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6.2 product complaint 6.2.1 definition

A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the biologic or drug component of the product. For a product this may include, but is not limited to, damaged/broken product or packaging, product appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the labeling/instructions (example: printing illegible), missing components/product, or packaging issues. Any information available to help in the determination of causality to the events outlined directly above should be captured. Product Complaints concerning the investigational product must be reported to the Sponsor within 24 hours of the study site's knowledge of the event via the Product Complaint eCRF. Product Complaints occurring during the study will be followed-up to a satisfactory conclusion. All follow-up information is to be reported to the Sponsor (or an authorized representative) and documented in source as required by the Sponsor. Product Complaints associated with adverse events will be reported in the study summary. All other complaints will be monitored on an ongoing basis. Product Complaints may require return of the product with the alleged complaint condition. In instances where a return is requested, every effort should be made by the investigator to return the product within 30 days. If returns cannot be accommodated within 30 days, the site will need to provide justification and an estimated date of return. The description of the complaint is important for AbbVie in order to enable AbbVie to investigate and determine if any corrective actions are required.  
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7.0 protocol deviations

AbbVie does not allow intentional/prospective deviations from the protocol unless when necessary to eliminate an immediate hazard to study subjects. The principal investigator is responsible for complying with all protocol requirements, and applicable global and local laws regarding protocol deviations. If a protocol deviation occurs (or is identified) after a subject has been enrolled, the principal investigator is responsible for notifying Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory authorities (as applicable), and the following AbbVie Clinical Monitor(s):
Primary Contact:
Alternate Contact:  
| Study Project Manager II AbbVie Corporation 8401 Trans-Canada Highway Saint-Laurent, Québec H4S 1Z1 Canada   | Study Project Manager I AbbVie s.r.o. METRONOM BUSINESS CENTER Bucharova 2817/13, Stodulky, 158 00 Praha 5 Czech Republic   |
|--------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| Phone:                                                                                                       | Phone:                                                                                                                      |  
 Fax:  
  
Such contact must be made as soon as possible to permit a review by AbbVie to determine the impact of the deviation on the subject and/or the study. In Japan, the Investigator will record all protocol deviations in the appropriate medical records at site.  
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8.0 statistical methods and determination

This section describes the planned statistical analyses to be performed using data captured according to this protocol. A complete statistical analysis plan (SAP) describing in more detail all planned analyses will be finalized prior to database lock.  
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. The following analysis sets are considered:
- 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.  
- **Per Protocol Set:** It includes all subjects in the randomized set without any major protocol violations which may affect the evaluation of the primary 94 efficacy endpoint. Major protocol violations will be defined in the SAP prior to the database lock. Subjects will be classified according to treatment assigned at the time of randomization. The per protocol set will be used for supportive analysis of efficacy endpoints.  
- **Safety Set:** It includes all subjects who received at least one dose of study drug and subjects will be classified according to treatment received. Thus a subject who is randomized to the rovalpituzumab tesirine arm but does not receive rovalpituzumab tesirine will be considered in the placebo arm for safety analysis. Dexamethasone treatment will not be taken into consideration for subjects' classification in the Safety set.  
- **Pharmacokinetic-Evaluable Set:** It consists of all subjects who receive at least one dose of study drug, with subjects classified according to the actual treatment received. A baseline measurement and at least one blood sample following a dose of study treatment is required for inclusion in this analysis.
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8.1.1 disposition of study subjects

The disposition of subjects will be summarized by treatment arm in the randomized set. The subject disposition includes the number of subjects for whom study drug was permanently discontinued (including the reasons for discontinuation), and the number of subjects who discontinued early from the study.
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8.1.2 demographics and baseline characteristics

Demographic and baseline characteristics will be summarized in the DLL3high set and randomized set.
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8.1.3 efficacy endpoints and analyses

Assessment of response and progression will be determined by the CRAC according to RECIST v1.1.  
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8.1.4 primary efficacy endpoints

Progression-free survival (PFS) and overall survival (OS) in subjects with DLL3high ED
SCLC are the two primary efficacy endpoints. PFS will be defined as the number of months from randomization to disease progression, as assessed by the CRAC per RECIST v1.1, or death of any cause, whichever occurs first.  
Disease progression and censoring rules will be based on published conventions.15 If a subject neither experienced disease progression nor died, then the data will be censored at the last date of post-baseline radiographic assessment. If a subject with no post-baseline assessment did not experience disease progression nor died, then the data will be censored at the date of randomization. Differences between the treatment arm and the placebo arm in PFS will be assessed by a log-rank test stratified by the randomization stratification factors, testing the null hypothesis (rovalpituzumab tesirine arm is not superior to placebo arm in PFS). 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. Median PFS and 95% confidence intervals will be estimated using Kaplan-Meier survival methodology, with the Kaplan-Meier survival curves presented to provide a visual description. PFS rates at 3, 6, 9, and 12 months after randomization with 95% confidence intervals will be reported. Estimates of the treatment effect will be expressed as hazard ratio including 95% confidence intervals estimated through a Cox proportionalhazards regression model adjusting for the main-effects of the stratification factors.  
Overall survival will be defined as the number of months from randomization to death of any cause. OS and censoring rules will be based on published conventions.15 If a subject has not died, the data will be censored at the last date documented to be alive. Differences between the treatment arm and the placebo arm in OS will be assessed by a log-rank test stratified by the randomization stratification factors, testing the null hypothesis (rovalpituzumab tesirine arm is not superior to placebo arm in OS). The 96 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. Median OS and 95% confidence intervals will be estimated using Kaplan-Meier survival methodology, with the Kaplan-Meier survival curves presented to provide a visual description. OS rate at 6, 12, 18, and 24 months and corresponding 95% confidence intervals will be reported. 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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8.1.5 secondary efficacy endpoints

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
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- 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.
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8.1.7 patient reported outcomes (pro)

The EORTC QLQ-C30/LC1313 scoring manual will be used to transform the raw scores into the domain scores (global heath, functional scales, symptom scales/items). Physical functioning scale score in EORTC QLQ-C30 is the key secondary endpoint. Change from baseline of the items and domains of the QLQ-C30/LC13 will be summarized by treatment arm. The EQ-5D-5L manual and the published weights will be used to convert the individual items to the utility scores. Change from baseline of the EQ-5D-5L utility 98 score and VAS will be summarized by treatment arm. The treatment group differences will be evaluated by analyzing the change from baseline using a one-way analysis of variance (ANOVA) model.
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8.1.8 planned sensitivity and subgroup

Efficacy analyses for the primary endpoints (PFS per CRAC and OS) will be performed in the per-protocol set.  
In the DLL3high and randomized sets, treatment effects for the primary endpoints (PFS per CRAC and OS) will be assessed in the following subgroups:
- RECIST v1.1 response after completion of first-line platinum-based therapy at screening assessment (SD vs. PR/CR)  
- DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above) for the randomized set only
- History of CNS metastases (Yes vs. No) - For subjects with no history of CNS metastases, PCI vs. No PCI
- Lactate dehydrogenase (LDH), ≤ ULN vs. > ULN  
- Number of metastatic sites, 0 - 1 vs. > 1 - Age group (age < 40 vs. 40 to < 60 vs. 60 or older)
- Gender  
- Race
- ECOG (0 vs. 1)
Differences between rovalpituzumab tesirine arm and the placebo arm for time-to-event endpoints will be assessed by an unstratified log-rank test for each subgroup. Hazard ratios of treatment arm over the placebo arm will be calculated by a Cox's model.
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8.1.9 pharmacokinetic and exposure-response analyses

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 99  
  
concentration and ATA data from this study may be combined with data from other studies and analyzed using population pharmacokinetic methodologies. The relationship between pharmacokinetics (e.g., exposure) and clinical trial findings including, but not limited to demographics, efficacy, and/or safety measures may also be explored. Additional analyses will be performed if useful. Results of the population pharmacokinetic and exposure-response analyses will be provided in a separate report.
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8.2 safety analyses

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, and concomitant medications used. NCI CTCAE version 4.0 will be used in the grading of adverse events and laboratory abnormalities that are reported as adverse events.
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8.2.1 treatment-emergent adverse events (teaes)

TEAEs reported during the study will be coded using a MedDRA16 dictionary. Incidence of TEAEs will be summarized by treatment arm and the following:
- System organ class and preferred term - System organ class, preferred term, and severity These summaries will be presented for the following subsets:
- Serious TEAEs - All TEAEs - Drug-related TEAEs For tables reporting AEs by severity, if a subject has multiple occurrences of an AE with the same organ class and preferred term, the most severe event will be presented.  
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8.2.2 clinical laboratory evaluation

Laboratory parameters will be summarized by treatment arm at each visit. Each summary will include the values of the laboratory parameters and changes from baseline. Shift tables from baseline will be presented for laboratory values in the chemistry and hematology panels. Parameters will be classified according to the laboratory reference normal ranges. A listing will be provided for out-of-normal range as well as clinically significant abnormal lab values.
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8.2.3 vital signs

Vital signs including pulse, blood pressure, temperature, and body weight will be summarized by treatment arm and time point. For each assessment of vital signs, change from baseline will be summarized by treatment arm.
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8.2.4 ecog performance status

ECOG performance status will be summarized for each visit by treatment arm. Shifts from baseline to the best and worst post-baseline score may be tabulated.
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8.2.5 electrocardiogram

ECG status will be summarized for each scheduled visit by treatment arm. Shifts from baseline may be tabulated.
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8.2.6 concomitant medications

Concomitant medications will be classified according to the anatomical therapeutic chemical (ATC) codes in the World Health Organization Drug (WHODRUG) dictionary. The incidence rate of each coded concomitant medication will be tabulated by treatment arm. The table will be sorted by the incidence use of the entire sample.
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8.3 type i error adjustment

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.  
102 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.  
Diagram of Hierarchical Testing of Primary and Secondary Endpoints is described in Figure 3.  
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abbvie

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

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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8.5 futility analysis

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 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.
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8.6 accrual/study duration considerations

On average, it is expected that accrual rates are 1, 7, 27, 36, and 42 with DLL3high subjects per month at study initiation, 3, 6, 9, and 12 month and thereafter, respectively. The total study duration and accrual duration are projected to be 31 months and 19 months with a 5% rate of loss to follow-up, respectively. A total of 740 subjects regardless of DLL3 expression level in tumor are expected to enroll during the accrual period. 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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8.7 randomization methods

The randomization numbers of the study will assign subjects in a 1:1 ratio to either receive 0.3 mg/kg rovalpituzumab tesirine or placebo, on Day 1 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 therapy at screening assessment (SD vs. PR/CR), DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of CNS metastases (Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI.
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9.0 ethics 9.1 independent ethics

Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the Investigator's Brochure,14 the informed consent and all other forms of subject information related to the study (e.g., advertisements used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and medical appropriateness of the study before it is conducted. IEC/IRB approval of the protocol, informed consent and subject information and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to a study site. Any amendments to the protocol will require IEC/IRB (Competent Authority, if applicable) approval prior to implementation of any changes made to the study design. The investigator will be required to submit, maintain and archive study essential documents according to ICH GCP and all other applicable regulatory requirements. Any serious adverse events that meet the reporting criteria, as dictated by local regulations, will be reported to both responsible Ethics Committees and Regulatory Agencies, as required by local regulations. During the conduct of the study, the investigator should promptly provide written reports (e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to subjects. Written documentation of the submission to the IEC/IRB should also be provided to AbbVie.
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9.2 ethical conduct of the

The study will be conducted in accordance with the protocol, International Conference on Harmonization (ICH) guidelines17,18 applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. Responsibilities of the clinical investigator are specified in Appendix A.
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9.3 subject information and consent

The investigator or his/her representative will explain the nature of the study to the subject, and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement will be reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements. A copy of the informed consent form will be given to the subject and the original will be placed in the subject's medical record. An entry must also be made in the subject's dated source documents to confirm that informed consent was obtained prior to any study-related procedures and that the subject received a signed copy. Information regarding incentives for subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the study can be found in the informed consent form. Tumor material obtained by biopsy procedure at the time of disease progression (for exploratory research) is optional and will only be performed if the subject has voluntarily signed and dated an optional tumor material biopsy procedure informed consent, approved by an IEC/IRB, after the nature of the testing has been explained and the subject has had an opportunity to ask questions. If the subject does not consent to the optional informed consent, it will not impact the subject's participation in the study. In the event a subject withdraws consent to participate from the study, stored biomarker and tumor specimen for exploratory research will continue to be used for research and analysis. In the event that a subject would like to withdraw consent for research using these samples, the subject may request that their samples be withdrawn. Once AbbVie receives the request, remaining biomarker and tumor specimen for exploratory research will be destroyed. If the subject changes his/her consent, and the samples have already been tested, those results will still remain as part of the overall research data.
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9.3.1 informed consent form and

In Japan, the principal investigator will prepare the consent form and explanatory material required to obtain subject's consent to participate in the study with the cooperation of the sponsor and will revise these documents as required. The prepared or revised consent forms and explanatory material will be submitted to the sponsor. Approval of the IRB will be obtained prior to use in the study.
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9.3.2 revision of the consent

In Japan, when important new information related to the subject's consent becomes available, the principal investigator will revise the consent form and explanatory material based on the information without delay and will obtain the approval of the IRB prior to use in the study. The investigator will provide the information, without delay, to each subject already participating in the study, and will confirm the intention of each subject to continue the study or not. The investigator shall also provide a further explanation using the revised form and explanatory material and shall obtain written consent from each subject of their own free will to continue participating in the study.  
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10.0 source documents and case

Source documents are defined as original documents, data and records. This may include hospital records, clinical and office charts, laboratory data/information, subjects' diaries or evaluation checklists, pharmacy dispensing and other records, recorded data from automated instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. Data collected during this study must be recorded on the appropriate source documents. The Investigator Awareness Date of SAE should be noted in the source. The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review, and regulatory inspection(s), providing direct access to source data documents.
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10.2 case report forms

Case report forms (CRF) must be completed for each subject screened/enrolled in this study. These forms will be used to transmit information collected during the study to AbbVie and regulatory authorities, as applicable. The CRF data for this study are being collected with an electronic data capture (EDC) system called Rave® provided by the technology vendor Medidata Solutions Incorporated, NY, USA. The EDC system and the study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR Part 11. The documentation related to the validation of the EDC system is available through the vendor, Medidata, while the validation of the study-specific eCRFs will be conducted by AbbVie and will be maintained in the Trial Master File at AbbVie. The investigator will document subject data in his/her own subject files. These subject files will serve as source data for the study. All eCRF data required by this protocol will be recorded by investigative site personnel in the EDC system. All data entered into the eCRF will be supported by source documentation.  
110 The investigator or an authorized member of the investigator's staff will make any necessary corrections to the eCRF. All change information, including the date and person performing the corrections, will be available via the audit trail, which is part of the EDC system. For any correction, a reason for the alteration will be provided. The eCRFs will be reviewed periodically for completeness, legibility, and acceptability by AbbVie personnel (or their representatives). AbbVie (or their representatives) will also be allowed access to all source documents pertinent to the study in order to verify eCRF entries. The principal investigator will review the eCRFs for completeness and accuracy and provide his or her electronic signature and date to eCRFs as evidence thereof. Medidata will provide access to the EDC system for the duration of the trial through a password-protected method of internet access. Such access will be removed from investigator sites at the end of the site's participation in the study. Data from the EDC system will be archived on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as a durable record of the site's eCRF data. It will be possible for the investigator to make paper printouts from that media. Patient reported data must be completed for each subject screened/enrolled in this study. Some of these data are being collected with an Electronic Patient Reported Outcome (ePRO) system called Trialmax, provided by the technology vendor CRF Health of Plymouth Meeting, PA, USA. The ePRO system is in compliance with Title 21 CFR Part 11. The documentation related to the system validation of the ePRO system is available through the vendor, CRF Health, while the user acceptance testing of the study-specific PRO design will be conducted and maintained at AbbVie. The subject will be entering the data on an electronic device; these data will be uploaded to a server. The data on the server will be considered source, and maintained and managed by CRF Health. Internet access to the ePRO data will be provided by CRF Health for the duration of the study. This access will be available for the duration of the study to the site investigator, as well as delegated personnel. Such access will be removed from investigator sites following the receipt of the study archive. Data from the ePRO system will be archived on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as a durable record of the site's ePRO data. It will be possible for the investigator to make paper print-outs from that media. The (instrument/scale) will be collected electronically via a Tablet/Laptop device into which the patient will directly enter the required pieces of information. The electronic device will be programmed to allow data entry for only the visits specified in the protocol and will not allow for patients to complete more than one of the same assessment at any one visit. All data entered on the device will be immediately stored to the device itself and (manually/automatically) uploaded to a central server administrated by (ePRO Vendor). The Investigator and delegated staff will be able to access all uploaded patient entered data via a password protected website, up until the generation, receipt and confirmation of the study archive.
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11.0 data quality assurance

Computer logic and manual checks will be created to identify items such as inconsistent study dates. Any necessary corrections will be made to the eCRF.
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12.0 use of information

Any research that may be done using optional exploratory research samples from this study will be experimental in nature and the results will not be suitable for clinical decision making or patient management. Hence, the subject will not be informed of individual results, should analyses be performed, nor will anyone not directly involved in this research. Correspondingly, researchers will have no access to subject identifiers. Individual results will not be reported to anyone not directly involved in this research other than for regulatory purposes. Aggregate data from optional exploratory research may be provided to investigators and used in scientific publications or presented at medical conventions. Optional exploratory research information will be published or presented only in a way that does not identify any individual subject.  
112
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13.0 completion of the study

The investigator will conduct the study in compliance with the protocol and complete the study within the timeframe specified in the contract between the investigator (Director of the Site in Japan) and AbbVie. Continuation of this study beyond this date must be mutually agreed upon in writing by both the investigator (Director of the Site in Japan) and AbbVie. The investigator will provide a final report to the IEC/IRB following conclusion of the study, and will forward a copy of this report to AbbVie or their representative. The investigator (Director of the Site in Japan) must submit, maintain, and archive any records related to the study according to ICH GCP and all other applicable regulatory requirements. If the investigator (Director of the Site in Japan) is not able to retain the records, he/she must notify AbbVie to arrange alternative archiving options. AbbVie will select the signatory investigator from the investigators who participate in the study. Selection criteria for this investigator will include level of participation as well as significant knowledge of the clinical research, investigational drug and study protocol. The signatory investigator for the study will review and sign the final study report in accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) Guidance on Investigator's Signature for Study Reports.  
The end-of-study is defined as the date of the last subject's last visit, or the date of the last subject's last survival follow-up contact, whichever is later.
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14.0 investigator's agreement

1. I have received and reviewed the Investigator's Brochure for rovalpituzumab tesirine and the product labeling for dexamethasone.  
2. I have read this protocol and agree that the study is ethical. 3. I agree to conduct the study as outlined and in accordance with all applicable regulations and guidelines.  
4. I agree to maintain the confidentiality of all information received or developed in connection with this protocol.  
5. I agree that all electronic signatures will be considered the equivalent of a handwritten signature and will be legally binding.  
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)
Protocol Date: 05 March 2019 Signature of Principal Investigator Date Name of Principal Investigator (printed or typed)
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15.0 reference list

1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539-44.  
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: a cancer journal for clinicians. 2012;62(1):10-29.  
3. Simon M, Argiris A, Murren JR. Progress in the therapy of small cell lung cancer.  
Crit Rev Oncol Hematol. 2004;49(2):119-33.  
4. Ready N, Pang H, Gu L, A, et al. Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small-cell lung cancer: a randomized, double-blind, placebo-controlled phase II study-CALGB 30504 (Alliance). J Clin Oncol. 2015;33(15):1660-5.  
5. Schiller JH, Adak S, Cella D, et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:2114-22.  
6. Saunders L, Bankovich A, Anderson W, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Science Transl Med. 2015;7(302):302ra136.  
7. Chapman G, Sparrow D, Kremmer E, et al. Notch inhibition by the ligand deltalike 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20(5):905-16.  
8. Dunwoodie S, Henrique D, Harrison S, et al. Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development. 1997;124(16):3065-76.  
9. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-inhuman, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42-51.  
10. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers (FDA, 2016).  
11. Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI,
NIH, DHHS. 28 May 2009 [cited 29 Sept 2016]. Available from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-0614_QuickReference_5x7.pdf.  
12. Eisenhauer E, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.  
13. Aaronson N, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQC30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76.  
14. AbbVie Stemcentrx LLC. Investigator's Brochure for Rovalpituzumab Tesirine
(SC 16LD6.5) Edition 5.0. 13 September 2016.  
15. Food and Drug Administration. Guidance for industry clinical trial endpoints for the approval of cancer drugs and biologics. 2007.  
16. AbbVie. Coding Guidelines for MedDRA Term Selection, AbbVie Global Pharmaceutical Research and Development (GPRD), Global Pharmacovigilance and Clinical Project Team. Current version on file at AbbVie.  
17. International Conference on Harmonisation. Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance. April 1996.  
18. International Conference on Harmonisation. Guideline for Industry, Clinical safety data management: definitions and standards for expedited reporting, E2A. March 1995.  
19. AbbVie. Rovalpituzumab Tesirine Dear Rova-T Investigator Letter. 05 December 2018.
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appendix a. responsibilities of the

Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site location. In signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is agreeing to the following:
1. Conducting the study in accordance with the relevant, current protocol, making changes in a protocol only after notifying AbbVie, except when necessary to protect the safety, rights or welfare of subjects.  
2. Personally conducting or supervising the described investigation(s). 3. Informing all subjects, or persons used as controls, that the drugs are being used for investigational purposes and complying with the requirements relating to informed consent and ethics committees (e.g., independent ethics committee [IEC] or institutional review board [IRB]) review and approval of the protocol and amendments.  
4. Reporting adverse experiences that occur in the course of the investigation(s) to AbbVie and the site director.  
5. Reading the information in the Investigator's Brochure/safety material provided, including the instructions for use and the potential risks and side effects of the investigational product(s).  
6. Informing all associates, colleagues, and employees assisting in the conduct of the study about their obligations in meeting the above commitments.  
7. Maintaining adequate and accurate records of the conduct of the study, making those records available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all study-related documents until notification from AbbVie.  
8. Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical investigation and all amendments.  
117 9. Reporting promptly, all changes in the research activity and all unanticipated problems involving risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, institution director) and/or directly to the ethics committees and AbbVie.  
10. Following the protocol and not making any changes in the research without ethics committee approval, except where necessary to eliminate apparent immediate hazards to human subjects. EudraCT 2016-003503-64
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appendix b. list of protocol

| 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                                |                                                                                                       |                     |                               |
| X X                                                                                  | X X X X                          | X X X X                                                                                               | X X                 | Coagulation Testsj X Xk X 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 | X                   |                               |
| X                                                                                    | X X                              |                                                                                                       |                     |                               |
| Treatment (Each Cycle)                                                               | X                                | X Xk X                                                                                                |                     |                               |
| X X                                                                                  |                                  |                                                                                                       |                     |                               |
| X                                                                                    |                                  |                                                                                                       |                     |                               |
| Screening                                                                            |                                  |                                                                                                       |                     |                               |
| Appendix C. Study Activities                                                         | Category Description             | X                                                                                                     | Informed Consentf X | Inclusion/Exclusion  Criteria |
| Safety  Assessments X                                                                | X                                | X                                                                                                     | Vital Signsi X      |                               |
| Medical and  Surgical History  including  Malignancy  Historyg                       | Hematology and  Serum Chemistryj |                                                                                                       |                     |                               |
| Phone Contact                                                                        | Physical  examinationh           |                                                                                                       |                     |                               |
| Location Clinic Visit                                                                |                                  |                                                                                                       |                     |                               |  
120  
  
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 XX X X X X X X Xp Xp          |                                                                                                       |                          |       |                  |
| X X XX X X X X X Xp Xp                                                               |                                 |                                                                                                       |                          |       |                  |
| X                                                                                    |                                 |                                                                                                       |                          |       |                  |
| X X                                                                                  | X X                             | X                                                                                                     | X                        | X X X | X XX X X X X X 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)                                                               | Urinalysisj X Xk X              | Pregnancy Testl X X                                                                                   | Echocardiogramn X X      |       |                  |
| Screening                                                                            | Category Description            | Procedure                                                                                             | -related                 | only  |                  |
| SAE/                                                                                 |                                 |                                                                                                       |                          |       |                  |
| X                                                                                    | XPerformance Status  (ECOG)     |                                                                                                       |                          |       |                  |
| Electrocardiogram  (ECG)m                                                            | Fluid Retention  Questionnaireo | SAE/Adverse  Events                                                                                   | Concomitant  Medications |       |                  |
| Safety  Assessments  (cont.)                                                         |                                 |                                                                                                       |                          |       |                  |  
121 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                    |                                                                                                       |                                                                             |                              |                                  |
| X Xr X                                                                               | X Xr X               | X                                                                                                     | X                                                                           |                              |                                  |
| X X                                                                                  | X 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)                                                               | X X                  |                                                                                                       |                                                                             |                              |                                  |
| X                                                                                    |                      |                                                                                                       |                                                                             |                              |                                  |
| X                                                                                    | X X                  | X X                                                                                                   | X X                                                                         | X X                          |                                  |
| Screening                                                                            | Category Description | Xt                                                                                                    |                                                                             |                              |                                  |
| Central  Radiographic  Assessment  Committee (CRAC)  Reviews                         |                      |                                                                                                       |                                                                             |                              |                                  |
| Treatment rovalpituzumab  tesirine or placebo                                        | dexamethasone or     | placebo                                                                                               | Disease/Response  Assessment  (Radiographic  Imaging)q Response  Assessment | Health Resource  Utilization | Patient Reported  Outcome (PRO)u |
| MRI/CT of the  Brain                                                                 | Survival Status      |                                                                                                       |                                                                             |                              |                                  |  
122  
  
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 Xx                                                                             | X Xx                                                                                                  |                                                    |                           |
| X X                                                                                  | Serosal Fluidaa Cycle 1 Day 1 through 70 days after last blinded study treatment |                                                                                                       |                                                    |                           |
| X                                                                                    | X                                                                                | 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 | X X                                                |                           |
| Treatment (Each Cycle)                                                               | X X                                                                              | X X                                                                                                   | X                                                  | Pharmacogeneticsz X       |
| Screening                                                                            | Category Description                                                             | X                                                                                                     | Blood (plasma) for  Inflammatory  Markers & ctDNAx |                           |
| Pharmacokinetics  (PK), Antitherapeutic  Antibody (ATA),  and neutralizing  antibodies (nAb)v Pharmacoki netic (PK),  Biomarkers,  and  Pharmacoge netic (PG)                                                                                      | Tumor Material at  Screeningw                                                    | Tumor Material at  Time of Disease  Progressionf                                                      | Blood (serum) for  Tumor & Soluble  Markersx       | Circulating Tumor  Cellsy |  
  
  
123 EudraCT 2016-003503-64 a. Every third cycle of treatment should be omitted and a clinic visit conducted. 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 non-treatment cycle to review the questionnaire. 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.b. 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 anticancer therapy if possible.c. For subjects who discontinue blinded investigational product 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.d. 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).e. 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. Randomization may occur within 3 days prior to C1D1. Starting at C2D1, study assessments may be performed within 3 days prior to the visit. Disease/Response Assessment and CRAC Review may be performed within 7 days prior to the Day 1 visit.f. 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. Informed consent is also required for the optional tumor biopsy at time of disease progression. The sample can be collected at the EOT or at the time of disease progression.g. Medical and Surgical History includes demographics and documentation of clinically significant medical condition, surgical history, and malignancy history.h. Height will be collected at the Screening visit only. For height assessments, the subject should not wear shoes.i. Vital signs include weight, sitting blood pressure, heart rate and body temperature. Weight will be collected in the clinic prior to dosing at each cycle and the recorded weight will be utilized for dosing calculations. If possible, blood pressure and heart rate measurements should not immediately follow scheduled blood collections. Vital signs should be collected prior to the infusion. j. All laboratory samples will be assessed using a certified 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. Refer to Table 2, Clinical Laboratory Tests for details. k. The screening clinical laboratory tests do not need to be repeated on C1D1 if performed within 7 days of randomization and meet eligibility criteria, unless clinically indicated. Starting at Cycle 2, lab assessment may be performed 3 days prior to Day 1 visits.  
EudraCT 2016-003503-64 l. For female subjects of childbearing potential, 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. Urine pregnancy tests will be performed at Day 1 of each 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. Post-menopausal 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.m. A resting 12-lead ECG will 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.n. 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 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.o. 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 and through the EOT visit, subjects will maintain a diary of daily weights (captured on the Fluid Retention Questionnaire). p. Collection of SAE/AE and Concomitant Medications may be required at this visit in order to meet the collection window requirement of Day 1 of study treatment through 70 days after last treatment. Any ongoing SAE/AE that require appropriate standard of care should also be conducted.q. 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 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 scans may be performed within 28 days prior to randomization. Disease response will be determined by the Investigator at each assessment according to RECIST v1.1. Effusion (pleural, pericardial, and etc.) assessments will be performed by a radiologist at each 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 v1.1 only if confirmed malignant by cytology or otherwise clearly disease-related. 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 TAMDshould be contacted for guidance. Subjects will continue to be monitored by the same diagnostic method throughout the study every 6 weeks after randomization.r. May be omitted if previous assessment was performed within the preceding 6 weeks.s. Site will collect the appropriate scans and ship by courier or submit electronically to the central facility at each subject's disease assessment. t. MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS progression is suspected) thereafter.u. PRO assessments are required at Screening, only C2D1, the first Non-Treatment Cycle, EOT, and PTFU (if applicable).  
125 EudraCT 2016-003503-64  
| v. Approximately 6 mL of blood will be collected by venipuncture for pharmacokinetic (PK), Anti-therapeutic antibody (ATA), and neutralizing antibodies (nAb) testing. The  pre-infusion sample will be collected prior to dosing on Day 1 (–3 days window is permitted) 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. The date and time of each sample collected will be recorded to the nearest minute.   | w. Archived or fresh tumor material must be submitted to the AbbVie designated central IHC laboratory for determination of DLL3 expression prior to randomization.   | x. On Day 1 (–3 days 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.   | y. 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.   | z. Pharmacogenetic collection should occur unless precluded by local or national regulations or policies. Pharmacogentic sample collected pre-infusion on Day 1 of Cycle 1.   | aa. 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 testing for any AE starting from C1D1 through 70 days after the last blinded study treatment. Collected fluid must also be tested locally for cytology if disease  progression due to appearance/worsening of effusion is suspected.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
126
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appendix d. performance status scales

| ECOG   | Karnofsky                                                                                                                                                                                 |         |                                                                                 |
|--------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|---------------------------------------------------------------------------------|
| Score  | Description                                                                                                                                                                               | Percent | Description                                                                     |
| 0      | Normal activity. Fully active, able to  carry on all pre-disease performance  without restriction.                                                                                        | 100     | Normal, no complaints, no evidence  of disease.                                 |
| 90     | Able to carry on normal activity;  minor signs or symptoms of disease.                                                                                                                    |         |                                                                                 |
| 1      | Symptoms, but ambulatory. Restricted  in physically strenuous activity, but  ambulatory and able to carry out work of  a light or sedentary nature (e.g., light  housework, office work). | 80      | Normal activity with effort; some  signs or symptoms of disease.                |
| 70     | Cares for self, unable to carry on  normal activity or to do active work.                                                                                                                 |         |                                                                                 |
| 2      | In bed < 50% of the time. Ambulatory  and capable of all self-care, but unable to  carry out any work activities. Up and  about more than 50% of waking hours.                            | 60      | Requires occasional assistance, but is  able to care for most of his/her needs. |
| 50     | Requires considerable assistance and  frequent medical care.                                                                                                                              |         |                                                                                 |
| 3      | In bed > 50% of the time. Capable of  only limited self-care, confined to bed or  chair more than 50% of waking hours.                                                                    | 40      | Disabled, requires special care and  assistance.                                |
| 30     | Severely disabled, hospitalization  indicated. Death not imminent.                                                                                                                        |         |                                                                                 |
| 4      | 100% bedridden. Completely disabled.  Cannot carry on any self-care. Totally  confined to bed or chair.                                                                                   | 20      | Very sick, hospitalization indicated.  Death not imminent.                      |
| 10     | Moribund, fatal processes  progressing rapidly.                                                                                                                                           |         |                                                                                 |
| 5      | Dead.                                                                                                                                                                                     | 0       | Dead.                                                                           |  
EudraCT 2016-003503-64 Appendix E. Calculated Creatinine Clearance Using Modified Cockcroft-Gault Equation MODIFIED COCKCROFT AND GAULT FORMULA For the calculation of estimated creatinine clearance rate (eCCR) using Ideal Body Mass [IBM] instead of Mass.  
eCCr = (140 - Age) - IBM (kg) - [0.85 if Female]
72 - Serum Creatinine (mg/dL)
Or, if serum creatinine is in μmol/L:
eCCr = (140 - Age) - IBM (kg) - [1.23 if Male, 1.04 if Female]
Serum Creatinine (μmol/L)
Ideal Body Mass should be used:
IBM (kg) = [(height cm - 154) - 0.9] + (50 if Male, 45.5 if Female)
128
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eudract 2016-003503-64 appendix f. new

| Class I   | Patients with no limitation of activities; they suffer no symptoms from ordinary activities.                                               |
|-----------|--------------------------------------------------------------------------------------------------------------------------------------------|
| Class II  | Patients with slight, mild limitation of activity; they are comfortable with rest or with  mild exertion.                                  |
| Class III | Patients with marked limitation of activity; they are comfortable only at rest.                                                            |
| Class IV  | Patients who should be at complete rest, confined to bed or chair; any physical activity  brings on discomfort and symptoms occur at rest. |  
Appendix G. Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1 for Tumor Response Response criteria will be assessed using RECIST (version 1.1).12 Changes in the measurable lesions over the course of therapy must be evaluated using the criteria listed below.  
| Measurability Measurable Lesions                         | Lesions accurately measured in at least one dimension with a  minimum size of:  - Longest diameter ≥ 10 mm (CT scan slice thickness no  greater than 5 mm) - 10 mm caliper measurement by clinical exam                                                                                                                           |
|----------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Non-Measurable                                           | All other lesions, including small lesions (longest diameter                                                                                                                                                                                                                                                                      |
| Lesions                                                  | < 10 mm) as well as truly non-measurable lesions. Lesions  considered truly non-measurable include: leptomeningeal  disease, ascites, pleural/pericardial effusion, inflammatory  breast disease, lymphangitic involvement of skin or lung and  also abdominal masses that are not confirmed and followed by  imaging techniques. |
| Measurable  Malignant Lymph  Nodes                       | To be considered pathologically enlarged and measurable, a  lymph node must be ≥ 15 mm in short axis when assessed by  CT scan (CT scan slice thickness recommended to be no  greater than 5 mm). At baseline and in follow-up, only the  short axis will be measured and followed.                                               |
| Non-Measurable  Malignant Lymph  Nodes                   | Pathological lymph nodes with ≥ 10 to < 15 mm short axis.                                                                                                                                                                                                                                                                         |
| Special  Considerations  Regarding Lesion  Measurability | Bone lesions Lytic bone lesions or mixed lytic-blastic lesions, with  identifiable soft tissue components, that can be evaluated by  cross sectional imaging techniques such as MRI/CT can be  considered as measurable lesions if the soft tissue component  meets the definition of measurability described above.130           |  
Blastic bone lesions are non-measurable. Cystic lesions Lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non measurable) since they are, by definition, simple cysts.  
'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.  
Lesions with prior local treatment Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.  
All measurements should be taken and recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as closely as possible to the beginning of treatment and not more than 28 days before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers. For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is recommended.
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methods of measurement

Spiral CT should be performed with cuts of 5 mm or less in slice thickness contiguously. This applies to tumors of the chest and abdomen. A scale should be incorporated into all radiographic measurements. MRI can be performed if required by local law or if CT is contraindicated, and should be documented in the subject's source. If prior to enrollment, it is known a subject is not able to undergo CT scans with IV contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI should be used to evaluate the subject at baseline and follow-up should be guided by the tumor type under investigation and the anatomic location of the disease. For subjects who develop contraindications to contrast after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI should be made based upon discussion with the AbbVie TA MD. For accurate objective response evaluation, ultrasound (US) should not be used to measure tumor lesions. The utilization of endoscopy and laparoscopy for objective tumor evaluation is not advised. However, such techniques can be useful in confirming complete pathological response when biopsies are obtained. Cytology and histology can be used to differentiate between partial response (PR) and complete response (CR) in rare cases.
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baseline documentation of "target" and

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Lymph nodes merit special mention since they are normal anatomical structures which may be visible by imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane). The smaller of these measures is the short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded or followed. A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. If lymph nodes are to be included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum LD will be used as reference by which to characterize the objective tumor response. All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence (stable, increasing or decreasing) or absence of each should be noted throughout follow-up.
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evaluation of target lesions complete

The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
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partial response (pr)

At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
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progressive disease (pd)

At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (baseline or after) or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
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stable disease (sd)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started (baseline or after).
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assessment of target lesions

Lymph nodes identified as target lesions should always have the actual short axis measurement recorded (measured in the same anatomical plane as the baseline examination), even if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if complete response criteria are met, since a normal lymph node is defined as having a short axis of < 10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions. All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small (< 5 mm). However, sometimes target lesions or lymph nodes become too small to measure. If it is in the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present, but too small to measure, a default value of 5 mm should be assigned (as derived from the 5 mm CT slice thickness). The measurement of these lesions is potentially non-reproducible; therefore providing this default value will prevent false responses or progression based upon measurement error.
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evaluation of non-target lesions complete

The disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
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non-cr/non-pd

Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
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progressive disease (pd)

Unequivocal progression of existing non-target lesions. In this setting, to achieve 'unequivocal progression' on the basis of non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 'increase' in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
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new lesions

The appearance of new malignant lesions denotes disease. While there are no specific criteria for the identification of new radiographic lesions, the findings of a new lesion should be unequivocal; i.e., not attributable to differences in scanning technique, timing of scanning, phase of contrast administration, change in imaging modality or finding thought to represent something other than tumor (e.g., some 'new' bone lesions may be simply healing or flare of pre-existing lesions). A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression. If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is a new lesion, then progression should be declared using the date of the initial scan.  
136 EudraCT 2016-003503-64  
| 137                                                                                                                                |                                                                                                                                                                                     |                                                                                                                                              |                                                                |
|------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|
| Life-threatening  respiratory or  hemodynamic  compromise; intubation or  urgent intervention  indicated                           | Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough  and marked chest discomfort.        | Capillary leak syndrome -                                                                                                                    |                                                                |
| Life-threatening  consequences; urgent  operative intervention  indicated                                                          | Life-threatening  consequences; urgent  intervention indicated                                                                                                                      | Life-threatening  consequences; urgent  intervention indicated                                                                               | Life-threatening  consequences; urgent  intervention indicated |
| Grade 4                                                                                                                            | Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.                                        | Pleural effusion Symptomatic with  respiratory distress and  hypoxia; surgical  intervention including  chest tube or pleurodesis  indicated |                                                                |
| Severe symptoms;  invasive intervention  indicated                                                                                 | Severe symptoms;  intervention indicated                                                                                                                                            |                                                                                                                                              |                                                                |
| Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.                  | Pericardial tamponade - – -                                                                                                                                                         |                                                                                                                                              |                                                                |
| Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.                      | Pericardial effusion -                                                                                                                                                              |                                                                                                                                              |                                                                |
| Grade 3                                                                                                                            | Effusion with                                                                                                                                                                       | physiologic  consequences                                                                                                                    |                                                                |
| Asymptomatic effusion size  small to moderate                                                                                      | Symptomatic; intervention  indicated (e.g., diuretics or  limited therapeutic  thoracentesis) Asymptomatic; clinical  or diagnostic  observations only;  intervention not indicated |                                                                                                                                              |                                                                |
| Symptomatic; medical  intervention indicated Asymptomatic; clinical  or diagnostic  observations only;  intervention not indicated | Symptomatic; medical  intervention indicated                                                                                                                                        |                                                                                                                                              |                                                                |
| Grade 2                                                                                                                            |                                                                                                                                                                                     |                                                                                                                                              |                                                                |
| Appendix H. CTCAE v 4.0 Grading of Relevant AEs                                                                                    | Group Adverse Event Grade 1                                                                                                                                                         | Ascites Serosal  Effusions                                                                                                                   |                                                                |  
EudraCT 2016-003503-64  
| 138                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                  |                                     |                                                   |                                                                                    |                                              |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|---------------------------------------------------|------------------------------------------------------------------------------------|----------------------------------------------|
| Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who  demonstrate a state of generalized leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias,  medications, or poisoning. It can lead to generalized edema and multiple organ failure. |                                                                                                                                                                                                                                                  |                                     |                                                   |                                                                                    |                                              |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                             | -                                                                                                                                                                                                                                                | -                                   | -                                                 |                                                                                    |                                              |
| Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.                                                                                                                                                                                                                                                             | Edema trunk                                                                                                                                                                                                                                      |                                     |                                                   |                                                                                    |                                              |
| Severe swelling; limiting  self-care ADL                                                                                                                                                                                                                                                                                                                                            | > 30% inter-limb  discrepancy in volume;  gross deviation from  normal anatomic                                                                                                                                                                  | contour; limiting selfcare ADL                                     | Gross deviation from                              | normal anatomic                                                                    | contour; limiting selfcare ADL                                              |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                             | Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.                                                                                                                                          |                                     |                                                   |                                                                                    |                                              |
| Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.                                                                                                                                                                                                                                                                             | Edema limbs                                                                                                                                                                                                                                      |                                     |                                                   |                                                                                    |                                              |
| edema; limiting instrumental  ADL                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                  |                                     |                                                   |                                                                                    |                                              |
| Localized facial edema Moderate localized facial                                                                                                                                                                                                                                                                                                                                    | > 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 | Readily apparent  obscuration of anatomic         | architecture; obliteration of  skin folds; readily apparent  deviation from normal | anatomic contour; limiting  instrumental ADL |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                             | 5 - 10% inter-limb  discrepancy in volume or circumference at point of  greatest visible  difference; swelling or  obscuration of anatomic                                                                                                       | architecture on close  inspection   | Swelling or obscuration  of anatomic architecture | on close inspection                                                                |                                              |
| Grade 1 Group Adverse Event                                                                                                                                                                                                                                                                                                                                                         | Edema Edema face                                                                                                                                                                                                                                 |                                     |                                                   |                                                                                    |                                              |
| Serosal  Effusions  (cont.)                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                  |                                     |                                                   |                                                                                    |                                              |  
EudraCT 2016-003503-64  
| 139                                                                                                                       |                                                                                                                               |                                                                                                                     |                                                                                                                             |
|---------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| < 500/mm3; < 0.5 × 109/L                                                                                                  |                                                                                                                               |                                                                                                                     |                                                                                                                             |
| Life-threatening  consequences; urgent  intervention indicated                                                            |                                                                                                                               |                                                                                                                     |                                                                                                                             |
| Grade 4                                                                                                                   | < 25,000/mm3; < 25.0 × 109/L                                                                                                  |                                                                                                                     |                                                                                                                             |
| -                                                                                                                         | Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen. | Platelet count decreased                                                                                            | Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen. |
| Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face. | Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.    | Neutrophil count decreased < LLN - 1500/mm3; < LLN - 1.5 × 109/L                                                    |                                                                                                                             |
| Edema associated with                                                                                                     | visual disturbance;  increased intraocular                                                                                    | pressure, glaucoma or  retinal hemorrhage; optic  neuritis; diuretics  indicated; operative  intervention indicated |                                                                                                                             |
| Severe localized edema                                                                                                    | and intervention  indicated; limiting selfcare ADL                                                                                                                               |                                                                                                                     |                                                                                                                             |
| Moderate localized edema                                                                                                  | and intervention indicated;  limiting instrumental ADL                                                                        | < 50,000 - 25,000/mm3; < 50.0 - 25.0 × 109/L                                                                        |                                                                                                                             |
| Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.         | Periorbital edema                                                                                                             | < 1000 - 500/mm3;  < 1.0 - 0.5 × 109/L                                                                              |                                                                                                                             |
| < 3 - 2 g/dL; < 30 - 20 g/L < 2 g/dL; < 20 g/L                                                                            |                                                                                                                               |                                                                                                                     |                                                                                                                             |
| Grade 3                                                                                                                   | Indurated or pitting edema;  topical intervention  indicated                                                                  | < 75,000 - 50,000/mm3;  < 75.0 - 50.0 × 109/L                                                                       |                                                                                                                             |
| < 1500 - 1000/mm3;  < 1.5 - 1.0 × 109/L                                                                                   |                                                                                                                               |                                                                                                                     |                                                                                                                             |
| Grade 2                                                                                                                   | Localized to dependent  areas, no disability or  functional impairment                                                        | < LLN - 75,000/mm3; < LLN - 75.0 × 109/L                                                                            |                                                                                                                             |
| Soft or non-pitting                                                                                                       |                                                                                                                               |                                                                                                                     |                                                                                                                             |
| Grade 1                                                                                                                   | < LLN - 3 g/dL;  < LLN - 30 g/L                                                                                               |                                                                                                                     |                                                                                                                             |
| Group Adverse Event                                                                                                       | Labs Hypo-albuminemia                                                                                                         |                                                                                                                     |                                                                                                                             |
| Localized edema Edema  (cont.)                                                                                            |                                                                                                                               |                                                                                                                     |                                                                                                                             |  
EudraCT 2016-003503-64  
| Target lesions covering  > 30% BSA; associated  with fluid or electrolyte  abnormalities; ICU care  or burn unit indicated                     | Life-threatening  consequences; urgent  intervention indicated                                 |                                                     |                                                                                                                                                                                                                                             |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------|-----------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet. | Photosensitivity                                                                               |                                                     |                                                                                                                                                                                                                                             |
| Grade 4                                                                                                                                        | -                                                                                              | Erythema covering  > 30% BSA and                    | erythema with blistering;  photosensitivity; oral  corticosteroid therapy  indicated; pain control  indicated (e.g., narcotics  or NSAIDs)                                                                                                  |
| Target lesions covering  > 30% BSA and                                                                                                         | associated with oral or                                                                        | genital erosions                                    | Severe skin changes  (e.g., peeling, blisters,  bleeding, edema, or  hyperkeratosis) with  pain; limiting self-care  ADL Skin changes (e.g., peeling,  blisters, bleeding, edema, or  hyperkeratosis) with pain;  limiting instrumental ADL |
| Grade 3                                                                                                                                        | Definition: A disorder characterized by target lesions (a pink-red ring around a pale center). | Palmar-plantar  erythrodysesthesia  syndrome        |                                                                                                                                                                                                                                             |
| Target lesions covering 10 - 30% BSA and associated                                                                                            | with skin tenderness                                                                           | Tender erythema covering  10 - 30% BSA              | Definition: A disorder characterized by an increase in sensitivity of the skin to light.                                                                                                                                                    |
| Grade 2                                                                                                                                        | Minimal skin changes or  dermatitis  (e.g., erythema, edema, or  hyperkeratosis) without  pain | Painless erythema and  erythema covering < 10%  BSA |                                                                                                                                                                                                                                             |
| Target lesions covering  < 10% BSA and not                                                                                                     | associated with skin  tenderness                                                               |                                                     |                                                                                                                                                                                                                                             |
| Grade 1 Group Adverse Event                                                                                                                    | Erythema multiforme Skin                                                                       |                                                     |                                                                                                                                                                                                                                             |  
  
140 EudraCT 2016-003503-64  
| Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the  most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.   |                                                        |                                                                                    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|------------------------------------------------------------------------------------|
| Grade 4                                                                                                                                                                                                                                                                              | - Macules/papules  covering > 30% BSA  with or without | associated symptoms;  limiting self-care ADL                                       |
| Grade 3                                                                                                                                                                                                                                                                              | Macules/papules covering  10 - 30% BSA with or         | without symptoms (e.g., pruritus, burning,  tightness); limiting  instrumental ADL |
| Grade 2                                                                                                                                                                                                                                                                              | Macules/papules  covering < 10% BSA  with or without   | symptoms (e.g., pruritus,  burning, tightness)                                     |
| Grade 1                                                                                                                                                                                                                                                                              | Cross reference: NCI CTCAE version 4.011               |                                                                                    |
| Group Adverse Event                                                                                                                                                                                                                                                                  | Rash maculo-papular Skin  (cont.)                      |                                                                                    |
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appendix i. fluid retention questionnaire

Subject ID: ____________________ Over the past 7 days, or since the last time this questionnaire was completed:
1. What has your daily weight been?  
- Please weigh yourself at the same time each day and record the date and your weight for that day below. Weight should be taken without outer garments such as hats, coats or shoes. Measurements while in light indoor clothing only, or undergarments only, are acceptable; however, please try to use the same or similar clothing (including any accessories or jewelry) from day to day when measuring weight.  
- Please complete one questionnaire for every 7 day/1 week period.  
| Date (DD/MMM/YYYY)   | Weight (Circle One: lb or kg) lb or kg lb or kg lb or kg lb or kg lb or kg lb or kg lb or kg   |
|----------------------|------------------------------------------------------------------------------------------------|  
2. Have you noticed any new or worsening edema - e.g., swelling of the ankles or legs during the days above?  
܆Yes or ܆No 3. Have you noticed any new or worsening shortness of breath during the days above?  
܆Yes or ܆No EudraCT 2016-003503-64 4. Please sign below to confirm that you have completed this questionnaire.  
____________________________________ Date: __________________ EudraCT 2016-003503-64
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appendix j. adverse events expected

Preferred Term (MedDRA Version 19.1)
Pleural effusion Malignant pleural effusion Metastases to pleura Dyspnoea Cough Non-cardiac chest pain Haemoptysis* Oesophageal obstruction Pneumonia* Vocal cord paralysis Dysphonia Dysphagia Superior vena cava syndrome Horner's syndrome Myasthenic syndrome Metastases to bone Metastases to lymph nodes Metastases to liver Metastases to spine Metastases to the mediastinum Metastases to pleura Metastases to adrenals Metastases to meninges Metastases to central nervous system Cancer pain Inappropriate Anti-Diuretic Hormone (SIADH) secretion Tumour pain Fatigue Asthenia Pulmonary embolism* Shock* Septic shock*  
| Preferred Term (MedDRA Version 19.1)   |
|----------------------------------------|  
Deep vein thrombosis*  
| Lower respiratory tract infection* Respiratory tract infection* Upper respiratory tract infection* Opportunistic infection* Viral infection* Fungal infection* Bacterial infection* Pulmonary haemorrhage* Lung abscess* Empyema* Sepsis* Lymphadenopathy Decreased appetite Malaise Weight decreased Headache Pain excluding chest pain Pyrexia   |                                            |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|
| *                                                                                                                                                                                                                                                                                                                                                  | Includes life threatening or fatal events. |  
EudraCT 2016-003503-64
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specific protocol changes

Section 1.0 Title Page "Sponsor/Emergency Contact:" previously read:
Therapeutic Area Medical Director AbbVie 200 Sidney Street Cambridge, MA 02139 Has been changed to read:
Senior Medical Director  
 AbbVie 1 North Waukegan Road North Chicago, IL 60064 USA  
Phone:  
 Cell Phone Fax: Email:
Section 1.2 Synopsis Previously read:  
  
| 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: 09 May 2017 |
| 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  Extensive Stage Small Cell Lung Cancer (MERU) |                                        |
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eudract 2016-003503-64

Objectives: Primary
- To evaluate if rovalpituzumab tesirine improves progression-free and overall survival in subjects with extensive-stage small cell lung cancer (ED SCLC) 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 rovalpituzumab tesirine anti-tumor activity by determining objective response rate
(ORR), clinical benefit rate (CBR), and duration of responses (DOR)
- To assess change in patient reported outcomes (PRO) with EORTC QLQ-C30/LC13 questionnaires.  
Exploratory
- 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
- To assess EQ-5D-5L during treatment with rovalpituzumab tesirine.  
Investigators: Multicenter, International Study Sites: Approximately 275 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).  
Number of Subjects to be Enrolled: Up to approximately 740 SCLC subjects, to obtain approximately 480 subjects with DLL3 high 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.
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diagnosis and main criteria for

1. Subject 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 studyspecific 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 extensive-stage SCLC 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. At least 3 but no more than 9 weeks between the administration of the last cycle of platinum-based chemotherapy and randomization.  
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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eudract 2016-003503-64 diagnosis and main

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 Cockroft-Gault formula 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 the disease under study.  
2. Any disease-directed radiotherapy (except PCI 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.  
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 within 6 months prior to randomization.
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eudract 2016-003503-64

Diagnosis and Main Criteria for Inclusion/Exclusion (Continued): Main Exclusion (Continued):  
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)- 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: Plasma 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) and overall survival (OS) are the two primary efficacy endpoints. No order of testing of these two endpoints is specified. 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, and 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.  
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 familywise 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.
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interim analysis

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 log-rank test. The O'BrienFleming 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.  
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eudract 2016-003503-64 statistical methods (continued)

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.
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sample size

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. 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 progressionfree survival for the placebo arm will be approximately 3 months. Treatment with rovalpituzumab tesirine is hypothesized to increase median progression-free 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 1 month or greater improvement in median PFS, would result in a statistically significant improvement in the PFS.  
Pharmacokinetic:
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.
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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.  
| AbbVie Inc.                                 | Protocol Number: M16-298   |
|---------------------------------------------|----------------------------|
| Name of Study Drug: rovalpituzumab tesirine | Phase of Development: 3    |
| (Rova-T)                                    | 152                        |
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has been changed to read

Name of Active Ingredient: rovalpituzumab tesirine Date of Protocol Synopsis: 05 March 2019 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).  
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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eudract 2016-003503-64 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.
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diagnosis and main criteria for

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.  
Statistical Methods (Continued): Pharmacokinetic:
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.
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section 3.3 rovalpituzumab tesirine last

In a Phase 1 study (SCRX16-001), rovalpituzumab tesirine dosed at 0.2 - 0.4 mg/kg exhibited encouraging efficacy in recurrent SCLC, achieving a 31% (8/26) and 85% (22/26) central review-adjudicated confirmed objective response rate (ORR) and clinical benefit rate (CBR), respectively, in subjects whose tumors expressed DLL3 in ≥ 50% of cells. Median overall survival was 7.7 months in DLL3 ≥ 50% subjects at all dose levels, with a 1-year survival rate of 30%.9 Therefore, rovalpituzumab tesirine appears to be an active anti-cancer therapy.  
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% 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 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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section 3.5 benefits and risks

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.
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section 3.5 benefits and risks

The most frequent treatment-emergent adverse event (TEAE) terms considered related to rovalpituzumab tesirine have included fatigue (35%), pleural effusion (31%) and peripheral edema (27%), while the most frequent, related TEAE groups of Grade 3 or higher have included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%).9 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 Stemcentrx data on file).  
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).
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section 4.0 study objectives previously

The primary objective of this study is to evaluate if rovalpituzumab tesirine improves progression-free and overall survival in subjects with extensive-stage SCLC 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 rovalpituzumab tesirine anti-tumor activity by determining objective response rate (ORR), clinical benefit rate (CBR), and duration of responses (DOR), and to assess change in patient reported outcomes (PRO) with EORTC QLQ-C30/LC-13 questionnaires.  
162 The exploratory objectives are 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, and to assess EQ-5D-5L during treatment with rovalpituzumab tesirine.  
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 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.  
Section 5.1 Overall Study Design and Plan: Description Second paragraph, last sentence previously read: Approximately 275 clinical sites will participate. Has been changed to read: Approximately 300 clinical sites will participate.
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figure 1. study schema

Footnote "3." previously read: At least 3 but no more than 9 weeks between the administration of the last cycle of platinum-based chemotherapy and randomization.  
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.
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section 5.2 selection of study

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.
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section 5.2.1 inclusion criteria criterion

1. Subject 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.  
3. Histologically or cytologically confirmed extensive-stage SCLC 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).  
5. At least 3 but no more than 9 weeks between the administration of the last cycle of platinum-based chemotherapy and randomization.  
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.  
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).  
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.
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section 5.2.1 inclusion criteria criterion

Calculated creatinine clearance ≥ 30 mL/min by the Cockroft-Gault formula (Refer to Appendix E)  
Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula (Refer to Appendix E)
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section 5.2.2 exclusion criteria criterion

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 the disease under study.  
2. Any disease-directed radiotherapy (except PCI 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.  
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 E) within 6 months prior to randomization.  
12. Any prior exposure to a pyrrolobenzodiazepine (PBD)- or indolinobenzodiazepinebased 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.  
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 preplanned radiotherapy for CNS metastases present prior to start of first-line therapy and non-progressing) after last dose of first-line chemotherapy.  
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.  
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.
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section 5.2.3.1 prior therapy first

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 irinotecan; administration of the last cycle of first-line chemotherapy must be at least 3 weeks but no more than 9 weeks prior to randomization.  
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 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.
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section 5.2.3.2 concomitant therapy last

However, due to the potential for rovalpituzumab tesirine-related skin photosensitivity, subjects should be advised during treatment and for 30 days after last treatment to avoid unprotected sun exposure, use a broad spectrum sunscreen with a sun protection factor (SPF) of at least 30 and re-apply sunscreen as activity-appropriate, and wear protective clothing, a broad-brimmed hat, and sunglasses when outdoors or when driving or riding in a car for more than 1 hour.  
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  
 EudraCT 2016-003503-64 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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section 5.2.3.2.1 allowed concomitant therapy

First paragraph, third sentence previously read: Bone modifying agents for bone metastases are also permitted per local institutional standards.  
Bone modifying agents (e.g., bisphosphonates, denosumab) for bone metastases are also permitted per local institutional standards. Section 5.3.1.1 Study Procedures Subsection Vital Signs First paragraph, second sentence previously read: Vital signs include weight, sitting blood pressure, heart rate and body temperature.  
Vital signs include actual weight, sitting blood pressure, heart rate and body temperature. Section 5.3.1.1 Study Procedures Subsection Vital Signs Second paragraph previously read: 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.  
169  
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. Section 5.3.1.1 Study Procedures Subsection Echocardiogram Previously read: Echocardiograms will be performed per Appendix C, Study Activities to assess any pericardial effusion, if present, as well as cardiac function (left ventricular ejection fraction, LVEF).  
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).