Conditions: Small Cell Lung Cancer
Keywords: Small cell lung cancer (SCLC) Delta-like protein 3 (DLL3) rovalpituzumab tesirine topotecan metastatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 444
Healthy volunteers: no

Brief summary:
The purpose of this randomized, open-label, 2-arm, phase 3 study is to assess the efficacy, safety and tolerability of rovalpituzumab tesirine versus topotecan in participants with advanced or metastatic SCLC with high levels of DLL3, who have first disease progression during or following front-line platinum-based chemotherapy.

Detailed description:

Arms:
arm 1: Rovalpituzumab tesirine IV administration (dosing based on actual body weight) on Day 1 of a 42-day cycle for 2 cycles, with up to 2 additional cycles permitted.

Dexamethasone coadministered orally (PO) twice daily at a dose of 8 mg on Day -1, Day 1, and Day 2 of each 42-day cycle in which rovalpituzumab tesirine is administered. arm 2: Topotecan given as an intravenous (IV) infusion over 30 minutes at a dose of 1.5 mg/m\^2 on Days 1 to 5 of each 21-day cycle.

Interventions: intervention 1: Rovalpituzumab tesirine intervention 2: Topotecan intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Powder for solution for infusion in vials. intervention 2: Powder or solution for infusion in vials. Topotecan is commercially available as both a powder and solution for infusion. Availability will vary by region. intervention 3: Oral tablet.

Protocol document:
Prot_000.pdf: 
Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
1
1.0
Title Page
Clinical Study Protocol M16-289
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 (TAHOE)
Incorporating Amendments 1, 2, 3, and 4
AbbVie Investigational
  Product:
Rovalpituzumab tesirine (Rova-T)
Date:
08 January 2019
Development Phase:
3
Study Design:
A randomized, open-label, multicenter study comparing the 
efficacy, safety and tolerability of rovalpituzumab tesirine versus 
topotecan for Subjects with Advanced or Metastatic DLL3high SCLC 
who have first disease progression during or following front-line 
platinum-based chemotherapy (TAHOE)
EudraCT Number:
2016-003726-17
Investigators:
Investigator information is on file at AbbVie
Sponsor:
AbbVie Inc.*
NCT03061812


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
2
Sponsor/Emergency 
  Contact:
Therapeutic Area Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Fax:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
3
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol
Date
Original
17 November 2016
Amendment 1
09 March 2017
Amendment 2
19 May 2017
Amendment 3
02 July 2018
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  For patients currently on treatment in Arm A, the IDMC 
recommends that sites and patients make individual decisions as to whether or not to 
continue treatment based on patient level response.
●
Update Section 1.0, Title Page, with correct title for Sponsor/Emergency 
Contact.
Rationale:  Corrected error.
●
Update Section 1.2, Synopsis, Section 5.1, Overall Study Design and Plan, 
Section 5.3.1.1 Study Procedures, Section 8.1.3, Efficacy Endpoints, 
Section 8.1.5 Secondary Efficacy Endpoints, Section 8.3, Type 1 Error 
Adjustment Procedure for Multiple Testing, Appendix C, Study Activities for 
Arm A (Rovalpituzumab Tesirine), table notes "e" and "t" and Appendix D, 
Study Activities for Arm B (Topotecan) table notes "d" and "s," to remove 
CRAC assessment of response and progression.
Rationale:  Hypothesis testing for the efficacy analysis will not be conducted 
as the study has stopped enrollment due to failure of OS primary endpoint.
●
Update Section 1.2, Synopsis, Section 5.1, Overall Study Design and Plan, 
Section 5.3.1.1 Study Procedures, Section 5.5.3, Topotecan (Arm B), 
Section 5.5.6, Selection and Timing of Dose for Each Subject, to clarify 
treatment duration will end no later than 04 December 2019 and survival 
follow up will occur up until and no later than 12 February 2020.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
4
Rationale:  To specify date of last dose and end of safety and survival follow 
up period for study participants.
●
Update Section 5.3.1.1, Study Procedures, Appendix C, Study Activities for 
Arm A (Rovalpituzumab Tesirine), and Appendix D, Study Activities for 
Arm B (Topotecan), footnotes "u" and "t" respectively, to remove collection of 
PRO post Cycle 1 Day 1.
Rationale:  PRO analysis will not be conducted due to failure of OS primary 
endpoint.
●
Update Section 1.2, Synopsis, Section 8.0, Statistical Methods and 
Determination of Sample Size, and Section 8.4, Determination of Sample Size, 
to clarify efficacy analysis and sample size.
Rationale:  Clarify original statistical methodologies will be utilized and final 
sample size.
●
Update Section 5.3.1.1, Study Procedures, Appendix C, Study Activities for 
Arm A (Rovalpituzumab Tesirine), and Appendix D, Study Activities for 
Arm B (Topotecan) when applicable, as follows:
○
to remove performance of echocardiogram at alternating cycles from 
Cycle 2 for Arm B subjects.
○
to remove collection of Fluid Retention Questionnaire for Arm B subjects
Rationale:  Removed procedures not required for analysis. 
●
Update Section 5.3.1.2, Collection and Handling of Biomarker and/or Optional 
Exploratory Research, Appendix C, Study Activities for Arm A 
(Rovalpituzumab Tesirine), footnotes "y," "zz," and Appendix D, Study 
Activities for Arm B (Topotecan), footnote "v," to remove collection of 
biomarker and pharmacogenetic samples post Cycle 1 Day 1, End of 
Treatment or at disease progression
Rationale:  Removed samples not required for analysis. 
●
Removed collection of Health Resource Utilization in Appendix C, Study 
Activities for Arm A (Rovalpituzumab Tesirine), and Appendix D, Study 
Activities for Arm B (Topotecan)
Rationale:  Removed procedures not required for analysis. 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
5
●
Removed performance of ECG at End of Treatment visit in Appendix D, 
Study Activities for Arm B (Topotecan)
Rationale:  Removed procedure not required for analysis. 
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix L.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
6
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-289
Name of Study Drug:  Rovalpituzumab tesirine 
(Rova-T)
Phase of Development:  3
Name of Active Ingredient:  Rovalpituzumab 
tesirine (SC16LD6.5)
Date of Protocol Synopsis:  08 January 2019
Protocol Title:  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 (TAHOE)
Objectives:
Primary 
•
To assess if treatment with rovalpituzumab tesirine improves overall survival (OS) compared to 
topotecan in subjects with advanced or metastatic DLL3high SCLC who have first disease 
progression during or following front-line platinum based chemotherapy.
Secondary
•
To assess if the treatment with rovalpituzumab tesirine improves progression free survival 
(PFS) compared to topotecan in subjects with advanced or metastatic DLL3high SCLC who have 
first disease progression during or following front-line platinum based chemotherapy. 
•
To assess the effect on patient reported outcomes (i.e., health-related quality of life and 
symptom assessment) due to treatment with rovalpituzumab tesirine compared to topotecan in 
subjects with advanced or metastatic DLL3high SCLC who have first disease progression during 
or following front-line platinum based chemotherapy.
•
To assess if the treatment with rovalpituzumab tesirine improves objective response rate (ORR) 
and clinical benefit rate (CBR) compared to topotecan in subjects with advanced or metastatic 
DLL3high SCLC who have first disease progression during or following front-line platinum 
based chemotherapy.
•
To compare the duration of objective response (DOR) between two arms.
Exploratory
•
To compare the safety and tolerability of rovalpituzumab tesirine to topotecan.
•
To assess the pharmacokinetics (PK) and immunogenicity of rovalpituzumab tesirine.
•
To evaluate DLL3 expression in circulating tumor cells.
•
To evaluate pharmacodynamic and predictive biomarkers for association with efficacy and 
safety.
Investigators:  Multicenter, International
Study Sites:  Approximately 225 globally
Study Population:  Subjects with advanced or metastatic DLL3high SCLC who have first disease 
progression during or following front-line platinum based chemotherapy.  DLL3high is defined as ≥ 75% 
tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC Assay.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
7
Number of Subjects to be Enrolled:  Approximately 600 subjects
Methodology:
This is a Phase 3, randomized, open-label, multicenter study comparing the efficacy, safety and 
tolerability of rovalpituzumab tesirine (Arm A) versus topotecan (Arm B) in subjects with advanced or 
metastatic DLL3high SCLC who have first disease progression during or following front-line 
platinum-based chemotherapy.  Subjects will be randomized in a 2:1 ratio to receive 0.3 mg/kg 
rovalpituzumab tesirine or 1.5 mg/m2 (or per the local label) topotecan.  Subjects receiving 
rovalpituzumab tesirine will also receive 8 mg orally (PO) of dexamethasone twice daily on Day –1, 
Day 1, and Day 2 of each cycle in which rovalpituzumab tesirine is administered.
Randomization will be stratified by prior history of brain metastases (yes versus no), prior PCI (yes vs. 
no) for subjects with no prior history of brain metastases, sensitivity to first line platinum-based regimen 
[sensitive (OR/SD after first line therapy and progression/recurrence-free interval ≥ 90 days) versus 
refractory/resistant (PD as best response to or < 90 days progression/recurrence-free interval after 
first line therapy)] and LDH (> ULN vs. ≤ ULN) at screening.
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to follow-up or 
withdraws consent, termination of the study by AbbVie, or until 12 February 2020 whichever occurs 
first.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult age 18 years or older, who have provided written informed consent.
2.
Histologically or cytologically confirmed advanced or metastatic SCLC with documented 
first disease progression during or following front-line platinum-based systemic regimen.
3.
Tumor must have high DLL3 expression (DLL3high) defined as having ≥ 75% tumor cells staining 
positive according to the VENTANA DLL3 (SP347) IHC Assay.  Archived or fresh tumor material 
can be used for the DLL3 testing.
4.
Measurable disease, as defined per Response Evaluation Criteria in Solid Tumors [RECIST] 
version 1.1 (Refer to Appendix H).
5.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.
Subjects with a history of central nervous system (CNS) metastases must have no active CNS 
disease prior to randomization, defined as radiographically (MRI/CT) confirmed stable or improved 
status assessed at least 2 weeks after completion of definitive treatment (surgical resection, WBRT 
or stereotactic RT) and at least 4 weeks following previous radiographic assessment, off or on a 
stable dose (≤ 10 mg prednisone equivalent) of corticosteroids.  No radiographic evidence of 
progression of definitively treated CNS disease can be present at the baseline tumor assessment.  
Subjects with history of CNS disease and high resolution MRI-confirmed CNS complete response 
to front line chemotherapy at least 6 months prior to randomization are eligible with no requirement 
for local treatment, provided no evidence of CNS disease by high resolution MRI is present at the 
screening assessment.
7.
Recovery to Grade 0 or 1 of any clinically significant toxicity (excluding alopecia) prior to initiation 
of study drug administration.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
8
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
8.
Satisfactory laboratory parameters:
a.
Absolute neutrophil count (ANC) ≥ 1,500/μL
b.
Platelet count ≥ 100,000/μL
c.
Hemoglobin ≥ 9.0 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 ≥ 40 mL/min by the Cockroft-Gault formula
g.
Albumin ≥ 3 g/dL
9.
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 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 Rova-T for 
subjects in Arm A or at least 1 month after the last dose of topotecan for subjects in Arm B.
If the male subject is sexually active, he must agree, from randomization through at least 6 months 
after the last dose of Rova-T for subjects in Arm A or at least 3 months after last dose of topotecan 
for subjects in Arm B to practice the protocol specified contraception.
10. 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) at 
Screening do not require pregnancy testing.
11. 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Any significant medical condition that, in the opinion of the investigator or Sponsor, may place the 
subject at undue risk from the study, including but not necessarily limited to uncontrolled 
hypertension and/or diabetes, clinically significant pulmonary disease or neurological disorder 
(e.g., seizure disorder active within 6 months).
2.
Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable 
angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association 
(NYHA) Class III – IV within 6 months prior to their first dose of study drug.
3.
Known leptomeningeal metastases.
4.
Isolated CNS disease progression with no evidence of progression outside of CNS.
5.
More than one prior systemic therapy regimen for SCLC (prior systemic maintenance therapy 
following front-line platinum based regimen, administered as part of a clinical trial is allowed).
6.
Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization or earlier history 
of recurrent Grade 2 or higher pleural or pericardial effusions with ongoing requirement for 
pericardiocentesis or thoracentesis.
7.
History of capillary leak syndrome.
8.
Serious infection within 2 weeks prior to randomization, including any Grade 3 or higher (per 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] 
version 4.0) viral, bacterial, or fungal infection.
9.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the 
study or for approximately 6 months, or for protocol specified period of time as per treatment 
randomization, after the last dose of study drug.
10. Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 6 months, or for protocol specified period of time as per treatment randomization, 
after the last dose of study drug.
11. Systemic therapy with corticosteroids at > 10 mg/day prednisone equivalent within 1 week prior to 
the first dose of study drug for subjects with history of CNS metastases.
12. 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.
13. Treatment with any of the following anti-cancer therapies within the noted time intervals prior to 
the first dose of study drug:
•
within 2 weeks:  small molecule targeted agents with half-life of < 7 days; radiation not 
involving the thoracic cavity.
•
within 4 weeks:  chemotherapy; radiation involving the thoracic cavity; small molecule 
targeted agents with half-life of ≥ 7 days; monoclonal antibodies, antibody-drug conjugates, 
radioimmunoconjugates, or T-cell or other cell-based therapies
14. Any prior exposure to a pyrrolobenzodiazepine (PBD)-based or indolinobenzodiazepine based 
drug, or known hypersensitivity to rovalpituzumab tesirine, or excipient contained in the drug 
formulation.
15. Prior exposure to topotecan, irinotecan or any other topoisomerase I inhibitors.
16. Participation in a previous study with rovalpituzumab tesirine as an investigational agent.
17. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
10
Investigational Product:
Rovalpituzumab tesirine (Rova-T)
Dose:
0.3 mg/kg
Mode of Administration:
Intravenous, on Day 1 of a 42-Day cycle
Co-Medication:
Dexamethasone
Dose:
8 mg
Mode of Administration:
Oral, twice daily on Day –1, Day 1 (the day of dosing Rova-T), and 
Day 2 of a 42-Day cycle
Reference Therapy or 
Investigational Product:
Topotecan
Dose:
1.5 mg/m2 (or per the local label)
Mode of Administration:
Intravenous, on Days 1 – 5 of each 21-Day cycle.
Duration of Treatment:
Regimen of Arm A will be administered for 2 cycles unless earlier discontinuation is warranted due to 
disease progression, unacceptable toxicity or any other reason; up to two additional cycles of 
rovalpituzumab tesirine may be permitted however the last dose on study must be administered no later 
than 04 December 2019 for subjects in Arm A who consent and satisfy all of the protocol defined 
criteria.  
Regimen of Arm B will be administered until disease progression, unacceptable toxicity, any other 
reason requiring treatment discontinuation, or no later than 04 December 2019, whichever comes first.
Follow up activities, including overall survival assessments, End of Treatment visits and AE/SAE 
reporting must occur no later than 12 February 2020.
Criteria for Evaluation:
Efficacy:
Overall Survival (OS):  After the End of treatment, survival information will be collected at 
approximately 6-week intervals (or as requested by sponsor to support data analysis) continuing until the 
endpoint of death, the subject becomes lost to follow-up, AbbVie terminates the study, or until 
12 February 2020.
Progression-Free Survival (PFS):  will be derived according to progressive disease per RECIST 
version 1.1 or death.  Radiographic tumor assessments for response will be conducted by CT scanning.
Patient-Reported Outcomes (PRO):  health-related quality of life (HRQOL) and symptom assessment 
will be assessed at baseline, during the treatment cycle, at the end of treatment visit and every 6 weeks 
thereafter until disease progression or initiation of new anti-cancer therapy via the European 
Organization for Research and Treatment of Cancer QLQ-C15-PAL (EORTC QLQ-C15-PAL), EORTC 
QLQ-LC13, and EuroQoL Five Dimensions Questionnaire (EQ-5D-5L) questionnaires.
Objective Response Rate (ORR):  will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning at baseline, every 6 weeks for 30 weeks, 
then every 9 weeks until progression or death.
Safety:
Adverse events, laboratory profiles, physical examinations and vital signs will be assessed throughout 
the study.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
11
Criteria for Evaluation (Continued):
Pharmacokinetic:
Serum concentrations of rovalpituzumab tesirine antibody-drug conjugate (ADC) and the presence of 
anti-therapeutic antibodies (ATA) will be determined.
Biomarkers/Pharmacogenetics:
Biomarker assessments will include analyses of tumor material and circulating tumor cells for DLL3 
expression, blood samples for inflammatory, tumor and safety 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.
Statistical Methods:
Efficacy:
Following the fourth safety review by the IDMC, on 04 December 2018, the IDMC recommended that 
enrollment in the study is discontinued due to overall survival concerns associated with the study drug.  
For patients currently on treatment in Arm A, the IDMC recommends that sites and patients make 
individual decisions as to whether or not to continue treatment based on patient level response.  The data 
collection plan has been minimized given the status change of this study.  With all these changes, no 
statistical testing will be performed for the efficacy endpoints.  The efficacy endpoints will be analyzed 
using the original statistical methodologies as appropriate.  The efficacy endpoints for which there is not 
enough data to implement the statistical models will be summarized by treatment arms.  The statistical
section remains unchanged to reflect the original analysis plan.
Efficacy analyses will be performed in the randomized set, including all randomized subjects, with 
subjects grouped according to the treatment assigned at randomization, following intent-to-treat 
principle, unless otherwise specified.  Assessment of response and progression will be determined by the 
CRAC according to RECIST v1.1.
Overall survival (OS) is the primary efficacy endpoint.  OS is defined as the time from the date of 
randomization to the date of death from any cause (i.e., date of subject's death – date of randomization + 
1).  For subjects who are alive at the time of the analysis, the data will be censored at the last date they 
were documented to be alive.  Subjects with no post-baseline information will be censored at the date of 
randomization plus 1 day.
Comparison between the two treatment arms will be performed via a one-sided log-rank test, stratified 
by the randomization stratification factors, testing the null hypothesis (rovalpituzumab tesirine arm 
(Arm A) is not superior to topotecan arm (Arm B) in OS).  The hazard ratio (HR) of Arm A over Arm B 
will be estimated using a stratified Cox proportional hazards model.  The OS curves for each arm will be 
estimated using the Kaplan-Meier (KM) product-limit method.  Two-sided, 95% confidence interval for 
median OS will be computed.  Landmark survival rate, defined as the survival rate estimated using the 
Kaplan-Meier approach at pre-defined timepoints from randomization (e.g., 6, 12 and 18 months), will 
be summarized, presenting two-sided 95% CIs.  
Secondary time-to-event endpoints of PFS and DOR will be analyzed using the same statistical method 
described for the analysis of OS.  Analysis of categorical endpoints such as ORR and CBR will be 
performed for the randomized subjects with measureable disease at baseline.  Comparison of the 
categorical endpoints will be carried out using a one-sided Cochran-Mantel-Haenszel (CMH) test, 
stratified by the randomization stratification factors. 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
12
Statistical Methods (Continued):
Testing Strategy:
To meet global regulatory requirements, a multiple testing strategy will be implemented to control the 
family-wise type I error for comparisons of rovalpituzumab tesirine arm versus topotecan arm with 
respect to the primary and secondary endpoints in the order specified below.
The following null hypotheses are considered:
H1:  Rovalpituzumab tesirine arm is not superior to topotecan arm in OS.
H2:  Rovalpituzumab tesirine arm is not superior to topotecan arm in PFS per CRAC.
H3:  Rovalpituzumab tesirine arm is not superior to topotecan arm in PRO physical functioning scale at 
C2D1 for rovalpituzumab tesirine arm and C3D1 for topotecan arm.
H4:  Rovalpituzumab tesirine arm is not superior to topotecan arm in ORR per CRAC.
H5:  Rovalpituzumab tesirine arm is not superior to topotecan arm in CBR per CRAC.
H6:  Rovalpituzumab tesirine arm is not superior to topotecan arm in DOR per CRAC.
The family of null hypotheses will be tested using a hierarchical procedure, i.e., in a fixed sequence of 
{H1, H2, H3, H4, H5, H6}.  Hypothesis H1 will be tested first, and no further tests will be performed if 
H1 is not rejected.  Thereafter, each hypothesis will be tested in the order specified if and only if H1 and 
all preceding null hypotheses are rejected.  Otherwise testing in the hierarchical sequence will stop.  
Safety:
A safety analysis will be performed for all subjects treated with the study drug.  For the study as a whole, 
adverse events will be evaluated and summarized.  Laboratory test results and vital signs will be 
summarized as appropriate.
Sample Size:
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC recommended that 
enrollment in the study is discontinued due to overall survival concerns associated with the study drug.  
444 subjects were enrolled in the study.  The following paragraph describes how the sample size was 
determined for the study.
The sample size of the study is primarily determined by the analysis of OS.  Approximately 600 subjects 
in total will be randomized to rovalpituzumab tesirine (Arm A) or topotecan (Arm B) in a 2:1 ratio.  It is 
assumed that median overall survival in the topotecan arm (Arm B) will be around 6.5 months.  Based 
on a log-rank test, at a one-sided significance level of 0.025 and a power of 85%, a total of 489 deaths 
are needed to detect an increase in median OS to 8.67 months in rovalpituzumab tesirine arm (Arm A), 
corresponding to a hazard ratio of 0.75 (i.e., a reduction in the hazard death of 25%).  It is projected that 
an observed hazard ratio of 0.829 or less, corresponding to 1.34 months or greater improvement in 
median OS, would result in statistical significance in the final analysis of OS.  
Interim Analysis:
No interim analysis is planned.  
Biomarkers:
Biomarkers will be measured at baseline and post-treatment, with analyses performed to identify 
markers associated with rovalpituzumab tesirine response, sensitivity, pharmacodynamics, or safety.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
13
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADC
Antibody-drug conjugate
AE
Adverse event
ALT
Alanine aminotransferase
ANA
Anti-nuclear antibodies
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASCL1
Achaete-scute homolog 1
ASTRO
American Society for Radiation Oncology
AST
Aspartate aminotransferase
AT
Aminotransferase
ATA
Anti-therapeutic antibody
ATC
Anatomical therapeutic chemical (codes)
ATEMS
AbbVie Temperature Excursion Management System
β-hCG
Beta-human chorionic gonadotropin
BUN
Blood urea nitrogen
CBR
Clinical benefit rate
CDSM
Clinical Drug Supply Management
CFR
Code of Federal Regulations
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CR
Complete response
CRF
Case report forms
CRP
C-reactive protein
CS
Clinically significant
CSC
Cancer stem cell
CT
Computerized tomography
CTC
Circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CYP3A4
Cytochrome P450 3A4


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
14
DILI
Drug-induced liver injury
DLL3
Delta-like protein 3
DLL3high
DLL3 high expression in tumor
DNA
Deoxyribonucleic acid
DOR
Duration of response
DOT
US Department of Transportation
eCCR
Estimated creatinine clearance rate
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
Electronic data capture
EFNS
European Federation of Neurological Societies
EGF
Epidermal growth factor
EMEA
European Agency for the Evaluation of Medicinal Products
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EQ-5D-5L
EuroQoL Five Dimensions Questionnaire
ESR
Erythrocyte sedimentation rate
EU
European Union
FDA
US Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
Gy
Gray
HIPPA
Health Insurance Portability and Accountability Act
HR
Hazard ratio
HRQOL
Health-related quality of life
IATA
International Air Transport Association
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IL
Interleukin
IMP
Investigational Medicinal Product


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
15
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous(ly)
KM
Kaplan-Meier
LCNEC
Large cell neuroendocrine cancer
LD
Longest diameter
LFT
Liver function tests
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
nAb
Neutralizing antibodies
NASH
Non-alcoholic steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCS
Not clinically significant
NEUROD1
Neurogenic differentiation 1
NSAID
Non-steroidal anti-inflammatory drug
NSE
Neuron-specific enolase
NYHA
New York Heart Association
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PBD
Pyrrolobenzodiazepine
PCI
Prophylactic cranial irradiation
PD
Progressive disease
PDX
Patient-derived xenografts
PET
Positron emission tomography
PET-CT
Positron emission tomography-computed tomography


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
16
PFS
Progression-free survival
PK
Pharmacokinetics
PO
Per os (by mouth)
POR
Proof of receipt
PR
Partial response
PRO
Patient reported outcome
PT
Prothrombin time
PTFU
Post-treatment follow up
q3wk
Every 3 weeks
q6wk
Every 6 weeks
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria in Solid Tumors
RF
Rheumatoid factor
Rova-T
Rovalpituzumab tesirine
ROVAT
AbbVie compound number for rovalpituzumab tesirine
RPTD
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SC-DR002
DNA cross-linking agent also known as D6.5
SC16
Humanized DLL3-specific IgG1 antibody
SCLC
Small cell lung cancer
SD
Stable disease
SGOT/AST
Serum glutamic-oxaloacetic transaminase
SGPT/ALT
Serum glutamic-pyruvic transaminase
SIADH
Syndrome of Inappropriate Anti-Diuretic Hormone
SMPC
Summary of product characteristics
SPF
Sun protection factor
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TIC
Tumor-initiating cells
ULN
Upper limit of normal
US
Ultrasound


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
17
VALG
Veterans Administration Lung Study Group
VAS
Visual analog scale
VEGF
Vascular endothelial growth factor
WBC
White Blood Cell
WHODRUG
World Health Organization Drug (Dictionary)
WOCBP
Women of Childbearing Potential


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
18
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................6
1.3
List of Abbreviations and Definition of Terms........................................13
2.0
Table of Contents...................................................................18
3.0
Introduction ...........................................................................23
3.1
Small Cell Lung Cancer...........................................................................23
3.2
Delta-Like Protein 3.................................................................................24
3.3
Rovalpituzumab Tesirine.........................................................................24
3.4
Differences Statement..............................................................................25
3.5
Benefits and Risks....................................................................................25
4.0
Study Objectives....................................................................26
5.0
Investigational Plan...............................................................27
5.1
Overall Study Design and Plan:  Description ..........................................27
5.2
Selection of Study Population..................................................................29
5.2.1
Inclusion Criteria .....................................................................................30
5.2.2
Exclusion Criteria ....................................................................................32
5.2.3
Prior and Concomitant Therapy...............................................................34
5.2.3.1
Prior Therapy ...........................................................................................35
5.2.3.2
Concomitant Therapy...............................................................................35
5.2.3.3
Allowed Concomitant Therapy................................................................35
5.2.3.4
Prohibited Therapy...................................................................................37
5.2.4
Contraception Recommendations ............................................................37
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic and 
Safety Assessments/Variables..................................................................39
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................39
5.3.1.1
Study Procedures .....................................................................................39
5.3.1.2
Collection and Handling of Biomarker and/or Optional 
Exploratory Research Samples ................................................................52
5.3.2
Drug Concentration Measurements .........................................................55
5.3.2.1
Collection of Samples for Analysis .........................................................55


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
19
5.3.2.2
Handling/Processing of Samples .............................................................55
5.3.2.3
Disposition of Samples ............................................................................56
5.3.2.4
Measurement Methods.............................................................................56
5.3.3
Efficacy Variables....................................................................................56
5.3.4
Safety Variables.......................................................................................57
5.3.5
Pharmacokinetic Variables ......................................................................57
5.3.6
Biomarker and/or Optional Exploratory Research Variables ..................57
5.4
Removal of Subjects from Therapy or Assessment.................................58
5.4.1
Discontinuation of Individual Subjects....................................................59
5.4.2
Discontinuation of Entire Study...............................................................60
5.5
Treatments................................................................................................61
5.5.1
Treatments Administered.........................................................................61
5.5.2
Rovalpituzumab Tesirine (Arm A) ..........................................................61
5.5.3
Topotecan (Arm B)..................................................................................62
5.5.4
Identity of Investigational Products.........................................................62
5.5.4.1
Packaging and Labeling...........................................................................64
5.5.4.2
Storage and Disposition of Study Drugs..................................................64
5.5.4.3
Preparation/Reconstitution of Dosage Forms ..........................................66
5.5.5
Method of Assigning Subjects to Treatment Arms..................................66
5.5.6
Selection and Timing of Dose for Each Subject......................................67
5.5.6.1
Dose Modifications..................................................................................67
5.5.6.1.1
Dose Treatment Delays Due to Toxicity or Progression (Arm A, 
Rovalpituzumab Tesirine)........................................................................67
5.5.6.1.2
Dose Reduction Guidelines (Arm A, Rovalpituzumab Tesirine) ............68
5.5.6.1.3
Dose Reductions, Delays and Discontinuation Due to Toxicity or 
Progression (Arm B, Topotecan) .............................................................71
5.5.7
Blinding....................................................................................................71
5.5.8
Data for Independent Data Monitoring Committee (IDMC)...................71
5.5.9
Treatment Compliance.............................................................................71
5.5.10
Drug Accountability.................................................................................71
5.6
Discussion and Justification of Study Design..........................................73
5.6.1
Discussion of Study Design and Choice of Control Groups....................73
5.6.2
Appropriateness of Measurements...........................................................73


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
20
5.6.3
Suitability of Subject Population .............................................................73
5.6.4
Selection of Doses in the Study ...............................................................74
6.0
Complaints .............................................................................75
6.1
Medical Complaints.................................................................................75
6.1.1
Definitions................................................................................................76
6.1.1.1
Adverse Event..........................................................................................76
6.1.1.2
Serious Adverse Events ...........................................................................76
6.1.1.3
Adverse Events Expected Due to SCLC or Progression of SCLC ..........78
6.1.2
Adverse Event Severity............................................................................78
6.1.3
Relationship to Study Drug......................................................................79
6.1.4
Deaths ......................................................................................................79
6.1.5
Adverse Event Collection Period.............................................................80
6.1.6
Adverse Event Reporting.........................................................................81
6.1.7
Pregnancy.................................................................................................83
6.1.8
Toxicity Management ..............................................................................84
6.1.8.1
Management of Serosal Effusions/Serositis ............................................84
6.1.8.2
Management of Skin Reactions ...............................................................85
6.1.8.3
Management of Potential Drug-Induced Liver Injury .............................86
6.1.8.4
Monitoring and Management of Edema ..................................................88
6.1.8.5
Pneumonitis..............................................................................................90
6.2
Product Complaint ...................................................................................91
6.2.1
Definition .................................................................................................91
6.2.2
Reporting..................................................................................................91
7.0
Protocol Deviations................................................................92
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................92
8.1
Statistical and Analytical Plans................................................................93
8.1.1
Disposition of Study Subjects..................................................................94
8.1.2
Demographic and Baseline Characteristics .............................................94
8.1.3
Efficacy Endpoints...................................................................................94
8.1.4
Primary Efficacy Endpoint and Analysis.................................................94
8.1.5
Secondary Efficacy Endpoints.................................................................95
8.1.6
Patient Reported Outcomes (PROs).........................................................97


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
21
8.1.7
Pharmacokinetic and Exposure-Response Analyses ...............................98
8.1.8
Planned Sensitivity and Subgroup Analyses............................................98
8.2
Safety Analyses........................................................................................99
8.2.1
Treatment-Emergent Adverse Events (TEAEs).......................................99
8.2.2
Clinical Laboratory Evaluation................................................................99
8.2.3
Vital Signs..............................................................................................100
8.2.4
ECOG Performance Status ....................................................................100
8.2.5
Electrocardiogram..................................................................................100
8.2.6
Concomitant Medications ......................................................................100
8.3
Type I Error Adjustment Procedure for Multiple Testing .....................100
8.4
Determination of Sample Size ...............................................................102
8.5
Interim Analysis.....................................................................................103
8.6
Accrual/Study Duration Considerations ................................................103
8.7
Randomization Methods ........................................................................103
9.0
Ethics.....................................................................................104
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................104
9.2
Ethical Conduct of the Study.................................................................104
9.3
Subject Information and Consent...........................................................105
9.3.1
Informed Consent Form and Explanatory Material ...............................106
9.3.2
Revision of the Consent Form and Explanatory Material .....................106
10.0
Source Documents and Case Report Form 
Completion ...........................................................................106
10.1
Source Documents .................................................................................106
10.2
Case Report Forms.................................................................................107
11.0
Data Quality Assurance ......................................................109
12.0
Use of Information...............................................................109
13.0
Completion of the Study .....................................................109
14.0
Investigator's Agreement....................................................111
15.0
Reference List ......................................................................112


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
22
List of Tables
Table 1.
Examples of Strong CYP3A4 Inhibitors..................................................37
Table 2.
Clinical Laboratory Tests.........................................................................46
Table 3.
Identity of Investigational Products.........................................................63
Table 4.
Non-Investigational Medicinal Products .................................................63
Table 5.
Dose Reductions for Rovalpituzumab Tesirine Investigational 
Product (IP)..............................................................................................69
Table 6.
Dose Reductions and Discontinuation for Unacceptable Toxicities........70
Table 7.
Recommended Management of Photosensitivity.....................................86
List of Figures
Figure 1.
Study Schema...........................................................................................29
Figure 2.
Adverse Event Collection ........................................................................81
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................114
Appendix B.
List of Protocol Signatories....................................................................116
Appendix C.
Study Activities for Arm A (Rovalpituzumab Tesirine)........................117
Appendix D.
Study Activities for Arm B (Topotecan)................................................123
Appendix E.
Performance Status Scales Conversion..................................................128
Appendix F.
New York Heart Association Classification..........................................129
Appendix G.
Calculated Creatinine Clearance Using Modified Cockcroft-Gault 
Equation .................................................................................................130
Appendix H.
Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1 
for Tumor Response...............................................................................131
Appendix I.
CTCAE v 4.0 Grading of Relevant AEs................................................138
Appendix J.
Fluid Retention Questionnaire ...............................................................142
Appendix K.
Adverse Events Expected Due to SCLC or Progression of SCLC ........144
Appendix L.
Protocol Amendment:  List of Changes.................................................146


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
23
3.0
Introduction
3.1
Small Cell Lung Cancer
Small cell lung cancer (SCLC) is an important unmet medical need, representing 15 –
20% of the 220,000 annual new cases of lung cancer.1,2  SCLC arises from epithelial cells 
with neuroendocrine differentiation.  Historically, SCLC has been staged using Veterans 
Administration Lung Study Group (VA LG) classification as limited versus extensive 
stage disease, the former being defined as disease limited to the chest that can be 
encompassed by a radiation field while the latter includes all other cases.  Approximately 
one-third of newly diagnosed subjects will have limited stage disease while the rest will 
be extensive.  TNM classification is also used to stage SCLC.  Systemic chemotherapy 
remains the cornerstone of therapy for all stages of SCLC.  Standard initial chemotherapy 
for all subjects with a suitable performance status consists of a platinum salt (carboplatin 
or cisplatin) in combination with a second agent, usually etoposide or irinotecan.  For 
subjects with limited stage disease, concurrent or sequential involved-field thoracic 
radiotherapy is indicated.  Response rates to initial therapy are high, ranging from 70 –
90% for limited stage and 60 – 70% for extensive stage; however, responses are typically 
not durable and recurrence rates are high in the limited stage disease and nearly universal 
in the extensive stage disease, leading to median survivals of 14 – 20 months and 9 –
11 months, respectively.3
Options for subjects with relapsed/recurrent SCLC disease are limited.  The only agent 
with several global regulatory approvals is topoisomerase I inhibitor topotecan, but its 
activity is less than impressive, and associated toxicity is significant.4  Response rate with 
topotecan is approximately 14%, while median PFS and OS are 2.7 and 6.5 months, 
respectively.  The strongest predictor of topotecan efficacy is sensitivity to front line 
therapy:  subjects with relapse after more than 90 days from the completion of front line 
therapy (sensitive) have better results with topotecan compared to subjects that progress 
while receiving front line therapy or in less than 90 days of its completion 
(refractory/resistant).  Several other single agent or combination regimens used in 
second line SCLC offer efficacy similar to topotecan.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
24
Therefore, exploration of new therapies in second line SCLC is warranted, with the goals 
of extending disease control and improving overall survival.
3.2
Delta-Like Protein 3
Delta-like protein 3 (DLL3) is an atypical, inhibitory ligand of the Notch receptor family, 
discovered by AbbVie Stemcentrx scientists as a novel therapeutic target in SCLC and 
other high-grade neuroendocrine carcinomas.  It was identified by whole transcriptome 
sequencing of tumor initiating cells (TICs) isolated from SCLC and large cell 
neuroendocrine cancer (LCNEC) patient-derived xenografts (PDXs), and found to be 
expressed in the majority of SCLC and LCNEC tumors, but with no detectable protein 
expression in normal tissues or non-neuroendocrine tumor types.5  DLL3 has been 
implicated in the regulation of cell fate decisions during development, and likely acts as 
an oncogene in high-grade neuroendocrine tumors where it is a downstream 
transcriptional target of the achaete-scute homolog 1 (ASCL1) transcription factor in 
SCLC tumor cells, and acts to inhibit the Notch receptor pathway, thereby facilitating 
neuroendocrine tumorigenesis.5-7
3.3
Rovalpituzumab Tesirine
Rovalpituzumab tesirine (SC16LD6.5) is a DLL3-targeted antibody-drug conjugate 
(ADC) consisting of the humanized DLL3-specific IgG1 monoclonal antibody SC16; the 
DNA cross linking pyrrolobenzodiazepine (PBD) agent SC-DR002 (D6.5); and a 
protease-cleavable linker that covalently links SC DR002 to SC16.  The primary 
mechanism of rovalpituzumab tesirine is binding of the ADC to DLL3 on target-
expressing cells, followed by internalization of the ADC-DLL3 complex and release of 
SC-DR002 via proteolytic cleavage in late endosomes.  Interstrand crosslinks of cellular 
DNA induced by intercalated SC-DR002 leads to cellular cytotoxicity.
In a Phase 1 study (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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
25
≥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% (AbbVie Stemcentrx, data on file).  
In a Phase 2 SCRX001-002 (TRINITY) study 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) had shown confirmed objective response rate 
of 16%, progression-free survival of 3.9 months and overall survival of 5.6 months in 3rd
line DLL3High patients.  Of note, prolonged stable disease with target lesion size reduction 
has been observed in a significant number of patients receiving additional post-
progression cycles of rovalpituzumab tesirine (AbbVie Stemcentrx, data on file).
Therefore, rovalpituzumab tesirine appears to be an active anti-cancer therapy in SCLC.
3.4
Differences Statement
This is the first randomized, open-label, multicenter, Phase 3 study comparing 
rovalpituzumab tesirine to topotecan in subjects with advanced or metastatic SCLC with 
high DLL3 expression (DLL3high) in tumor and who have had first disease progression 
during or following front-line platinum based chemotherapy.
3.5
Benefits and Risks
Activity of the current second line standard of care topotecan is suboptimal and high 
unmet need in this setting is widely recognized.  Based on the Phase 1 results of 
rovalpituzumab tesirine, this agent may offer improved efficacy over current second line 
standard.  This study will assess the efficacy, tolerability, and safety of rovalpituzumab 
tesirine in SCLC subjects with first disease progression during or following front-line 
platinum-based chemotherapy (e.g., cisplatin or carboplatin plus etoposide).
The most frequent treatment-emergent adverse event (TEAE) terms considered related to 
rovalpituzumab tesirine have included fatigue (37.6%), pleural effusion (29.4%) 
peripheral edema (29.1%) and decreased appetite (27.3%), while the most frequent, 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
26
related TEAE groups of Grade 3 is thrombocytopenia (10.3%), pleural effusions (6.2%), 
and anaemia (5.4%).  In addition, preclinical toxicology studies conducted in the rat and 
the cynomolgus monkey have identified bone marrow, lung, liver and kidney as potential
sources of clinical adverse events (AEs) (AbbVie Stemcentrx data on file).  Accordingly, 
safety assessments will include regular assessments at protocol-specified time points of 
routine physical examination, laboratory and imaging tests, echocardiograms, a fluid 
retention questionnaire, daily weights, and spot urine protein testing.
4.0
Study Objectives
The primary objectives of the study are to assess if treatment with rovalpituzumab tesirine 
improves overall survival (OS) compared to topotecan in subjects with advanced or 
metastatic DLL3high SCLC who have first disease progression during or following front-
line platinum based chemotherapy.
The secondary objectives of the study are as follows:  to assess if the treatment with 
rovalpituzumab tesirine improves progression free survival (PFS) compared to topotecan; 
to assess the effect on patient reported outcomes (i.e., health-related quality of life and 
symptom assessment) between two arms; to assess if treatment with rovalpituzumab 
tesirine improves objective response rate (ORR) and clinical benefit rate (CBR) compared 
to topotecan; and to compare the duration of objective response between two arms in 
subjects with advanced or metastatic DLL3high SCLC who have first disease progression 
during or following front-line platinum based chemotherapy.
The exploratory objectives are to compare the safety and tolerability of rovalpituzumab 
tesirine to topotecan; to assess the pharmacokinetics (PK) and immunogenicity of 
rovalpituzumab tesirine; to evaluate DLL3 expression in circulating tumor cells and to 
evaluate pharmacodynamic and predictive biomarkers for association with efficacy and 
safety.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
27
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study was designed to enroll approximately 600 subjects with advanced or metastatic 
DLL3high SCLC to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  DLL3high is defined as 
≥75% tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC 
Assay.
This is a Phase 3, randomized, open-label, multinational, and multicenter study comparing 
the efficacy, safety and tolerability of rovalpituzumab tesirine versus topotecan in subjects 
with advanced or metastatic DLL3high SCLC who have first disease progression during or 
following front-line platinum-based chemotherapy.  Approximately 225 clinical sites will 
participate.
All subjects must have tumor samples analyzed to confirm eligibility.  Tumors must be 
DLL3high as determined by the AbbVie designated central immunohistochemistry (IHC) 
laboratory.  Archived or fresh tumor material can be used for the DLL3 testing.  Testing 
for DLL3 status may occur at any time after initial diagnosis.
Eligible subjects will be randomized in a 2:1 ratio to receive rovalpituzumab tesirine 
(Arm A) or topotecan (Arm B):
●
Subjects assigned to Arm A will receive 0.3 mg/kg rovalpituzumab tesirine 
(IV) on Day 1 of a 42-Day cycle for 2 cycles, along with 8 mg orally (PO) of 
dexamethasone twice daily on Day –1, Day 1, and Day 2.  Regimen of Arm A 
will be administered for the 2 cycles planned unless earlier discontinuation is 
warranted due to disease progression, unacceptable toxicity or any other 
reason.  Up to two additional cycles of rovalpituzumab tesirine may be 
permitted, however the last dose on study must be administered no later than 
04 December 2019 for subjects in Arm A meeting certain criteria, as described 
in Section 5.3.1.1.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
28
●
Arm B subjects will receive 1.5 mg/m2 topotecan (IV) on Days 1 – 5 of each 
21-Day cycle.  Topotecan may be administered at a lower dose if required by 
the local label.  The Arm B regimen will be administered until disease 
progression, unacceptable toxicity or any other reason requiring treatment 
discontinuation, or no later than 04 December 2019, whichever comes first.
Subjects will be stratified by prior history of brain metastases (yes vs. no), prior PCI (yes 
vs. no) for subjects with no prior history of brain metastases, sensitivity to first line 
platinum-based regimen [sensitive (OR/SD after first line therapy and 
progression/recurrence-free interval ≥ 90 days) vs. refractory/resistant (PD as best 
response or < 90 days8 progression/recurrence-free interval after first line therapy)] and 
LDH level (> ULN vs. ≤ ULN) at screening.
Post-baseline radiographic assessments will be performed every 6 weeks for the 
first 30 weeks and then every 9 weeks until radiographic progression or death.  
Radiographic information will be collected to determine response according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1.  For subjects receiving post-
progression doses of rovalpituzumab tesirine radiographic assessments will continue until 
the second event of disease progression as outlined in Section 5.3.1.1.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
clinically significant laboratory result, the site will attempt to provide follow-up until a 
satisfactory clinical resolution of the laboratory results or adverse event is achieved.
Subjects no longer undergoing clinical assessments will have survival information 
reported approximately every 6 weeks (or as requested by sponsor to support data 
analysis) beginning at the last clinical assessment and continuing until the endpoint of 
death, the subject has become lost to follow-up, or termination of the study by AbbVie.
A schematic of the study is provided in Figure 1, Study Schema.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
29
Figure 1.
Study Schema
Empty arrowhead = Rovalpituzumab tesirine administration cycle; Dotted arrowhead = Additional Rovalpitizumab 
tesirine administration cycle; Filled arrowhead = Topotecan administration cycle; PTFU = post-treatment follow-up; 
OS = overall survival
1.
Tumor material collection and testing for DLL3 status may occur at any time after initial diagnosis, including 
outside of the Screening window, depending on completion of the appropriate consent process.
2.
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A meeting certain 
criteria, as described in Section 5.3.1.1.
3.
Topotecan will be administered until disease progression, unacceptable toxicity or any other reason requiring 
treatment discontinuation.
5.2
Selection of Study Population
The study population will consist of adult subjects with histologically or cytologically 
confirmed advanced or metastatic SCLC with documented disease progression during or 
following one prior systemic, platinum-based regimen and confirmed DLL3high SCLC.
Subjects must meet all inclusion criteria and none of the exclusion criteria within 28 days 
of randomization.  (Tumor material collection and testing for DLL3 status may occur at 
any time after initial diagnosis, including outside of the Screening window, depending on
completion of the appropriate consent process.)  Subjects should be assessed for eligibility 
based on the most recent data collected prior to randomization.  Eligibility criteria may 
not be waived by the Investigator and are subject to review in the event of a Good Clinical 
Practice (GCP) audit and/or regulatory authority inspection.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
30
5.2.1
Inclusion Criteria
1.
Adult age 18 years or older, who have provided written informed consent.
2.
Histologically or cytologically confirmed advanced or metastatic SCLC with 
documented first disease progression during or following front-line platinum-based 
systemic regimen.
3.
Tumor must have high DLL3 expression (DLL3high) defined as having ≥ 75% 
tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC 
Assay.  Archived or fresh tumor material can be used for the DLL3 testing.
4.
Measurable disease, as defined per Response Evaluation Criteria in Solid Tumors 
[RECIST] version 1.1 (Refer to Appendix H).
5.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.
Subjects with a history of central nervous system (CNS) metastases must have no 
active CNS disease prior to randomization, defined as radiographically (MRI/CT) 
confirmed stable or improved status assessed at least 2 weeks after completion of 
definitive treatment (surgical resection, WBRT or stereotactic RT) and at least 
4 weeks following previous radiographic assessment, off or on a stable dose 
(≤10 mg prednisone equivalent) of corticosteroids.  No radiographic evidence of 
progression of definitively treated CNS disease can be present at the baseline tumor 
assessment.  Subjects with history of CNS disease and high resolution MRI-
confirmed CNS complete response to front line chemotherapy at least 6 months 
prior to randomization are eligible with no requirement for local treatment, 
provided no evidence of CNS disease by high resolution MRI is present at the 
screening assessment.
7.
Recovery to Grade 0 or 1 of any clinically significant toxicity (excluding alopecia) 
prior to initiation of study drug administration.
8.
Satisfactory laboratory parameters:
a.
Absolute neutrophil count (ANC) ≥ 1,500/μL


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
31
b. Platelet count ≥ 100,000/μL
c.
Hemoglobin ≥ 9.0 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 ≥ 40 mL/min by the Cockroft-Gault formula 
(Refer to Appendix G)
g. Albumin ≥ 3 g/dL
9.
If female, subject must be either postmenopausal 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 Women of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at randomization through 
at least 6 months after the last dose of Rova-T for subjects in Arm A or at least 
1 month after the last dose of topotecan for subjects in Arm B.
If the male subject is sexually active, he must agree, from randomization through at 
least 6 months after the last dose of Rova-T for subjects in Arm A or at least 
3 months after last dose of topotecan for subjects in Arm B to practice the protocol 
specified contraception (Section 5.2.4).
10.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at randomization.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
32
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.
11.
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.
Rationale for Inclusion Criteria
1 – 6
To select and/or collect data on the subject population
7 – 8
For the safety of the subjects
9 – 10
The impact of rovalpituzumab tesirine on pregnancy in humans is unknown
11
In accordance with Harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Any significant medical condition that, in the opinion of the investigator or 
Sponsor, may place the subject at undue risk from the study, including but not 
necessarily limited to uncontrolled hypertension and/or diabetes, clinically 
significant pulmonary disease or neurological disorder (e.g., seizure disorder active 
within 6 months).
2.
Documented history of a cerebral vascular event (stroke or transient ischemic 
attack), unstable angina, myocardial infarction, or cardiac symptoms consistent 
with New York Heart Association (NYHA) Class III – IV within 6 months prior to 
their first dose of study drug.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
33
3.
Known leptomeningeal metastases.
4.
Isolated CNS disease progression with no evidence of progression outside of CNS.
5.
More than one prior systemic therapy regimen for SCLC (prior systemic 
maintenance therapy following front-line platinum based regimen, administered as 
part of a clinical trial is allowed).
6.
Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization 
or earlier history of recurrent Grade 2 or higher pleural or pericardial effusions with 
ongoing requirement for pericardiocentesis or thoracentesis.
7.
History of capillary leak syndrome.
8.
Serious infection within 2 weeks prior to randomization, including any Grade 3 or 
higher (per NCI CTCAE version 4.0)9 viral, bacterial, or fungal infection.
9.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 6 months, or for protocol specified period of 
time as per treatment randomization, after the last dose of study drug.
10.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 6 months, or for protocol specified period of time as per 
treatment randomization, after the last dose of study drug.
11.
Systemic therapy with corticosteroids at > 10 mg/day prednisone equivalent within 
1 week prior to the first dose of study drug for subjects with history of CNS 
metastases.
12.
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.
13.
Treatment with any of the following anti-cancer therapies within the noted time 
intervals prior to the first dose of study drug:
●
within 2 weeks:  small molecule targeted agents with half-life of < 7 days; 
radiation not involving the thoracic cavity.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
34
●
within 4 weeks:  chemotherapy; radiation involving the thoracic cavity; small 
molecule targeted agents with half-life of ≥ 7 days; monoclonal antibodies, 
antibody-drug conjugates, radioimmunoconjugates, or T-cell or other 
cell-based therapies
14.
Any prior exposure to a pyrrolobenzodiazepine (PBD)-based or 
indolinobenzodiazepine based drug, or known hypersensitivity to rovalpituzumab 
tesirine, or excipient contained in the drug formulation.
15.
Prior exposure to topotecan, irinotecan or any other topoisomerase I inhibitors.
16.
Participation in a previous study with rovalpituzumab tesirine as an investigational 
agent.
17.
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells.
Rationale for Exclusion Criteria
1 – 8, 17
For the safety of the subjects
9 – 10
The impact of rovalpituzumab tesirine on pregnancy in humans is unknown
11 – 16
To select the appropriate subject population
5.2.3
Prior and Concomitant Therapy
Any concomitant medication or vaccine (including over-the-counter or prescription 
medicines, vitamins and/or herbal supplements) that the subject is receiving at the time of 
study drug administration, or receives during the study through the safety reporting period 
(Section 6.1.4), must be recorded along with the reason for use, date(s) of administration 
including start and end dates, and dosage information including dose, route and frequency.
Any concomitant therapy given for a protocol-related AE should be recorded from the 
time of informed consent.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
35
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies.
5.2.3.1
Prior Therapy
Subjects must have received at least one cycle of platinum-based therapy (carboplatin or 
cisplatin in combination with etoposide) for the treatment of SCLC.  Subjects with a 
history of CNS metastases must have received definitive treatment for CNS disease.  
Definitive treatment may include surgical resection with negative margins, whole brain 
irradiation, and/or stereotactic radiation therapy performed in accordance with a regimen 
endorsed by the NCCN, European Federation of Neurological Societies (EFNS), or 
American Society for Radiation Oncology (ASTRO).
5.2.3.2
Concomitant Therapy
All subjects randomized to Arm A will receive oral dexamethasone (PO) as premedication 
at 8 mg twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each cycle in 
which rovalpituzumab tesirine is administered.  The first dose of the dexamethasone on 
the day of dosing should be at least 30 minutes but no more than 4 hours prior to the 
rovalpituzumab tesirine infusion.
In the event that a subject arrives for rovalpituzumab tesirine administration on Day 1, but 
has not taken any or all required dexamethasone doses on Day –1 and/or Day 1, 
rovalpituzumab tesirine administration may not proceed, and rovalpituzumab tesirine will 
be held until the required dexamethasone dosing has occurred.
5.2.3.3
Allowed Concomitant Therapy
Standard supportive care for drug-related toxicity is permitted, including growth factors 
and blood product transfusions per local institutional standards and per local topotecan 
label for subjects in the topotecan arm (Arm B).  For subjects receiving topotecan 
(Arm B), myelopoietic growth factors cannot be initiated until 24 hours after completion 
of treatment with topotecan within a given cycle.  Other standard supportive care for 
symptom control or drug-related toxicity is allowed, such as analgesics, anti-emetics, 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
36
electrolyte replacement, and hydration.  Bone modifying agents (e.g., bisphosphonates, 
denosumab) for bone metastases are also permitted per local institutional standards.  Other 
prescribed medications for non-neoplastic conditions are allowed, as well as vitamins and 
nutritional supplements. 
Concomitant prednisone (or equivalent) may be used at a dose of ≤ 10 mg/day.  The use 
of intermittent high-dose corticosteroid treatment to prevent or manage infusion reactions, 
serosal effusions (see Section 6.1.8.1), or other non-cancer-related symptoms including 
premedication for known hypersensitivity reactions to contrast agent for CT scans is 
allowed.
Routine prophylaxis with vaccines is permitted; however, vaccines used should not 
contain live micro-organisms.
If the subject is taking chronic suppressive anti-infectives (antiviral, antifungal, or 
antibacterial), appropriate investigation must be completed prior to randomization, and 
documentation must exclude active infection.  After exclusion of active infection, 
otherwise eligible subjects should complete or continue anti-infectives as prescribed.
If a subject requires palliative radiation during the study (e.g., symptomatic worsening of 
a bone lesion) diagnostic imaging has to be performed to assess for radiographic 
progression prior to radiation, and documentation of non-progressive status by 
radiography will be captured in the eCRF.  Any cancer-directed therapy a subject receives 
due to disease improvement will be subject to TA MD approval and must be discussed 
with the TA MD in advance.
In the event of isolated CNS progression during study treatment for subjects in Arm A, 
investigational product will be withheld while palliative treatment is administered 
(e.g., radiotherapy) in accordance with institutional practice.  During this time, the subject 
should be fully evaluated for other sites of progressive disease.  If progression is isolated 
to the CNS, investigational product may be restarted at least 1 week after the completion 
of local CNS disease-directed therapy if the disease status does not warrant an alternative 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
37
treatment strategy due to clinical symptoms or signs indicating threat to vital organs or 
critical anatomical sites or decline in performance status.  If investigator continues 
treating the subject with rovalpituzumab tesirine after the first event of progressive 
disease, scans will continue to be collected until second event of progressive disease.
5.2.3.4
Prohibited Therapy
Subjects may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy during the study, other than as allowed 
in Section 5.2.3.2 and Section 5.2.3.3.  Additionally, strong inhibitors of cytochrome P450 
3A4 (CYP3A4) should be avoided if a subject is randomized to Arm A (refer to Table 1).
Table 1.
Examples of Strong CYP3A4 Inhibitors
Enzyme/Transporter
Strong Inhibitor Examples10
CYP3A4
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir and ritonavir, diltiazem, elvitegravir 
and ritonavir, idelalisib, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
nefazodone, nelfinavir paritaprevir and ritonavir 
and (ombitasvir and/or dasabuvir), posaconazole, 
ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, troleandomycin, 
voriconazole
(CYP) Cytochrome P450. 
Note:
This is not an exhaustive list; so if in question, please refer to the appropriate product label.
5.2.4
Contraception Recommendations
If female, subject must be either postmenopausal 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 a FSH level > 40 IU/L.
OR


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
38
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR For Women of Childbearing Potential (WOCBP)
Practicing at least one of the following methods of birth control, at randomization (or 
earlier) through at least 6 months after the last dose of investigational product if 
randomized to Arm A, and at least 1 month after the last dose, if randomized to Arm B.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to randomization.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
randomization.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If male, subject must be surgically sterile (vasectomy with medical assessment confirming 
surgical success) or if the male subject has a female partner who is postmenopausal or 
permanently sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no 
contraception is required.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
39
If the male subject is sexually active with female partner(s) of childbearing potential, he 
must agree to use condoms from randomization through 6 months after the last dose of 
investigational product if randomized to Arm A, and through 3 months after the last dose 
of topotecan, if randomized to Arm B, and to practice contraception with:
●
Female partner(s) must use at least one of the contraceptive measures (as 
defined in the protocol for female study subjects of childbearing potential).
●
True abstinence:  Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
Additionally, male subject agrees not to donate sperm from randomization through 
6 months after the last dose of investigational product if randomized to Arm A, and 
through 3 months after the last dose of topotecan, if randomized to Arm B.
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic 
and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C and Appendix D, Study Activities.
5.3.1.1
Study Procedures
Unless otherwise stated, the baseline measurement for any given variable will be defined 
as the last value obtained for the variable prior to the first dose of investigational product.
The collection of tumor material for DLL3 testing may be done at any time after the 
informed consent is signed and prior to randomization.  Screening procedures and 
radiographic assessments (CT scan or MRI) must be performed within 28 days prior to 
randomization.  Randomization of the subject in the Interactive Response Technology 
(IRT) may occur within 3 calendar days prior to C1D1.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
40
Subsequent study procedures should be performed within 3 business days prior to the 
scheduled treatment visit.  For visits where no treatment is administered, procedures may 
be performed within ± 3 day window relative to due date.  Radiographic assessments must 
be scheduled so that the results are known prior to the treatment visit.  Post-treatment 
follow up, and survival follow up phase visits may occur within ± 1 week window relative 
to due date unless otherwise indicated.
The results of all screening and evaluations at the time of randomization must be within 
clinically acceptable limits, upon review by the investigator, before a subject can be 
randomized.  Subjects will not be randomized in the study if laboratory or other screening 
results are unacceptable.  Subjects are allowed to rescreen and have laboratory samples 
redrawn to meet eligibility within the same 28 day screening window.  Subjects who meet 
the inclusion criteria and do not meet any of the exclusion criteria may be randomized. 
Therapeutic Area Medical Director (TAMD) review and approval is required in cases 
where a second rescreen is required.
Subjects receiving additional doses of rovalpituzumab tesirine as described in 
Section 5.3.1.1 and Section 5.5.2 will follow the same study schedule from Day 1 through 
EOT and PTFU as in Cycles 1 and 2.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative before any study-specific procedures are undertaken or before 
any prohibited medications are withheld from the subject in order to participate in this 
study.  Certain standard of care procedures (i.e., ECG) may be utilized as appropriate to 
prevent repeat protocol-required Screening procedures, but should be discussed with the 
sponsor.  Informed consent may be obtained before the 28-day screening window.  
Informed consent is also required for tumor biopsy for subjects without archived tumor 
material at screening.  For the optional tumor biopsy at time of disease progression, 
informed consent must be obtained at the time of initial consent.  Details about how 
informed consent will be obtained and documented are provided in Section 9.3.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
41
Subjects will be considered screen failures if the informed consent has been signed and a 
study-specific procedure has been performed (e.g., central laboratories drawn), but subject 
does not randomize into the study.  The reason for screen failure will be documented in 
the source documentation and will be captured in the eCRF.
Tumor Material at Screening
For all subjects, archived or fresh tumor material must be submitted to the AbbVie 
designated central IHC laboratory for determination of DLL3 expression prior to 
randomization, as per Appendix C and Appendix D, Study Activities Tables.
Tumor material testing for DLL3 status may occur at any time after initial diagnosis for 
subjects who provide consent.  These subjects must be registered in IRT.  Eligibility at the 
time of tumor progression will depend on DLL3 status (as determined at any time after 
initial diagnosis), as well as the fulfillment of all other inclusion and exclusion criteria and 
the trial status (whether the study is still open for accrual).
If archived tissue provided for tumor material testing is not DLL3high, re-testing can occur 
once the subject is re-screened using a fresh tissue biopsy.
Medical and Oncologic History; Adverse Event and Prior/Concomitant Medication 
Assessment
The following will be collected during the Screening Visit:
●
Complete medical history, including demographics and documentation of any 
clinically significant medical condition and surgical history
●
History of tobacco and alcohol use: 
○
current smoker [subject who has > 100 smoking events in their lifetime 
and has smoked within the last 12 months] Date of initial cancer diagnosis
○
past smoker [subject who has > 100 smoking events in their lifetime and 
has not smoked in past 12 months]
○
never smoked [subject with ≤ 100 smoking events in lifetime]
●
Detailed oncology history including:


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
42
○
Histology
○
Date of initial cancer diagnosis
○
Date of disease progression
○
TNM Stage at diagnosis (if available)
○
VALG Stage at diagnosis (Extensive vs. Limited)
○
Category of best response to front line platinum-based therapy (PD, SD, 
PR, CR)
○
History of CNS metastases
○
History of malignant pleural effusions
○
Mutational status, if performed
○
Any surgical cancer-related procedures
○
Anti-cancer treatments administered (including first and last dose dates and 
type of modality)
●
Detailed prior medication usage including dates of usage and dosing 
information for all other medications and supplements taken
On Cycle 1 Day 1, any changes observed from the Screening assessments (prior to 
dosing) will be recorded in the subject's medical history.  At each visit, including the End 
of Treatment (EOT) Visit, the subject's medical history will be reviewed and any changes 
from baseline will be recorded on the adverse event eCRF.
All medication (prescription or over-the-counter, including vitamins and/or herbal 
supplements) will be recorded beginning with first study drug administration through the 
70 days following the last dose of investigational product.
Physical Examination
A physical examination, including body weight, will be performed per Appendix C and 
Appendix D, Study Activities Tables.  If the Screening physical examination is performed 
within 7 days of C1D1, it is not required to be repeated on C1D1 unless clinically 
indicated.  Clinically significant changes from baseline will be documented in the source 
documentation and eCRFs as adverse events.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
43
Height will be measured at the Screening visit only.  For height assessments, the subject 
should not wear shoes.
Investigators should assess subjects for pleural and pericardial effusion prior to dosing of 
investigational product on Day 1 of each cycle.
Physical exam will include cardiac, pulmonary (including cardiopulmonary exam for 
pleural or pericardial effusions), evaluation of extremities for peripheral edema, 
neurological (sensory, motor, cranial nerves), head and neck, lymphatic, hepatobiliary, 
gastrointestinal, genitourinary, and skin evaluation per local standard of care.
Vital Signs
Vital signs will be performed per Appendix C and Appendix D, Study Activities Tables.  
Vital sign determinations include weight, sitting blood pressure, heart rate and body 
temperature.  If possible, blood pressure and heart rate measurements should not 
immediately follow scheduled blood collections.
Weight will be collected in the clinic prior to dosing at each cycle and the recorded actual 
weight will be utilized for dosing calculations.  For weight assessments, the subject 
should not wear shoes.
Vital signs should be collected prior to the infusion.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed per Appendix C and Appendix D, Study 
Activities Tables.  ECGs consist of a single 12-lead study performed within a 5-minute 
window after at least 5 minutes of quiet rest in a supine position.  Additional ECG 
monitoring may occur as clinically indicated during the study.
A qualified physician will determine whether any findings outside of normal 
physiological variation are clinically significant (in consultation with a cardiologist if 
necessary).  The physician will document whether findings are clinically significant (CS) 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
44
or not clinically significant (NCS) on the tracing and sign and date the tracing.  The 
original annotated ECG tracing containing the physician's assessment will be retained in 
the subject's records at the study site.
Echocardiogram
Subjects will have echocardiograms performed per Appendix C and Appendix D, Study 
Activities Tables to assess any pericardial effusion during Screening, and prior to dosing 
at every cycle for subjects on Arm A, if present, as well as cardiac function (left 
ventricular ejection fraction, LVEF).  Additional echocardiograms may occur as clinically 
indicated during the study.
ECOG Performance Status
The ECOG performance status will be documented according to Appendix C and 
Appendix D, Study Activities Tables.  Refer to Appendix E, Performance Status Scales 
Conversion for details.
Documentation of Non-Childbearing Status and Pregnancy Testing
For each female subject, the investigator will document non-childbearing status 
(surgically sterile or post-menopausal for at least 1 year) or potential childbearing status.
Should a female study subject become pregnant or suspect she is pregnant while 
participating in this study, she should inform the treating investigator immediately 
(Section 6.1.6).
For female subjects of childbearing potential, pregnancy testing should be performed 
according to Appendix C and Appendix D, Study Activities Tables.  A serum pregnancy 
test will be performed at Screening and the results must be available prior to the 
administration of the first dose of investigational product on C1D1.  Subjects with 
borderline pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days later to 
document continued lack of a positive result.  Urine pregnancy tests will be performed at 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
45
Day 1 of each cycle, EOT Visit, and PTFU visits until 6 months after the last dose of 
investigational product.
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in Section 5.2.4) at Screening do not require pregnancy testing.  
Postmenopausal female subjects ≤ 55 years of age must have a FSH level > 40 IU/L and 
will have FSH performed at Screening and assessed by the investigator.
Clinical Laboratory Tests
Samples for chemistry, hematology, coagulation, and urinalysis will be collected per 
Appendix C and Appendix D, Study Activities Tables.  Specific laboratory assessments 
are outlined in Table 2, Clinical Laboratory Tests.
If the Screening assessment is performed within 7 days of C1D1, it is not required to be 
repeated on C1D1 unless clinically indicated.  All laboratory samples will be assessed 
using a certified central laboratory and these results will be used for all data analysis.  The 
central laboratory will provide instructions regarding the collection, processing, and 
shipping of samples.  A qualified (e.g., certification or accreditation) local laboratory may 
be used to perform laboratory analyses for treatment decisions as per standard of care.
Qualified medical staff at the site will review, initial and date all local and central 
laboratory results.  Any laboratory value outside the reference range that is considered 
clinically significant by the investigator will be followed as appropriate.  Clinically 
significant laboratory values will be recorded as adverse events if they meet the criteria as 
specified in Section 6.1.1.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
46
Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis – Dipstick Only
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands (if indicated)
Lymphocytes
Monocytes
Basophils (if indicated)
Eosinophils (if indicated)
Platelet count (estimate not 
acceptable)
Mean corpuscular volume
Mean corpuscular hemoglobin 
concentration
RBC distribution width
Blood Urea Nitrogen (BUN)
Serum Creatinine
Total bilirubin
Albumin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Total protein
Glucose
Chloride
Magnesium
Amylase
Lipase
Lactate dehydrogenase (LDH)
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Urobilinogen
Bilirubin
Leukocyte esterase
Coagulation
Serum Pregnancy Test
Activated Partial
Thromboplastin Time
(aPTT)
Prothrombin time (PT)
International Normalized Ratio
(INR)
Beta-Human Chorionic 
Gonadotropin (β-hCG) (if 
applicable)
Follicle-stimulating hormone 
(FSH) (if applicable)
Disease/Response Assessment (Radiographic Imaging)
Treatment response will be assessed by radiographic assessment at protocol-specified 
time points as outlined in the Appendix C and Appendix D, Study Activities Tables.  
Diagnostic quality, spiral CT scans are recommended; other CT methods or MRI may be 
used if performed consistently throughout the study for each individual subject.  Scans of 
the chest and abdomen must be obtained; scans of the neck and pelvis must also be 
obtained if there is documented or suspected involvement in these regions.  Screening 
radiographic assessment must include brain MRI/CT.  Only non-CNS disease will be 
considered measurable.  Disease response will be determined by the investigator at each 
assessment according to RECIST v1.1 (Appendix H, Response Evaluation Criteria for 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
47
Solid Tumors (RECIST) v 1.1).10  Radiographic assessments must be scheduled so that 
the results are known prior to the treatment visit.  
Effusion (pleural, pericardial, etc.) assessments will be performed at each radiographical 
assessment and any new findings communicated to the investigator prior to the next dose 
of investigational product.  Effusions should contribute to disease status assessment per 
RECIST v.1.1 only if confirmed malignant by cytology or otherwise clearly disease-
related; if disease progression is suspected solely based on the appearance of new or 
increase of existing effusions, confirmation of malignant nature of such effusions is 
strongly recommended prior to making the decision on treatment discontinuation due to 
known adverse event profile of rovalpituzumab tesirine.  If collected, effusion fluid must 
be tested centrally and/or locally for cytology if disease progression due to 
appearance/worsening of effusion is suspected.
For subjects whose tumors meet the criteria of partial or complete response (PR or CR), 
tumor measurements must be confirmed by repeat assessments performed no less than 
4 and no more than 6 weeks after the criteria for response are first met.
Isolated CNS-only progression will not require removal of the subject from therapy.  
Refer to Section 5.2.3.3, Allowed Concomitant Therapy for details associated with CNS 
only progression.
The EOT radiographic assessment may be omitted if the previous radiographic assessment 
was performed within the preceding 6 weeks.
Scheduled radiographic assessments will not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 
throughout the study every 6 weeks after randomization for the first 30 weeks and then 
every 9 weeks until radiographic disease progression.  Subjects who discontinue treatment 
for reasons other than radiographic disease progression will continue to be followed 
according to the above schedule, until disease progression occurs.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
48
For subjects in Arm A, if the investigator chooses to continue treating the subject post-
progression and the subject consents to additional doses of rovalpituzumab tesirine, scans 
will continue to be collected every 6 weeks for the first 30 weeks from additional Cycle 3 
Day 1 and then again every 9 weeks until the second event of progressive disease.  If 
clinically indicated, radiographic assessments may be performed at times other than those 
indicated in Appendix C and Appendix D.  
MRI/CT of the Brain
MRI of the brain will be assessed at protocol-specified time points as outlined in the 
Appendix C and Appendix D, Study Activities Tables.  Brain MRI may be substituted by 
CT with intravenous contrast at the discretion of the investigator if MRI testing is
clinically contra-indicated or not available.  MRI/CT of the brain is required after 
screening only when clinically indicated (e.g., CNS metastasis history and if CNS 
progression is suspected).
Randomization and Subject Number Assignment
An Interactive Response Technology system (IRT) will be utilized to register subjects.
Subjects who complete all Screening procedures and meet the eligibility criteria will 
proceed to randomization.  Refer to Section 5.5.5 for details associated with subject 
assignment to treatment arms.
Patient Reported Outcomes (PRO)
Health-related quality of life and symptom assessments will be performed per Appendix C
and Appendix D, Study Assessments using the EORTC QLQ-C15-PAL, the EORTC 
QLQ-LC13, and the European Quality of Life-5 Dimensions (EQ-5D-5L).
The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C15-PAL)11 is a shortened version of the EORTC QLQ-
C30, a widely used instrument for measuring QOL in cancer research.  It was developed 
to ease the difficulty of completing long surveys in subjects who may have a high 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
49
symptom burden and short life expectancy.  The QLQ-C15-PAL questionnaire contains 
four multi-item scales (physical & emotional functioning, fatigue and pain) along with 
six individual items (nausea & vomiting, dyspnea, insomnia, appetite loss, constipation, 
and global quality of life).
The EORTC QLQ-LC13 is a lung cancer specific module which will supplement the 
EORTC QLQ-C15-PAL, resulting in a 28-item disease and cancer site-specific quality of 
life and symptom questionnaire.  The QLQ-LC13 module items evaluate symptoms such 
as cough, haemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling 
hands or feet, hair loss, and pain.
The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) is a generic preference instrument that 
has been validated in numerous populations.  The EQ-5D-5L is composed of 5 questions 
and a visual analog scale (VAS) assessing overall health that can be converted into a 
single health status or "utility" score for use in an economic evaluation to adjust life-years 
gained by the subject's health-related quality of life.
Fluid Retention Questionnaire (Including Subject Daily Weight)
Throughout the treatment period as outlined in the Appendix C and Appendix D, Study 
Activities Tables, subjects will be asked about the development of any new or worsening 
peripheral edema or dyspnea (Appendix J, Fluid Retention Questionnaire).  The Arm A 
assessments on Cycle Days 8, 15, 29 and 36 may take place by phone, with the site 
contacting the subject and reviewing the questionnaire.  
Starting on Day 1 through the EOT visit, subjects in Arm A will maintain a diary of daily 
weight (captured on the Fluid Retention Questionnaire).  Subjects should be instructed to 
use a consistent device throughout the study.  The site should advise the subjects in cases 
where sudden weight gain is observed; the subject should contact the site and possibly be 
assessed in the clinic.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
50
Additional Two Cycles of Rovalpituzumab Tesirine (Arm A only) 
Up to two additional cycles of rovalpituzumab tesirine may be permitted, however the last 
dose on study must be administered no later than 04 December 2019 for subjects in 
Arm A who provide consent and who satisfy all of the following criteria:
●
achieved clinical benefit defined as stable disease or better with two initial 
cycles of rovalpituzumab tesirine 
●
have findings indicative of disease progressing (not limited to CNS) at least 
12 weeks after the second dose of rovalpituzumab tesirine 
●
received no other systemic anti-cancer therapy after two initial cycles of 
rovalpituzumab tesirine 
●
had no prior on-study serosal effusions (Appendix I) or edema of > Grade 2 or 
other non-hematological treatment-related AEs of ≥ Grade 3 or potential DILI 
and any treatment-related AEs have resolved to Grade 1 or baseline 
●
have no clinically significant symptoms or signs related to disease progression 
and/or indicating threat to vital organs and no disease progression at critical 
anatomical sites necessitating urgent alternative treatment
●
have no decline in performance status as compared to the last radiographic 
assessment at which no progressive disease was identified 
Any new or progressing CNS disease of such subject must be definitively treated 
(radiotherapy or surgery) in order for the subject to be eligible for the two additional 
cycles of treatment.  Subjects remaining in rovalpituzumab tesirine treatment post-
progression not limited to CNS will be followed radiographically until the second event of 
progressive disease.  CT/MRI scan must be performed within one week prior to the 
4th dose of rovalpituzumab tesirine.  
Subjects who do not provide consent for two additional doses of rovalpituzumab tesirine 
should proceed to the End of Treatment (EOT) visit before continuing on to the Survival 
Follow Up period.   


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
51
The last radiographic assessment prior to additional doses of rovalpituzumab tesirine will 
be used as a new baseline for purposes of subsequent disease assessment.
End of Treatment (EOT) Visit
The visit during which an investigator identifies radiographic disease progression or the
subject is not eligible for two additional doses of rovalpituzumab tesirine (Arm A only), 
or a subject meets other criteria for study treatment discontinuation will be considered the 
EOT Visit.  The EOT visit is the last visit during the treatment phase before a subject 
enters the Post Treatment Follow Up and/or Survival Follow Up period.  The EOT visit 
should occur within 7 days of documentation of the decision to discontinue treatment and 
prior to subjects beginning any new anti-cancer therapy, if possible.  The reason(s) for the 
discontinuation from study treatment will be recorded and assessments will be performed 
per Appendix C and Appendix D, Study Activities Tables.
Disease/Response assessment, including MRI/CT if clinically indicated, may be omitted if 
performed within the last 6 weeks.
Post-Treatment Follow Up (PTFU)
For all subjects without disease progression (including those who discontinue study 
treatment for reasons other than disease progression), the first follow-up visit will occur at 
6 weeks (± 1 week) after the last Disease/Response Assessment, then every 6 weeks 
(± 1 week) until disease progression or initiation of new anti-cancer therapy, whichever 
occurs first.  Refer to Appendix C and Appendix D, Study Activities Tables for details of 
required assessments.
At progression, an optional fresh tumor material sample may be collected from subjects 
who have provided consent (Section 5.3.1.2, Collection and Handling of Biomarker and 
Optional Exploratory Research has details regarding tumor material at Time of Disease 
Progression).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
52
Survival Follow Up (OS)
After disease progression or if a subject stops treatment and declines further study 
radiographic assessments prior to the endpoint of disease progression, the subject enters 
the Survival Follow Up period.  During this period, the subject will be followed every 
6 weeks (± 1 week) for subsequent anti-cancer therapies (dates and responses), and 
survival status until the endpoint of death, the subject becomes lost to follow-up, 
termination of the study by AbbVie, or until 12 February 2020 whichever occurs first.  If 
the subject withdraws from study follow-up, the study staff may use a public information 
source (such as county records) to obtain information about survival status only, as 
appropriate per local regulations.  Refer to Appendix C and Appendix D, Study Activities 
Tables for details of required assessments.
5.3.1.2
Collection and Handling of Biomarker and/or Optional 
Exploratory Research Samples
Biomarker Samples
Blood, tumor material, and serosal fluid will be collected as noted in Appendix C and 
Appendix D, Study Activities Tables and may be utilized to evaluate known and/or novel 
markers (nucleic acids, peptides/proteins and/or metabolites) of disease status, related 
conditions or to evaluate the association with pharmacokinetics, safety or efficacy.  The 
biomarker rationale is discussed in the Biomarker Research Variables Section 
(Section 5.3.6).
All biomarker samples should be labeled and shipped as outlined in the study-specific 
laboratory manual.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be 
retained while research on rovalpituzumab tesirine (or drugs of this class) or this disease 
and related conditions continues, but for no longer than 20 years after study completion, 
or per local requirement.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
53
Tumor Material at Screening
Archived or fresh tumor material remaining after DLL3 IHC testing may be utilized for 
various biomarkers such as DLL3 expression by additional methodologies, routine 
hematoxylin and eosin for morphology, IHC for confirmation of diagnosis (e.g., for 
synaptophysin, chromogranin-A, or CD56), or scoring of immune infiltrates (e.g., IHC for 
CD3+, CD4+, CD8+, and Foxp3+ cells).  Tumor material may also be utilized for 
exploratory research that includes assessments of nucleic acid or protein based biomarkers 
of drug sensitivity, resistance, or disease biology and development of a companion 
diagnostic assay.
Blood (Plasma) for Inflammatory Markers and Circulating Tumor DNA (ctDNA)
At the indicated times noted in Appendix C, Study Activities, blood will be collected, 
processed to plasma for testing of inflammatory markers including erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), 
rheumatoid factor (RF) and ctDNA.  Samples will be collected on Cycle 1 Day 1 (pre-
infusion).
Blood (Serum) for Tumor and Soluble Markers
At the indicated times noted in Appendix C, Study Activities, blood will be collected, 
processed as serum for possible testing of tumor-specific biomarkers that may reflect 
disease burden such as but not necessarily limited to neuron-specific enolase (NSE) and 
biomarkers that may be related to the pharmacodynamics effects of rovalpituzumab 
tesirine such as but not necessarily limited to soluble DLL3, circulating chemokines, or 
cytokines such as vascular endothelial growth factor (VEGF), epidermal growth factor 
(EGF), interleukin (IL)-6, or IL-8.  Other biomarkers based on emerging science may also 
be assessed.  Samples will be collected on Cycle 1 Day 1 (pre-infusion).
Blood for Circulating Tumor Cells
At the indicated times noted in Appendix C and Appendix D, Study Activities, blood 
samples will be collected for assessment and characterization of circulating tumor cells 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
54
(CTCs) as a possible reflection of disease burden and DLL3 expression.  Whole blood 
sample will be collected for CTC analysis during screening, and pre-dose on Cycle 1 
Day 1.
Serosal Fluid
Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part 
of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) must be procured for 
possible PK, pharmacodynamic, and/or biomarker testing.  See the laboratory manual for 
additional details.
Pharmacogenetic Samples
Whole blood samples for DNA and RNA isolation will be collected on Cycle 1 Day 1 
(pre-infusion) (–3 business days window is permitted) from each subject.  
Pharmacogenetic samples should be collected at both timepoints unless precluded by local 
or national regulations or policies.
Samples will be shipped frozen to AbbVie or a designated laboratory for long-term 
storage.  Instructions for the preparation and shipment of the pharmacogenetic samples 
will be provided in a laboratory manual.
Optional Exploratory Research Samples
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the main study even if they decide not to participate in this optional 
exploratory research.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on rovalpituzumab tesirine 
(or drugs of this class) or this disease and related conditions continues, but for no longer 
than 20 years after study completion.  The procedure for obtaining and documenting 
informed consent for exploratory research samples is discussed in Section 9.3.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
55
Tumor Material at the Time of Disease Progression
An optional tumor material collection by biopsy procedure may be obtained at the time of 
disease progression, from subjects who consent to undergo biopsy procedure.  DLL3 
expression and other nucleic acid or protein based biomarkers related to the response to 
rovalpituzumab tesirine and SCLC biology may be assessed.
Biomarker samples will be shipped to AbbVie (or a designated laboratory) for long-term 
storage.  Instructions for the preparation and shipment of the biomarker exploratory 
research samples will be provided in a laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood Samples for Arm A (Rovalpituzumab Tesirine)
Approximately 6 mL of blood will be collected by venipuncture for pharmacokinetic 
(PK), Anti-therapeutic antibody (ATA) and neutralizing antibodies (nAb) testing as 
indicated in Appendix C, Study Activities.  
Blood samples should not be drawn from the same arm in which rovalpituzumab tesirine 
is administered.  Samples collected post-infusion should be collected after the full 
infusion procedure is complete.
The time of each sample collected will be recorded to the nearest minute.
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood/serum samples and subsequent preparation 
and storage of the samples for the assays will be provided by the central laboratory, 
AbbVie, or its designee.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
56
5.3.2.3
Disposition of Samples
The frozen serum samples for the rovalpituzumab tesirine ADC, rovalpituzumab tesirine 
ADC ATA and neutralizing antibodies (nAb) assays will be packed in dry ice sufficient to 
last during transportation and shipped from the study site to the central laboratory.
An inventory of the included samples will accompany the package and an electronic copy 
of the manifests (including subject number, study day, the time of sample collection and 
barcode) will be sent to the contact person at sample.receiving@abbvie.com and/or 
gprd_lupet@abbvie.com.
5.3.2.4
Measurement Methods
Serum concentrations of rovalpituzumab tesirine ADC and relative titers of 
rovalpituzumab tesirine ADC ATA will be determined using validated methods.  Any 
additional related analytes may be analyzed using non-validated methods.  Serum samples 
collected for the PK, ATA and nAb analysis may be used for future assay development or 
validation activities.  Rovalpituzumab tesirine ADC nAb samples upon request may be 
used for the analysis of neutralizing anti-drug antibodies in a validated assay.
5.3.3
Efficacy Variables
The primary objective in the study will be assessed based on the endpoint of OS in 
subjects with DLL3high SCLC receiving rovalpituzumab tesirine (Arm A) compared to 
those receiving topotecan (Arm B).  To assess the treatment effect of rovalpituzumab 
tesirine on OS, median OS and OS rates at pre-specified timepoints will be estimated 
using Kaplan-Meier survival methodology.  Estimates of the treatment effect will be 
presented as hazard ratio through a Cox proportional-hazards analysis.
The secondary objectives of the study are listed in Section 4.0.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
57
5.3.4
Safety Variables
AbbVie will assess adverse events, laboratory data, ECGs and vital signs throughout the 
study.  Adverse events intensity and laboratory evaluation changes will be assessed by 
utilizing NCI CTCAE Version 4.0.9
During the conduct of the study, the AbbVie medical and safety team will be monitoring 
subject laboratory results and adverse event data as they are reported.
Safety endpoints will be summarized using data from the Safety set.  Safety analyses will 
involve examination of the incidence, severity, and type of treatment-emergent adverse 
events (TEAEs) reported, changes in vital signs and laboratory test results from baseline 
(the assessment prior to first dose) to specified time points throughout the study.
5.3.5
Pharmacokinetic Variables
Individual concentrations of rovalpituzumab tesirine ADC and anti-drug antibody will be 
determined, tabulated and summarized for subjects treated with rovalpituzumab tesirine 
(Arm A) and summary statistics provided.
5.3.6
Biomarker and/or Optional Exploratory Research Variables
Biomarker Research Variables
Blood, serosal fluid, and tumor material samples will be collected to conduct analyses to 
investigate biomarkers.  The types of biomarkers to be analyzed may include nucleic 
acids, proteins, lipids or metabolites.
Tumor material and CTCs will be tested for DLL3 expression and analyses will be 
performed to correlate the expression levels to rovalpituzumab tesirine response.
Enumeration of CTCs, soluble DLL3 in plasma, or markers that are related to the disease 
or to drug response will be measured at baseline and post-treatment.  The information 
learned from analyzing these samples may be used to investigate factors influencing 
response to treatment, pharmacodynamics, PK, safety, scientific questions related to 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
58
SCLC, and/or in the development of new therapies and diagnostic tests.  The results of 
biomarker testing may not be included with the study summary.
Whole blood for pharmacogenetic analysis may include but not be limited to DLL3, 
ASCL1, or NEUROD1.
Exploratory Research Variables
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be analyzed as 
part of a multi-study assessment of factors influencing the subjects' response to the 
investigational product (or drugs of the same or similar class) or the development and 
progression of the subjects' disease or related conditions.  The samples may also be used 
to develop new diagnostic tests, therapies, research methods or technologies.  The results 
from these analyses are exploratory in nature and may not be included with the study 
report.
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from study treatment at any time.  In addition, the 
investigator may discontinue a subject from the study treatment at any time for any reason 
if the investigator considers it necessary, including the occurrence of an adverse event or 
noncompliance with the protocol.  Each subject will be withdrawn from the study or study 
treatment (as applicable) per Section 5.4.1 if any of the following occur:
●
The subject has radiographic progression according to RECIST version 1.1 
(with the exception of CNS only progression, Arm A) and the subject is not 
eligible or does not provide consent to receive an additional two doses of 
rovalpituzumab tesirine (Arm A).
●
The subject requires cancer-directed radiotherapy or surgery related to clinical 
disease progression (with the exception of CNS only progression, Arm A), or 
alternate anti-cancer agents during the study period.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
59
●
The subject experiences treatment toxicity which, in the investigator's opinion, 
prohibits further therapy or the investigator believes it is otherwise in the best 
interest of the subject.
●
Subject is suspected to be pregnant; pregnancy is confirmed or begins 
breastfeeding during the treatment portion of the study.
●
The subject decides to withdraw consent for any reason.
●
Any other medical reason that AbbVie or the study investigator deems 
appropriate.
●
Significant non-compliance to the protocol.
Discontinued subjects will not be replaced.
All subjects will receive a final dose of study drug no later than 04 December 2019.  
Follow up activities, including Overall Survival assessments, End of Treatment visits and 
AE/SAE collection should occur no later than 12 February 2020.
5.4.1
Discontinuation of Individual Subjects
Subjects who complete therapy or who discontinue study treatment prior to reaching an 
event of radiographic disease progression are to continue assessments until disease 
progression.  Refer to Section 5.3.1 for more details.
When a subject discontinuation from the study (without reaching a protocol-defined 
endpoint) is planned, the investigator is to notify the AbbVie Therapeutic Area Medical 
Director (TA MD) or the clinical team representative (Section 7.0) as soon as possible 
(provided, in each case, subject care and safety are not compromised).  If not notified 
prior to discontinuation, the AbbVie TA MD may contact the site to discuss the reason for 
withdrawal from the study.
The visit an investigator identifies radiographic disease progression or the subject is not 
eligible or does not consent for two additional doses of rovalpituzumab tesirine (Arm A 
only), or a subject meets other criteria for study treatment discontinuation will be 
considered the EOT Visit.  The reason(s) for the discontinuation from study treatment will 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
60
be recorded and assessments will be performed per Appendix C and Appendix D, Study 
Activities Tables.  It is preferable that EOT Visit procedures be conducted prior to the 
initiation of another anti-cancer therapy.  However, these procedures should not interfere 
with the initiation of any new treatments or therapeutic modalities that the investigator 
feels are necessary to treat the subject's condition.
If a subject is discontinued with an ongoing adverse event or an unresolved clinically 
significant laboratory result, the site will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory results or adverse event is achieved.
Subjects no longer undergoing clinical assessments will have survival information 
collected at every 6 weeks (± 1 week) until the endpoint of death, the subject becomes lost 
to follow-up or termination of the study by AbbVie, whichever occurs first or until 
12 February 2020.
In the event that a positive result is obtained on a pregnancy test for a subject during the 
study, the administration of investigational product to that subject must be discontinued 
immediately.  The site must report the positive pregnancy test result within 24 hours to 
AbbVie by entering the information into the Pregnancy eCRF in the EDC system.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator and provide written instructions for study termination.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
61
5.5
Treatments
5.5.1
Treatments Administered
5.5.2
Rovalpituzumab Tesirine (Arm A)
Rovalpituzumab tesirine, the investigational agent under study in this protocol, is an 
ADC.  Rovalpituzumab tesirine will be given by IV infusion over approximately 
30 minutes (window 20 – 45 minutes), adjusted to subject tolerability, at a dose of 
0.3 mg/kg on Day 1 of a 42-Day cycle for 2 cycles.  Dexamethasone will be co-
administered orally (PO) twice daily at a dose of 8 mg to all subjects randomized to 
Arm A on Day –1, Day 1, and Day 2 of each 42-day cycle in which rovalpituzumab 
tesirine is administered.  Dexamethasone dosing should occur such that there are 
approximately 12-hours (i.e., 10 – 14 hours) between AM and PM doses.  The first dose 
of the dexamethasone on the day of dosing should be at least 30 minutes but no more than 
4 hours prior to the rovalpituzumab tesirine infusion.  If the dose of dexamethasone is 
vomited within 15 minutes of taking the medication, the subject should retake the 
medication.
In the event that a subject arrives for rovalpituzumab tesirine administration on Day 1, but 
has not taken any or all required dexamethasone doses on Day –1 and/or Day 1, 
rovalpituzumab tesirine administration may not proceed, and rovalpituzumab tesirine will 
be held until the required dexamethasone dosing has occurred.
Dosing is based on actual body weight of the subject to the nearest kilogram, assessed in 
the clinic on Day 1 of each cycle, and administered according to the calculated dose.  In 
cases of weight gain due to fluid retention, dosing should be based on most recent pre-
fluid retention actual weight.
Subjects must meet all of the following on infusion day before receiving study drug:
●
Absolute neutrophil count ≥ 1,000/μL
●
Platelet count ≥ 75,000/μL


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
62
●
Resolution of study drug-related AEs, including findings indicative of pleural 
or pericardial effusions, and clinically-significant laboratory abnormalities to 
Grade 0 or 1 (excluding ANC and alopecia), or to baseline grade.
All subjects assigned to Arm A will be administered 2 cycles of rovalpituzumab tesirine 
no later than 04 December 2019 unless earlier discontinuation is warranted due to disease 
progression (see exception below), unacceptable toxicity or any other reason.  
Subjects developing CNS-only disease progression during the initial cycle of 
rovalpituzumab tesirine may be allowed to remain on treatment after receiving local 
definitive treatment for CNS disease. 
Up to two additional cycles of rovalpituzumab tesirine may be permitted, however the last 
dose on study must be administered no later than 04 December 2019 for subjects in 
Arm A who provide consent and who satisfy all of the appropriate criteria as described in 
Section 5.3.1.1.  
5.5.3
Topotecan (Arm B)
Topotecan is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with 
topoisomerase I-inhibitory activity.  Topotecan will be given as an IV infusion over 
30 minutes at a dose of 1.5 mg/m2 on Days 1 – 5 of 21-Day cycle.  Topotecan may be 
administered at a lower dose if required by the local label.
All subjects assigned to Arm B will continue to receive topotecan until disease 
progression or 04 December 2019 (whichever is later), unless earlier discontinuation is 
warranted due to unacceptable toxicity or any other reason.
5.5.4
Identity of Investigational Products
Rovalpituzumab tesirine is supplied as lyophilized drug packaged in a 10 mL, clear glass 
vial.  Each vial provides 30 mg rovalpituzumab tesirine.  When reconstituted with 3.2 mL 
of sterile water for injection, each vial provides 10 mg/mL rovalpituzumab tesirine (30 mg 
total).  Vials of rovalpituzumab tesirine will be supplied to each participating site.  A 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
63
complete description of the chemistry and formulation may be found in the Investigator's 
Brochure.12
Topotecan is the comparator chemotherapy, and will be administered at a starting dose of 
1.5 mg/m2 by IV infusion over 30 minutes, daily for 5 consecutive days, starting on Day 1 
of a 21 day cycle.  Topotecan may be administered at a lower dose if required by the local 
label.  Instructions for use are available in the local approved product labeling.  Topotecan 
will be supplied by AbbVie for all countries except for the United States of America.  
Table 3.
Identity of Investigational Products
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Rovalpituzumab 
tesirine
Powder for solution 
for infusion in vials
30 mg vial (10 mg/mL when 
reconstituted with 3.2 mL of 
sterile water for injection)
IV infusion after 
further dilution
AbbVie
Topotecan*
Powder or solution for 
infusion in vials**
1 mg, 2 mg and/or 4 mg 
vials***
IV infusion after 
further dilution
various****
*
Topotecan will be supplied as an investigational medicinal product by AbbVie except in USA.
**
Topotecan is commercially available as both a powder and solution for infusion.  Availability will vary by region.
*** Where provided by AbbVie, Topotecan, will be supplied as 4 mg vials unless unavailable.
****Topotecan will be sourced from various commercial manufacturers depending on availability and region.
Table 4.
Non-Investigational Medicinal Products
Drug Product
Dosage 
Form
Dose
Route of 
Administration
Supplier
Dexamethasone
Tablets
8 mg twice daily (BID) to all 
subjects randomized to Arm A 
Oral
AbbVie/Clinical 
Sites
AbbVie will provide non-investigational medicinal products unless specified otherwise by 
AbbVie.  AbbVie may provide non-investigational products depending on operational or 
regulatory requirements.  For countries where dexamethasone is obtained locally from 
commercial sources (Australia, Japan and USA), AbbVie may reimburse for 
dexamethasone to participating sites as required.  Instructions for use are available in the 
approved product labeling.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
64
All non-investigational medicinal products (not provided by AbbVie) should be obtained 
from a licensed pharmacy or wholesaler.  Each site will be responsible for maintaining 
drug accountability records, including product description, manufacturer, and lot numbers 
for all non-investigational products dispensed by the site.
5.5.4.1
Packaging and Labeling
Rovalpituzumab Tesirine
Vials of rovalpituzumab tesirine will be packaged in cartons.  Each vial and carton will be 
labeled per country requirements.  Labels must remain affixed to the vial and carton.  
Rova-T drug product is classified as a Dangerous Goods/Hazardous Material and is 
packaged and shipped by AbbVie according to US Department of Transportation (DOT) 
and International Air Transport Association (IATA) certified regulations.
Dexamethasone
Dexamethasone supplied by AbbVie will be provided in commercial primary packaging 
with a study label affixed to the primary container and/or secondary packaging.  Each 
bottle, carton and/or blister will be labeled per country requirements.
Labels must remain affixed to the bottle, carton and/or blister.
Topotecan
Topotecan supplied by AbbVie will be provided in commercial primary packaging with a 
study label affixed to the primary container and/or secondary packaging.  Each vial and 
carton will be labeled per country requirements.
Labels must remain affixed to the vial and carton.
5.5.4.2
Storage and Disposition of Study Drugs
For all storage areas and refrigerators, temperature logs will be maintained to document 
proper storage conditions.  The temperature must be recorded on temperature logs to 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
65
verify proper function on each business day.  Temperature excursions must be reported to 
AbbVie immediately.
Sites should use the AbbVie Temperature Excursion Management System (ATEMS) 
module via IRT, if available, or fax copies of the temperature log indicating the extent of 
the excursion (time, duration of the temperature excursion, min/max values and study 
drugs affected) to AbbVie Clinical Drug Supply Management (CDSM) including the 
Storage Temperature Excursion Reporting Form.
In case of a temperature excursion, study medication should be quarantined and not 
dispensed until AbbVie CDSM or ATEMS deems the medication as acceptable.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to the destruction facility.
Rovalpituzumab Tesirine
Lyophilized rovalpituzumab tesirine must be stored at refrigerated temperature (2° to 
8°C/36° to 46°F), protected from light, and must not be frozen.  Specific storage 
conditions for reconstituted and diluted IP will be provided in a separate document outside 
of this protocol.
Dexamethasone
Dexamethasone supplied by AbbVie should be stored at 15° to 25°C (59° to 77°F) and 
protected from light.  If dexamethasone is obtained locally from commercial sources, the 
approved product labeling should be referenced for appropriate storage conditions.
Topotecan
Topotecan supplied by AbbVie must be stored refrigerated at 2° to 8°C (36° to 46°F).  
Keep the vial in the outer carton to protect from light.  If topotecan is obtained locally 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
66
from commercial sources, the approved product labeling should be referenced for 
appropriate storage conditions.
5.5.4.3
Preparation/Reconstitution of Dosage Forms
Rovalpituzumab Tesirine
Rovalpituzumab tesirine is supplied as lyophilized drug in a 30 mg vial.  When 
reconstituted with 3.2 mL of sterile water for injection, each vial provides 30 mg of 
rovalpituzumab tesirine at a solution concentration of 10 mg/mL.  Rovalpituzumab 
tesirine is intended for intravenous infusion after further dilution in a suitable diluent such 
as 0.9% sodium chloride for injection.
Since rovalpituzumab tesirine dosing is based on body weight, multiple vials of 
reconstituted drug product may be required to achieve the desired dose.  Specific dose 
preparation and documentation details will be provided to the site pharmacy in a separate 
document.
Topotecan
The preparation of topotecan for dosing and administration should be done in accordance 
with the locally approved product label or Summary of Product Characteristics (SmPC).
5.5.5
Method of Assigning Subjects to Treatment Arms
All subjects in the study will be randomized using an Interactive Response Technology 
(IRT) system.  Before the study is initiated, directions for the IRT will be provided to each 
site.  The site will contact the IRT to obtain a Screening (subject) number once the subject 
has signed the informed consent and a study-specific procedure has been performed 
(i.e., central laboratory samples drawn).  Once the screening number is assigned, if the 
subject is not randomized into the study, the reason for screen failure will be documented 
in the source document and in the eCRF.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
67
The IRT will randomize subjects in a 2:1 ratio, with two-thirds of the subjects randomized 
to the rovalpituzumab tesirine treatment arm and the other one-third to the topotecan arm.  
The stratification data used for randomization should be the last values obtained for the 
stratification factor prior to randomizing the subject in IRT.
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Clinical Statistics Department at AbbVie prior to the start of the study.
5.5.6
Selection and Timing of Dose for Each Subject
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subjects in Arm A will receive 2 cycles of rovalpituzumab tesirine, 0.3 mg/kg via IV on 
Day 1 of the 42-Day cycle.  Two additional cycles of rovalpituzumab tesirine may be 
permitted for subjects in Arm A as described in Section 5.3.1.1.  Prior to dosing 
rovalpituzumab tesirine, subjects will receive 8 mg twice daily oral dexamethasone (PO) 
as premedication on Day –1, Day 1 (the day of dosing) and Day 2.
Subjects in Arm B will receive topotecan at 1.5 mg/m2 via IV on Days 1 - 5 of each 
21-Day cycle.  Topotecan may be administered at a lower dose if required per the local 
label.
5.5.6.1
Dose Modifications
5.5.6.1.1
Dose Treatment Delays Due to Toxicity or Progression 
(Arm A, Rovalpituzumab Tesirine)
Subjects who experience toxicity during a cycle must have recovered as specified above 
before the next cycle may proceed.  Any dose modifications except those indicated as 
mandatory below (including dose delay, reduction, resumption, and discontinuation) are 
to be performed at the discretion of the investigator.  Further guidelines suggesting dose 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
68
modifications based on prior studies of rovalpituzumab tesirine are provided in 
Section 5.5.6.1.2, Dose Reduction Guidelines.
In cases of treatment delays of > 28 days due to toxicity, the subject will be discontinued 
from treatment.  In cases where treatment benefit is observed, longer dose delays due to 
toxicity, if required, can be discussed with the TAMD.  
For subjects in Arm A, in the event of isolated CNS progression during Cycle 1 (see 
Section 5.3.2.3), Cycle 2 of the investigational product may be administered no sooner 
than 1 week after the completion of CNS disease-directed local therapy.
5.5.6.1.2
Dose Reduction Guidelines (Arm A, Rovalpituzumab 
Tesirine)
Investigational product dose reductions and discontinuation of investigational product for 
specific toxicities should occur as outlined in Table 5, Dose Reductions for 
rovalpituzumab tesirine Investigational Product (IP) and Table 6, Dose Reductions and 
Discontinuation for Unacceptable Toxicities.  Dose reductions for unacceptable toxicities 
described in Table 6 are mandatory.  Reduced dose levels are described in (Table 5).  
Generally, if an unacceptable toxicity recurs after two dose reductions, treatment will be 
discontinued (for further details, refer to Table 6).  If the investigational product dose is 
reduced, no re-escalation will be allowed.  If different unacceptable toxicities occur in 
sequential treatment cycles (e.g., Grade 3 LFT after the first dose and Grade 3 
thrombocytopenia lasting more than 7 days after the second dose), dose reduction will 
proceed to the next lower dose level.  If different unacceptable toxicities occur within 
one cycle, maximum specified dose reduction will be implemented.  Dose reductions and 
discontinuation are not allowed for dexamethasone.  If the full dose of dexamethasone 
cannot be administered due to an AE, the rovalpituzumab tesirine infusion should be 
delayed until the full dose of dexamethasone can be administered.
Exceptions to the dose modification guidelines should be discussed with the TA MD prior 
to implementation. 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
69
Table 5.
Dose Reductions for Rovalpituzumab Tesirine Investigational 
Product (IP)
Starting Dose
First Dose Reduction (Reduce Dose)
Second Dose Reduction (Reduce Dose)
0.3 mg/kg
0.2 mg/kg
0.1 mg/kg


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
70
Table 6.
Dose Reductions and Discontinuation for Unacceptable Toxicities
Toxicitya
First Occurrence
Second Occurrence
Grade 3 thrombocytopenia lasting more than 
7 days
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 4 thrombocytopenia/Grade 3 
thrombocytopenia with bleeding/Need for 
platelet transfusion
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade 4 neutropenia lasting more than 
7 days
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 3 febrile neutropenia
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 4 febrile neutropenia
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade 3 Liver Function Tests (LFTs)b
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 4 LFTs or Grade 3 LFTs with 
concomitant Bilirubin Grade 2 or higherb
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade 3 or 4 hypoalbuminemia
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Any other Grade 3 or 4 laboratory 
abnormality considered clinically significant 
and treatment-related
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 3 serosal effusions or edema or 
Grade 2 capillary leak syndrome
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade 4 serosal effusions or edema or 
Grade ≥ 3 capillary leak syndrome
Discontinue Rova-T
N/A
Grade 2 serosal effusions or edema
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 3 photosensitivity reaction
Reduce dose to 0.2 mg/kg
See Section 6.1.8.2
Reduce dose to 0.1 mg/kg
See Section 6.1.8.2
Grade 4 photosensitivity reaction
Discontinue Rova-T
N/A
Potential DILI (Drug-induced liver injury)
See Section 6.1.8.3
See Section 6.1.8.3
Grade 2 pneumonitis
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade ≥ 3 pneumonitis
Discontinue Rova-T
N/A
Any other Grade 3 or Grade 4 non-
laboratory treatment-related toxicity with the 
exception of fatigue, asthenia, nausea, or 
other manageable constitutional symptom
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
a.
Refer to Appendix I, for Serosal effusions and edema AE group definition and CTCAE v 4.0 Grading of Relevant 
AEs for definitions of NCI-CTCAE severity grades.
b.
If potential DILI is suspected please follow guidelines of Section 6.1.8.3.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
71
5.5.6.1.3
Dose Reductions, Delays and Discontinuation Due to 
Toxicity or Progression (Arm B, Topotecan)
Dose reductions, delays and discontinuation for topotecan should occur as outlined in the 
local label.
In cases of treatment delays of > 28 days due to toxicity, the subject will be discontinued 
from treatment. In cases where treatment benefit is observed, longer dose delays due to 
toxicity, if required, can be discussed with the TAMD.  
5.5.7
Blinding
This is an open-label study.
5.5.8
Data for Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will be formed and constituted 
according to appropriate regulatory guidelines.  Detailed information regarding the 
composition of the committee and detailed procedures will be documented in a separate 
charter.  The IDMC will review the efficacy and safety data periodically and provide 
recommendations according to the charter.  The IDMC may recommend stopping the trial 
for efficacy or futility, or recommend adjusting the size of the study.
5.5.9
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
5.5.10
Drug Accountability
The site will record the dose of rovalpituzumab tesirine and topotecan given to each 
subject in the source documents and on the eCRF.  If the investigator will obtain 
topotecan commercially, site inventory and accountability will not be performed in IRT 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
72
and drug accountability forms will not be provided by AbbVie.  It will be the 
responsibility of the investigator/site to maintain local accountability of topotecan sourced 
commercially.  If the investigative site has received topotecan centrally sourced by 
AbbVie, site inventory and accountability of these drugs will be performed in the IRT 
system and drug accountability forms will be provided.
Upon receipt of a shipment of rovalpituzumab tesirine and, if applicable, topotecan, the 
representative at each site will; 1) open and inspect the shipment; 2) verify that the study 
drug has been received intact, in the correct amounts and at the correct address; 3) sign 
and date the Proof of Receipt (POR) or similar documentation accompanying the 
shipment; 4) register the shipment as received via the IRT; 5) if applicable, transfer the 
Temptale files (shipment temperature record) to AbbVie CDSM.  Note:  some regions 
may receive drug in shipment containers without the use of Temptales.  In these instances, 
a special validated shipping container will be used.  All study drugs must be retained in 
the designated secure area under proper storage conditions.  This will be documented by 
signing and dating the POR or similar document or via direct recording in the IRT.
An overall accountability of the study drug supplied by AbbVie will be performed and 
verified by the site monitor throughout the study and at the study site closeout visit.  An 
accurate running inventory of rovalpituzumab tesirine and if applicable topotecan and/or 
dexamethasone will be maintained utilizing the IRT drug accountability module and, if 
required, according to the policy of the investigative site and will include the lot number, 
POR number(s), the bottle/kit numbers, and the date study drug was dispensed for each 
subject.
Upon completion or termination of the study, all original vials containing rovalpituzumab 
tesirine and, if applicable, topotecan and/or dexamethasone (empty containers will be 
defaced and discarded on site) will be returned to AbbVie according to AbbVie's 
instructions, or if pre-arranged between the sponsor and site, destruction of used and 
unused study drug will be performed at the site.  Rova-T is classified as a Dangerous 
Good/Hazardous Material according to US Department of Transportation (DOT) and 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
73
International Air Transport Association (IATA).  Dangerous Goods/Hazardous Materials 
must be packaged and shipped according to applicable regulations.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is an open-label study where subjects will be randomized in a 2:1 ratio to 
rovalpituzumab tesirine or topotecan in the second line treatment of advanced or 
metastatic SCLC.  Rovalpituzumab tesirine has previously demonstrated promising 
preliminarily efficacy and tolerability in Phase 1 and 2 trials in second and later lines 
SCLC.  Topotecan has been chosen as the comparator chemotherapy since it is currently 
the only approved treatment for second line SCLC.
5.6.2
Appropriateness of Measurements
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications.  Adverse events and, when 
applicable, clinical laboratory data will be graded using NCI CTCAE, version 4.0.9
Response will be assessed according to RECIST v1.110 which includes standard criteria 
for evaluating response in solid tumors.  The intervals of evaluation in this protocol are 
appropriate for disease management.
Standard tests will be performed to detect the possible presence of specific antibodies to 
investigational product.  Pharmacokinetic assessments for drug activity are also common 
in clinical studies.
5.6.3
Suitability of Subject Population
Subjects with advanced or metastatic DLL3high SCLC experiencing first disease 
progression during or following front-line platinum-based chemotherapy and meeting 
inclusion and exclusion selection criteria as outlined in the Section 5.2.1 and Section 5.2.2
are appropriate for this study.  Such subjects are appropriate to define efficacy and safety 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
74
of rovalpituzumab tesirine since it is an intended indication for this investigational agent.  
This population is also suitable for topotecan treatment since it is the second line standard 
of care in this tumor type.
5.6.4
Selection of Doses in the Study
In a recent Phase 1 study (Study SCRX16-001) with rovalpituzumab tesirine, the 
maximum tolerated dose (MTD) was established at 0.4 mg/kg every 3 weeks based on the 
incidence of Cycle 1 toxicities, while the recommended Phase 2 dose (RPTD) in SCLC 
was chosen as 0.3 mg/kg every 6 weeks for a total of two doses with the allowance to 
retreat at the same dose level and schedule upon progression.  The RPTD is based on the 
toxicity and efficacy profile during multiple cycles of dosing (AbbVie Stemcentrx data on 
file).
The chosen dose regimen, two doses of 0.3 mg/kg rovalpituzumab tesirine administered 
6 weeks apart, is based on the safety and efficacy observed in Study SCRX16-001, where 
delayed and/or cumulative toxicities were observed with both q3wk and q6wk schedules 
and appeared to be related to total dose administered.  The dosing regimens of 0.2 mg/kg 
q3wk for a total of 3 doses (q3wk × 3) and 0.3 mg/kg q6wk for a total of 2 doses 
(q6wk × 2) were evaluated in expansion cohorts.
Both regimens were tolerated, but the 0.3 mg/kg q 6wk regimen demonstrated a trend 
towards lower rates of treatment-emergent adverse events (TEAE), related TEAEs, 
Grade 3/4 TEAEs and related Grade 3/4 TEAEs.  In addition, although the 0.3 mg/kg 
regimen appeared to have a higher incidence of Grade 3/4 thrombocytopenia, this AE was 
generally clinically manageable.  On the other hand, objective responses appear to be 
more durable in subjects treated with the 0.3 mg/kg q6wk regimen based on preliminary 
data.  Therefore, 0.3 mg/kg q6wk × 2 is the chosen dose regimen for this study.  The 
maximum dose of rovalpituzumab tesirine in this study will not exceed 0.3 mg/kg at each 
dose.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
75
The starting dose of topotecan is 1.5 mg/m2 administered intravenously daily for 
5 consecutive days starting on Day 1 of a 21-day cycle.  Topotecan may be administered 
at a lower dose if required by the local label.  Subjects may continue receiving topotecan 
until disease progression, unacceptable toxicity, or other reason for study 
discontinuations.
6.0
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this study is defined as rovalpituzumab tesirine or 
topotecan, depending on country specific requirements.  Complaints associated with any 
component of this investigational product must be reported to the Sponsor (Section 6.2.2).  
For AEs, please refer to Sections 6.1.1 through 6.1.6.  For product complaints, please refer 
to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide another cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
76
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, [meets protocol specific criteria (see Section 6.1.8 regarding toxicity 
management)] and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the pre-
existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
77
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
78
6.1.1.3
Adverse Events Expected Due to SCLC or Progression of 
SCLC
Adverse events that may be expected from primary SCLC lesions, compression of 
adjacent thoracic structures or distant metastases are presented in Appendix K, Adverse 
Events Expected Due to SCLC or Progression of SCLC of the protocol.
These adverse events may occur alone or in various combinations and are considered 
expected adverse events for regulatory reporting in SCLC subjects for this protocol.
The term "disease progression" should not be used when reporting AEs or SAEs, instead 
associated symptoms should be reported.  However, in cases of fatal events clearly related 
to the progression of disease under study the terms "malignant neoplasm progression" or 
"disease progression" are acceptable when the immediate cause of death is not known.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.0).9  If a reported adverse event increases in severity, the initial adverse event 
should be given an outcome date and a new adverse event reported on a different date 
from the end date of the previous adverse event to reflect the change in severity.  For all 
reported serious adverse events that increase in severity, the supplemental eCRFs also 
need to be updated to reflect the change in severity.
When CTCAE criteria cannot be used, the event should be graded as defined below:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3/4
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening (severe). 
Grade 5
The adverse event resulted in death of the subject (severe).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
79
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Deaths
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
Deaths that occur during the protocol specified AE reporting period (Section 6.1.6) that 
are more likely related to disease progression will therefore be considered as an expected 
SAE and will not be subject to expedited reporting.  These events should be recorded on 
the AE eCRF as described in Section 6.1.1.3.  After the AE reporting period, deaths 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
80
attributed to progression of disease under study should be not be recorded on the AE 
eCRF.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the AE eCRF.  Generally, only one such event should be reported.  The term 
"sudden death" should only be used for the occurrence of an abrupt and unexpected death 
due to presumed cardiac causes in a patient with or without pre-existing heart disease, 
within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed death, 
within 24 hours after the patient was last seen alive and stable.  If the cause of death is 
unknown and cannot be ascertained at the time of reporting, "unexplained death" should 
be recorded on the AE eCRF.  If the cause of death later becomes available (e.g., after 
autopsy), "unexplained death" should be replaced by the established cause of death.
6.1.5
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 70 days, 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, protocol-related 
serious adverse events and protocol-related non-serious adverse events will be collected 
from the time the subject signed the study-specific informed consent, only if considered 
by the investigator to be casually related to study-required procedures.
Adverse event information will be collected as shown in Figure 2.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
81
Figure 2.
Adverse Event Collection
*
Only if considered by the investigator to be causally related to study-required procedures.
6.1.6
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  
FAX to:  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
82
For safety concerns, contact the Oncology Safety Management Team at:
Oncology Safety Team
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
Therapeutic Area Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Telephone Contact Information:
Office:
Mobile:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
83
global and local guidelines and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
6.1.7
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours of the 
investigative site becoming aware of the pregnancy.  Subjects who become pregnant 
during the study must be discontinued (Section 5.4.1).
All subjects should be informed that contraceptive measures (refer to Section 5.2.4, 
Contraception Recommendations and Pregnancy Testing for the details on contraception) 
should be taken throughout the study and for at least 6 months after the last dose of study 
drug.  Male subjects should be informed that contraceptive measures should be taken by 
their female partner.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of a pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information, 
and the pregnancy will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
84
6.1.8
Toxicity Management
Subjects will be monitored continuously for toxicity while on study treatment.  Toxicity 
will be assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Version 4.0.9  If a subject has an AE possibly related to 
investigational product administration, then dose interruptions/holds with possible 
modifications as described below may be implemented.  Adjustments to these guidelines 
may occur based on the clinical judgment of the investigator with notification to the TA 
MD.
6.1.8.1
Management of Serosal Effusions/Serositis
Serosal effusions (pleural or pericardial, or ascites) have been observed with 
rovalpituzumab tesirine and have the potential to be life-threatening (e.g., cardiac 
tamponade).  Therefore, development of any of these events or worsening from baseline 
warrants prompt evaluation by the investigator or designee.  Alternative causes such as 
infection, congestive heart failure, or disease progression, should be ruled out.  When 
appropriate, a unifying diagnosis should be reported, e.g., "heart failure," not the signs and 
symptoms "pleural effusion" and "edema limbs."
When considered clinically significant (e.g., Grade 2 or higher and considered related to 
investigational product):
●
Systemic corticosteroids, when initiated promptly, have been reported to be 
beneficial in some prior cases.  The investigator should consider a tapering 
regimen, such as dexamethasone up to 8 mg orally twice a day for 5 days, 
followed by 4 mg orally twice a day for 5 days, then 2 mg orally twice a day 
for 5 days.  Alternatively, nonsteroidal therapies for serositis may be 
considered, such as non-steroidal anti-inflammatory drugs (NSAIDs, 
e.g., ibuprofen 400 – 600 mg orally three to four times daily) or colchicine 
(e.g., 0.6 mg orally two to three times daily) given for 1 – 2 weeks.
●
Until clinical experience suggests otherwise, guidance for dose delay and/or 
reduction, as well as criteria for ongoing dosing, should follow Section 5.5.6.1


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
85
6.1.8.2
Management of Skin Reactions
All cutaneous reactions which develop during treatment warrant prompt evaluation.  Skin 
toxicity with rovalpituzumab tesirine may consist of photosensitivity but possibly other 
reactions such as palmar-plantar erythrodysesthesia or erythema multiforme.  As such, 
development of a cutaneous reaction during treatment warrants prompt evaluation by the 
investigator or designee.
Photosensitivity reactions may occur hours to days after sun exposure.  Patients should be 
advised to avoid direct and indirect sun exposure as much as possible from Cycle 1 Day 1 
until 30 days after the final dose.  When sun exposure is unavoidable, patients should 
wear protective clothing and sunglasses, and use a broad-spectrum sunscreen and lip balm 
(SPF 30 or greater). 31 – 90 days after last dose, the patient may resume outdoor 
activities with appropriate sun protection including broad brimmed hat, protective 
clothing and sunscreen SPF 30 or higher
If clinically consistent with photosensitivity, the AE should be reported as such (using 
medically accurate and descriptive AE terminology), and managed as described in 
Table 7.  Photodocumentation of skin toxicity should be available upon request by the TA 
MD.  The investigative site will take measures to protect the identity of the patient.  These 
measures include taking the photograph very close to the affected skin region to exclude 
facial features, or if facial features cannot be excluded due to the location of the skin 
reaction, covering identifying features (such as the eyes) with a black rectangle.
Formal evaluation by a dermatologist, including possible skin biopsy, to rule out 
alternative etiologies such as erythema multiforme (which may warrant discontinuation of 
investigational product) and to facilitate the most appropriate terminology for AE 
reporting, is recommended.
All events of cutaneous toxicity should be monitored until resolution or return to baseline.  
Recommendations for management of photosensitivity reactions are outlined in Table 7.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
86
Table 7.
Recommended Management of Photosensitivity
CTCAE v4.0
Treatment Recommendations
Rova-T Dose 
Modifications
Grade 1
Painless erythema and 
erythema covering < 10% BSA
Low-potency topical steroid (face) 
High-potency topical steroid (body)
–
Grade 2
Tender erythema covering 10 –
30% BSA
Low-potency topical steroid (face) 
High-potency topical steroid (body) 
Nonsteroidal anti-inflammatory 
agents orally as needed
–
Grade 3
Erythema covering > 30% BSA 
and erythema with blistering; 
photosensitivity; oral 
corticosteroid therapy 
indicated; pain control 
indicated (e.g., narcotics or 
NSAIDs)
Low-potency topical steroid (face) 
High-potency topical steroid (body) 
Prednisone 0.5 mg/kg × 7 days
Reduce dose
Grade 4
Life-threatening consequences; 
urgent intervention indicated
Low-potency topical steroid (face) 
High-potency topical steroid (body) 
Prednisone 0.5 mg/kg × 7 days 
Hospitalization
Discontinue
In order to simplify the collection of detailed Safety Data associated with dermatological 
issues, prior to the verification of a specific diagnosis the general term of "Skin Toxicity" 
should be recorded on the Adverse Event eCRF and the corresponding details should be 
captured on the Skin Toxicity Supplemental eCRF (as outlined in the form).  Once a final 
dermatological diagnosis is verified, the AE eCRF should be updated to reflect the 
specific diagnosis.
6.1.8.3
Management of Potential Drug-Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential drug-induced liver injury (DILI) event.  
All occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
87
A potential DILI is defined as:
●
ALT or AST elevation > 3 times (3×) upper limit of normal (ULN) and
●
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) and
●
No other immediately apparent possible causes of aminotransferase (AT) 
elevation and hyperbilirubinemia including but not limited to viral hepatitis, 
pre-existing chronic or acute liver disease or tumor(s), or the administration of 
other drug(s) known to be hepatotoxic
In general, an increase of AT to > 3 × ULN should be followed by repeat testing within 48 
– 72 hours of all four of the usual measures (ALT, AST, alkaline phosphatase, and total 
bilirubin) to confirm the abnormalities and to determine if they are increasing or 
decreasing.  An inquiry regarding symptoms should also be made (e.g., fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash).  Subjects may be retested 
locally, but normal laboratory ranges should be recorded and results made available to the 
investigator immediately.  All data must be recorded in the CRF.  If symptoms persist or 
repeat testing shows AT > 3 × ULN for subjects with normal baseline measures or 2-fold 
increases above baseline values for subjects with elevated values before drug exposure, 
close observation should be initiated.  If close monitoring is not possible, investigational 
product should be discontinued.
Close observation includes:
●
Repeating liver enzyme and serum bilirubin tests two or three times weekly.  
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or the trial drug has been discontinued and the subject is 
asymptomatic.
●
Obtaining a more detailed history of symptoms and prior or concurrent 
diseases
●
Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
88
●
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; non-alcoholic steatohepatitis (NASH); hypoxic/ischemic 
hepatopathy; and biliary tract disease
●
Obtaining a history of exposure to environmental chemical agents
●
Obtaining additional tests to evaluate liver function, as appropriate 
(e.g., international normalized ratio [INR], direct bilirubin)
●
Considering gastroenterology or hepatology consultations
The investigational product will be discontinued if potential DILI is suspected and:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks
●
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia
All subjects showing possible DILI should be followed until all abnormalities return to 
normal or to the baseline state.
6.1.8.4
Monitoring and Management of Edema
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.
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. 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
89
Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in 
some prior cases.
Reported Term
Grade 1
Grade 2
Grade 3
Grade 4
Generalized 
edema
(Anasarca)
Noted on exam; 1+ 
pitting edema
Interfering with 
instrumental ADLs; 
oral therapy initiated
Interferes with 
self care ADL; 
intravenous 
therapy indicated; 
skin breakdown
Life-
threatening 
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


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
90
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 providethe 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 or 
discontinuation of Rova-T for Grades 3 and 4 are required, please see Section 5.5.6.1 of 
the protocol.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
91
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.
6.2.2
Reporting
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 form.  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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
92
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:
Study Management Associate III
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
Alternate Contact:
Therapeutic Area Medical Director
AbbVie
 
1 North Waukegan Road
North Chicago, IL 60064
Office:
Fax:
Email:
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.
8.0
Statistical Methods and Determination of Sample 
Size
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  For patients currently on treatment in Arm A, the IDMC 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
93
recommends that sites and patients make individual decisions as to whether or not to 
continue treatment based on patient level response.  The data collection plan has been 
minimized given the status change of this study.  With all these changes, no statistical 
testing will be performed for the efficacy endpoints.  The efficacy endpoints will be 
analyzed using the original statistical methodologies as appropriate.  The efficacy 
endpoints for which there is not enough data to implement the statistical models will be 
summarized by treatment arms.  The statistical section remains unchanged to reflect the 
original analysis plan.   
8.1
Statistical and Analytical Plans
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 final analysis will be performed when at least 489 deaths have occurred, which is 
projected to be approximately 35 months after study initiation.
The following analysis populations are considered:
●
Randomized Set:  It includes all randomized subjects, with subjects grouped 
according 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 the efficacy endpoints.
●
Per Protocol Set:  It includes all subjects in the randomized set without any 
major protocol violations which may affect the evaluation of the primary 
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.  This 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
94
●
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.
8.1.1
Disposition of Study Subjects
The disposition of subjects will be summarized by treatment arm for 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.
8.1.2
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized in the randomized set.
8.1.3
Efficacy Endpoints
Efficacy endpoints will be analyzed in the randomized set, including all randomized 
subjects, with subjects grouped according to the treatment assigned at randomization, 
following intent-to-treat principle, unless otherwise specified.  Assessment of response 
and progression will be determined by the CRAC according to RECIST v1.1.
8.1.4
Primary Efficacy Endpoint and Analysis
Overall survival (OS) is the primary efficacy endpoint.  OS is defined as the time from the 
date of randomization to the date of death from any cause (i.e., date of subject's death –
date of randomization + 1).  For subjects who are alive at the time of analysis, the data 
will be censored at the last date they were documented to be alive.  Subjects with no post-
baseline information will be censored at the date of randomization plus 1 day.
Comparison between the two treatment arms at the final analysis will be performed via a 
one-sided log-rank test, stratified by the randomization stratification factors, testing the 
null hypothesis (rovalpituzumab tesirine arm (Arm A) is not superior to topotecan arm 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
95
(Arm B) in OS).  The hazard ratio (HR) of Arm A over Arm B will be estimated using a 
stratified Cox proportional hazards model.  The OS curves for each arm will be estimated 
using the Kaplan-Meier (KM) product-limit method.  Two-sided, 95% confidence interval 
for median OS will be computed.  Landmark survival rate, defined as the survival rate 
estimated using the Kaplan-Meier approach at pre-defined timepoints from randomization 
(e.g., 6, 12 and 18 months), will be summarized, presenting two-sided 95% CIs.
8.1.5
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
●
Progression-free survival (PFS) based on the CRAC per RECIST v1.1
●
Patient reported outcomes (PROs) – physical functioning domain at C2D1 for 
Rovalpituzumab tesirine arm and C3D1 for topotecan arm
●
Objective response rate (ORR:  CR + PR) based on the CRAC per RECIST 
v1.1
●
Clinical benefit rate (CBR:  CR + PR + SD) based on the CRAC per RECIST 
v1.1
●
Duration of objective response (DOR) based on the CRAC per RECIST v1.1
PFS is defined as the time from randomization to documented CRAC-assessed disease 
progression based on RECIST v1.1 or death from any cause (whichever occurs earlier).  
For the analysis of PFS, data for subjects without disease progression or death will be 
censored at the time of the last radiographic assessment (or, if no radiographic assessment 
was performed after the baseline visit, subject's data will be censored at the time of 
randomization plus 1 day).  Data from subjects who are lost to follow-up will be included 
in the analysis as censored observations on the last date of radiographic assessment that 
the subject was documented to be progression free.  The PFS rates at 6 and 12 months and 
corresponding 95% CIs will also be estimated using KM estimates on the PFS curve for 
each arm.  Methods for PFS analysis are similar to those described for the OS endpoint.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
96
A sensitivity analysis of PFS will be performed based on investigator-assessed disease 
progression or death from any cause.  Accounting for subjects who initiated a new anti-
cancer therapy prior to progressive disease or death, an additional sensitivity analysis of 
PFS will be performed, considering the date of last radiographic assessment by CRAC 
prior to or on the start date of new anti-cancer therapy/procedure, as a censoring date.
Analyses of ORR and CBR will be performed for the randomized subjects with at least 
one measureable disease at baseline.  For subjects whose tumors meet the criteria of 
partial or complete response (PR or CR), tumor measurements must be confirmed by 
repeat assessments performed no less than 4 and no more than 6 weeks after the criteria 
for response are first met.
Objective response rate includes confirmed complete response (CR) and confirmed partial 
response (PR) assessed by the CRAC based on RECIST v1.1 from the date of 
randomization until disease progression or death, whichever comes first.  A subject who 
did not meet CR or PR, including those who did not have post-baseline radiological 
assessments will be considered as non-responder.  
Comparison of ORR will be carried out using a one-sided Cochran-Mantel-Haenszel 
(CMH) test, stratified by the randomization stratification factors.  Odds ratio will be 
presented with two-sided 95% CI.  The difference in ORR will be provided with 
two-sided 95% CI.  Rates and corresponding 95% exact CI will be calculated by Clopper-
Pearson method for each arm.  Sensitivity analysis based on investigator-determined ORR 
will also be performed. 
Clinical benefit includes complete response (CR), partial response (PR), and stable 
disease (SD) assessed by the CRAC based on RECIST v1.1 from the date of 
randomization until disease progression or death, whichever comes first.  A subject who 
did not meet CR, PR, or SD, including those who did not have post-baseline radiological 
assessments, will be considered as non-responder.  The same statistical methodology will 
be used as that for ORR endpoint. 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
97
A sensitivity analysis of ORR and CBR will be performed, accounting for subjects who 
initiated a new anti-cancer therapy.  Modified endpoints of ORR and CBR, defined as 
rates of response from the date of randomization until initiation of new anti-cancer 
therapy/procedure, disease progression, or death, whichever comes first, will be analyzed 
using the same methodology as that for the endpoints of ORR and CBR.
Only subjects with an objective response will be included in the analysis of duration of 
response (DOR).  DOR is defined as the time between the date of first response (CR or 
PR by CRAC, whichever is recorded first) to the date of the first documented tumor 
progression (assessed by CRAC per RECIST 1.1) or death due to any cause, 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.  Methods for DOR analysis are similar to those described for the OS endpoint. 
8.1.6
Patient Reported Outcomes (PROs)
The EORTC QLQ-C15-PAL/LC13 scoring manual will be used to transform the raw 
scores into the domain scores (global heath, functional scales, symptom scales/items).  
Physical functioning domain of the QLQ-C15-PAL PRO questionnaire is a secondary 
endpoint in the hypothesis testing hierarchy (see Section 8.3).  The other scales will be 
analyzed on an exploratory basis.  Change from baseline of the items and domains of the 
QLQ-C15-PAL/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 score and VAS will be summarized by 
treatment arm.  
Treatment group differences will be evaluated by analyzing the change from baseline 
using a one-way analysis of variance (ANOVA) model.  Proportion of subjects with 
clinically meaningful worsening in physical functioning will be compared between the 
treatment arms.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
98
8.1.7
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 
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.
8.1.8
Planned Sensitivity and Subgroup Analyses
Analysis of OS will be performed in the per protocol set.  The same methodology as for 
analyses specified in Section 8.1.4 will be applied.
For randomized subjects, analysis for OS will be performed in the following subgroups:
●
Prior history of brain metastases (yes versus no)
○
PCI (yes vs no) in subjects with no prior history of brain metastases
●
Sensitivity to first line platinum-based regimen (sensitive [OR/SD after 
first line therapy and progression/recurrence-free interval ≥ 90 days] versus 
refractory/resistant [PD as best response to or < 90 days 
progression/recurrence-free interval after first line therapy])
●
LDH (> ULN vs. ≤ ULN) at Screening
●
Overall VALG stage (Limited Disease vs Extensive Disease) at initial 
diagnosis
●
Gender
●
Race


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
99
Difference in OS between rovalpituzumab tesirine and topotecan arms will be assessed by 
an unstratified log-rank test for each subgroup.  Hazard ratios will be calculated by a 
Cox's model.  
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.
8.2.1
Treatment-Emergent Adverse Events (TEAEs)
TEAEs reported during the study will be coded using a MedDRA12 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.
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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
100
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.
8.2.3
Vital Signs
Vital signs including pulse, blood pressure, temperature, height, 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.
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.
8.2.5
Electrocardiogram
ECG status will be summarized for each scheduled visit by treatment arm.  Shifts from 
baseline may be tabulated.
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.
8.3
Type I Error Adjustment Procedure for Multiple Testing
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 topotecan arm with respect to the primary and secondary endpoints in the 
order specified below.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
101
The following null hypotheses are considered:
H1:  Rovalpituzumab tesirine arm is not superior to topotecan arm in OS.
H2:  Rovalpituzumab tesirine arm is not superior to topotecan arm in PFS.
H3:  Rovalpituzumab tesirine arm is not superior to topotecan arm in PRO physical 
functioning scale at C2D1 for rovalpituzumab tesirine arm and C3D1 for topotecan arm.
H4:  Rovalpituzumab tesirine arm is not superior to topotecan arm in ORR.
H5:  Rovalpituzumab tesirine arm is not superior to topotecan arm in CBR.
H6:  Rovalpituzumab tesirine arm is not superior to topotecan arm in DOR.
The family of null hypotheses will be tested using a hierarchical procedure, ie, in a fixed 
sequence of {H1, H2, H3, H4, H5, H6}.  Hypothesis H1 will be tested first, and no further 
tests will be performed if H1 is not rejected.  Thereafter, each hypothesis will be tested in 
the order specified if and only if H1 and all preceding null hypotheses are rejected.  
Otherwise testing in the hierarchical sequence will stop.  All the testing at final analysis 
will be carried out at one-sided 0.025 level of significance. 
See flowchart below for illustration.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
102
8.4
Determination of Sample Size
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  444 subjects were enrolled in the study.  The following 
paragraph describes how the sample size was determined for the study.
The sample size of the study is primarily determined by the analysis of OS.  
Approximately 600 subjects in total will be randomized to rovalpituzumab tesirine 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
103
(Arm A) or topotecan (Arm B) in a 2:1 ratio.  It is assumed that median overall survival in 
the topotecan arm (Arm B) will be around 6.5 months.  Based on a log-rank test, at a 
one-sided significance level of 0.025 and a power of 85%, a total of 489 deaths are needed 
to detect an increase in median OS to 8.67 months in rovalpituzumab tesirine arm 
(Arm A), corresponding to a hazard ratio of 0.75 (i.e., a reduction in the hazard death of 
25%).  It is projected that an observed hazard ratio of 0.829 or less, corresponding to 
1.34 months or greater improvement in median OS, would result in statistically 
significance in the final analysis of OS.  
8.5
Interim Analysis
No interim efficacy analysis is planned.  
8.6
Accrual/Study Duration Considerations
The total study duration and accrual duration are approximately projected to be 35 months 
and 24 months, respectively.  A total of 600 subjects are expected to enroll during the 
accrual period.
8.7
Randomization Methods
The randomization numbers of the study will assign to subjects in a 2:1 ratio to either 
receive 0.3 mg/kg rovalpituzumab tesirine or topotecam.  Randomization will be stratified 
as follows: 
●
prior history of brain metastases (yes versus no), 
●
prior PCI (yes vs. no) for subjects with no prior history of brain metastases
●
sensitivity to first line platinum-based regimen [sensitive (OR/SD after 
first line therapy and progression/recurrence-free interval ≥ 90 days) versus 
refractory/resistant (PD as best response to or < 90 days 
progression/recurrence-free interval after first line therapy)],
●
LDH level (> ULN vs. ≤ ULN) at screening.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
104
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, 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 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.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
105
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.
Informed consent will be obtained for treatment post radiologic disease progression, and 
consent form should be signed at the time of progressive disease if treatment is to be 
continued (Arm A).
The tumor biopsy at the time of disease progression is an optional research sample and 
will only be performed if the subject has voluntarily signed and dated an informed 
consent, approved by an IRB/IEC, 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 tumor biopsy at the time of disease progression, 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 material 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 material for 
exploratory research will be destroyed.  If the subject changes his/her consent, and the 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
106
samples have already been tested, those results will still remain as part of the overall 
research data.
9.3.1
Informed Consent Form and Explanatory Material
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.
9.3.2
Revision of the Consent Form and Explanatory Material
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.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
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 (SAE CRF) may serve 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
107
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
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.
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
108
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 subject 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 subjects 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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
109
to access all uploaded subject entered data via a password protected website, up until the 
generation, receipt and confirmation of the study archive.
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.
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.
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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
110
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
111
14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for rovalpituzumab 
tesirine and the product labeling for topotecan and dexamethasone, as appropriate.
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, 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 (TAHOE)
Protocol Date:
08 January 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
112
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 Cancer J Clin.  
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.
Hycamtin® (topotecan) [package insert].  Research Triangle Park, NC; 
GlaxoSmithKline, 2015.
5.
Saunders LR, Bankovich AJ, Anderson WC, 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.
6.
Chapman G, Sparrow D, Kremmer E, et al.  Notch inhibition by the ligand delta-
like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal 
dysostosis.  Hum Mol Genet.  2011;20(5):905-16.
7.
Dunwoodie SL, Henrique D, Harrison SM, 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):3065-7.
8.
von Pawel J, Jotte R, Spigel DR, et al.  Randomized phase III trial of amrubicin 
versus topotecan as a second-line treatment for patients with small-cell lung cancer.  
J Clin Oncol.  2014;32(35):2012-19.
9.
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_2010-06-
14_QuickReference_5x7.pdf.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
113
10.
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in 
solid tumours:  Revised RECIST guideline (version 1.1).  Eur J Cancer.  
2009;45(2):228-47.
11.
Groenvold M, Petersen MAa, Aaronson NK, et al, EORTC Quality of Life Group.  
The development of the EORTC QLQ-C15-PAL:  a shortened questionnaire for 
cancer patients in palliative care.  Eur J of Cancer.  2006;42(1):55-64.
12.
AbbVie Stemcentrx LLC.  Rovalpituzumab Tesirine (SC 16LD6.5) Investigator's 
Brochure Edition 5.  13 September 2016.
13.
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
114
Appendix A.
Responsibilities of the Clinical Investigator
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
115
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 make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
116
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Pharmacokinetics
Clinical Drug Supply 
Management
Statistics
Bioanalysis


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
117
Appendix C.
Study Activities for Arm A (Rovalpituzumab Tesirine)
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visitcc
X
X
X
X
X
Phone Contactcc
X
X
X
X
X
Safety 
Assessments
Informed Consentf
X
Inclusion/Exclusion Criteria
X
Medical and Surgical History 
Including Malignancy 
Historyg
X
Physical examinationh
X
X
X
X
Vital Signsi
X
X
X
X
Hematology and Serum 
Chemistryj
X
Xk
X
X
Coagulation Testsj
X
Xk
X
Urinalysisj
X
Xk
X
X
Pregnancy Test
X
X
X
Xl
Electrocardiogram (ECG)m
X
X
Echocardiogramn
X
X
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
118
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Performance Status (ECOG)
X
X
X
Fluid Retention 
Questionnaireo
X
X
X
X
X
X
X
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xp
Xp
Xp
Concomitant Medications
X
X
X
X
X
X
X
Xp
Xp
Treatment
Rovalpituzumab Tesirine
X
Dexamethasone
X
X
X
Response 
Assessment
Disease/Response 
Assessment (Radiographic 
Imaging)q
X
Xs
Xr
Xs
Xs
MRI/CT of the Braint
X
Patient Reported Outcome 
(PRO)u
X
X u
Survival Status
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
119
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PK and PD/ 
Biomarker
Pharmacokinetics, Anti-
therapeutic Antibody (ATA) 
and Neutralizing Antibodies 
(nAb)v
X
X
Archived or Fresh Tumor 
Materialw
X
Tumor Material at Time of 
Disease Progressionx
X
X
Blood for Inflammatory 
Markers and ctDNA (10 mL)y
X y
Blood for Tumor & Soluble 
Markers (5 mL)y
X y
Circulating Tumor Cells 
(10 mL)z
X
X z
Pharmacogenetics 
(DNA/RNA)aa
Xaa
Serosal Fluidbb
Day 1 through 70 days after last study treatment
a.
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A meeting criteria as described in Section 5.3.1.1.  Subjects receiving additional 
doses of rovalpituzumab tesirine will follow the same study schedule as in Cycles 1 and 2. 
b.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.  Subjects in 
Arm A should be evaluated for eligibility of two additional doses of rovalpituzumab tesirine prior to proceeding with EOT procedures.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
120
c.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated. 
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits may be performed within 3 business days prior to the 
visit.  Disease/Response Assessment may be performed within 7 days prior to the Day 1 visit unless otherwise indicated.
f.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window for DLL3 
testing.
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.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.
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 actual 
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 (including C1D1).
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 clinical laboratory tests performed at Screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1 of each cycle, at the EOT Visit, and during the PTFU period until 6 months 
after the last dose of study drug.  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 a 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
121
n.
Echocardiograms are required at Screening, Day 1 of each cycle starting C2D1, and EOT.  Screening echocardiogram will be performed within 3 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 J, 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 Day 1 (during the treatment period for Arm A) 
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 scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study.
r.
May be omitted if assessment was performed within the preceding 6 weeks.
s.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.  If the subject qualifies to 
receive 2 additional cycles of Rova-T, radiographic assessments will continue to occur every 6 weeks for the first 30 weeks and then every 9 weeks until second progression 
or death.
t.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
u.
PRO assessments are required at Screening and before infusion on C1D1. 
v.
At each cycle, 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 business days window is permitted) and the second sample will be collected 30 minutes 
(± 10 minutes) post-infusion.  Only one collection will be required at the EOT visit.  The date and time of each sample collected will be recorded to the nearest minute.
w.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT. 
x.
An optional tumor biopsy may be obtained at the time of disease progression, from subjects who consent to undergo biopsy procedure.  Informed consent is 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
y.
On Cycle 1 Day 1 (–3 business days window is permitted), the collection of blood for inflammatory markers, ctDNA, tumor and soluble markers will be pre-infusion.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
122
z.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1.  –3 business days window is permitted.  CTCs implemented only at 
specific sites based on feasibility.
aa.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogentic sample to be collected on Day 1 of Cycle 1 only and is 
collected pre-infusion (–3 business days window is permitted).
bb. Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) must be procured 
for testing, for any AE starting from C1D1 through 70 days after the last study treatment.  Collected fluid must also be tested centrally and/or locally for cytology if disease 
progression due to appearance/worsening of effusion is suspected.
cc.
Procedures for visits where no treatment is administered and phone contacts from Day 8 to Day 36 of each cycle may be performed within ± 3 day window relative to the due 
date.  Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and 
pericardial), peripheral edema, cutaneous reactions (e.g., photosensitivity).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
123
Appendix D.
Study Activities for Arm B (Topotecan)
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visit
X
X
X
X
X
X
X
X
Phone Contactx
X
X
X
Screening, 
Baseline, 
and Safety 
Assessments
Informed Consente
X
Inclusion/Exclusion Criteria
X
Medical and Surgical 
History Including 
Malignancy Historyf
X
Physical examinationg
X
X
X
Vital Signsh
X
X
X
Hematology and Serum 
Chemistryi
X
Xj
X
Coagulation Testsi
X
Xj
Urinalysisi
X
Xj
Pregnancy Testk
X
X
X
X
Electrocardiogram (ECG)-l
X
Echocardiogram
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
124
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Performance Status 
(ECOG)
X
X
X
Fluid Retention 
Questionnairen
Xn
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xo
Xo
Xo
Concomitant Medications
X
X
X
X
X
X
X
Xo
Xo
Xo
Treatment
Topotecan
X
X
X
X
X
Response 
Assessment
Disease/Response 
Assessment (Radiographic 
Imaging)p
X
Xr
Xq
Xr
Xr
MRI/CT of the Brain
Xs
Patient Reported Outcome 
(PRO)t
X
Xt
Survival Status
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
125
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PD/ 
Biomarker
Archived or Fresh Tumor 
Materialu
X
Circulating Tumor Cells 
(10 mL)v
X
X v
Pharmacogenetics 
(DNA/RNA)w
Xw
a.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.
b.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
c.
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).
d.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated.  
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits may be performed within 3 days prior to the visit.  
Disease/Response Assessment may be performed within 7 days prior to the Day 1 visit unless otherwise indicated.
e.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window.  Informed 
consent is also required for the optional tumor biopsy at time of disease progression.
f.
Medical and Surgical History includes demographics and documentation of clinically significant medical condition, surgical history, and malignancy history.
g.
Height will be collected at the Screening visit only.  For height assessments, the subject should not wear shoes.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
126
h.
Vital sign determinations include weight, sitting blood pressure, heart rate and body temperature.  Weight will be collect prior to dosing at each cycle and recorded actual 
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 (including C1D1).
i.
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.
j.
The clinical laboratory tests performed at screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
k.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1, at the EOT visit, and during the PTFU period until 1 month after the last dose of 
study drug.  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 a FSH level > 40 IU/L and will have FSH performed at Screening and assessed by the investigator.
l.
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.
m.
Screening echocardiogram will be performed within 3 business days of randomization and results should be available prior to randomization to assess for the presence of any 
pericardial effusion as swell as cardiac function (left ventricular ejection fraction, LVEF).  Additional Echocardiogram monitoring may occur as clinically indicated during the 
study.
n.
Subjects will be asked about the development of any new or worsening peripheral edema or dyspnea (Appendix J, Fluid Retention Questionnaire).  Assessments will occur 
only in Cycle 1.  
o.
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.
p.
Diagnostic quality, spiral CT scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study. 
q.
May be omitted if previous assessment was performed within the preceding 6 weeks.
r.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
127
s.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
t.
PRO assessments are required at Screening and before infusion on C1D1.
u.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT.
v.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1.  –3 business day window is permitted. CTCs implemented only at 
specific sites based on feasibility.
w.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogenetic sample to be collected on Day 1 of Cycle 1 only and 
is collected pre-infusion (–3 business days window is permitted).
x.
Procedures for visits where no treatment is administered phone contacts for Day 8 and Day 15 of each cycle may be performed within ± 3 day window relative to the due date.  
Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and pericardial), 
peripheral edema, cutaneous reactions (e.g., photosensitivity).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
128
Appendix E.
Performance Status Scales Conversion
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
129
Appendix F.
New York Heart Association Classification
Class I
Subjects with no limitation of activities; they suffer no symptoms from ordinary 
activities.
Class II
Subjects with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion.
Class III
Subjects with marked limitation of activity; they are comfortable only at rest.
Class IV
Subjects who should be at complete rest, confined to bed or chair; any physical activity 
brings on discomfort and symptoms occur at rest.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
130
Appendix G.
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)


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
131
Appendix H.
Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1 for 
Tumor Response
Response criteria will be assessed using RECIST (version 1.1).10  Changes in the 
measurable lesions over the course of therapy must be evaluated using the criteria listed 
below.
Eligibility
Subjects with measurable disease at baseline can have objective tumor response evaluated 
by RECIST (version 1.1).  Measurable disease is defined by the presence of at least 
one measurable lesion.  If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology if possible.
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 
Lesions
All other lesions, including small lesions (longest diameter 
< 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
132
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.
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 subject, 
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 randomization.
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
133
Methods of Measurement
Conventional 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, but should have sponsor approval.
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 medical monitor.
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.
Baseline Documentation of "Target" and "Non-Target" Lesions
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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
134
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.
Evaluation of Target Lesions
Complete Response (CR):
The disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
135
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.
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.
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).
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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
136
providing this default value will prevent false responses or progression based upon 
measurement error.
Evaluation of Non-Target Lesions
Complete Response (CR):
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).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
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.
New Lesions
The appearance of new malignant lesions denotes disease progression.  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 


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
137
study in an anatomical location that was not scanned at baseline is considered a new 
lesion and will indicate disease progression.  An example of this is the subject who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The subject's brain metastases are considered evidence of progressive 
disease even if he/she did not have brain imaging at baseline.
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
138
Appendix I.
CTCAE v 4.0 Grading of Relevant AEs
Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Serosal 
Effusions
Ascites
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated
Symptomatic; medical 
intervention indicated
Severe symptoms; invasive 
intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Definition:  A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Pericardial effusion
–
Asymptomatic effusion size small 
to moderate
Effusion with physiologic 
consequences
Life-threatening consequences; 
urgent intervention indicated
Definition:  A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial 
tamponade
–
–
–
Life-threatening consequences; 
urgent intervention indicated
Definition:  A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pleural effusion
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated
Symptomatic; intervention 
indicated (e.g., diuretics or 
limited therapeutic thoracentesis)
Symptomatic with respiratory 
distress and hypoxia; surgical 
intervention including chest 
tube or pleurodesis indicated
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
–
Symptomatic; medical 
intervention indicated
Severe symptoms; 
intervention indicated
Life-threatening consequences; 
urgent intervention indicated
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.
Edema
Edema face
Localized facial edema
Moderate localized facial edema; 
limiting instrumental ADL
Severe swelling; limiting self-
care ADL
–
Definition:  A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
139
Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Edema 
(cont.)
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.
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.
Localized edema
Localized to dependent areas, 
no disability or functional 
impairment
Moderate localized edema and 
intervention indicated; limiting 
instrumental ADL
Severe localized edema and 
intervention indicated; 
limiting self-care ADL
–
Definition:  A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema; 
topical intervention indicated
Edema associated with visual 
disturbance; increased 
intraocular pressure, 
glaucoma or retinal 
hemorrhage; optic neuritis; 
diuretics indicated; operative 
intervention indicated
Definition:  A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
140
Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Labs
Hypo-albuminemia
< LLN – 3 g/dL;
< LLN – 30 g/L
< 3 – 2 g/dL;
< 30 – 20 g/L
< 2 g/dL;
< 20 g/L
Life-threatening consequences; 
urgent intervention indicated
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
< 1500 – 1000/mm3;
< 1.5 – 1.0 × 109/L
< 1000 – 500/mm3;
< 1.0 – 0.5 × 109/L
< 500/mm3;
< 0.5 × 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
< LLN – 75,000/mm3;
< LLN – 75.0 × 109/L
< 75,000 – 50,000/mm3;
< 75.0 – 50.0 × 109/L
< 50,000 – 25,000/mm3;
< 50.0 – 25.0 × 109/L
< 25,000/mm3;
< 25.0 × 109/L
Definition:  A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Respiratory, 
thoracic and 
mediastinal 
disorders
Pneumonitis
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated
Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL
Severe symptoms; limiting 
self-care ADL; oxygen 
indicated
Life-threatening respiratory 
compromise; urgent 
intervention indicated 
(e.g., tracheotomy or 
intubation)
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma
Skin 
Erythema multiforme
Target lesions covering < 10% 
BSA and not associated with 
skin tenderness
Target lesions covering 10 – 30% 
BSA and associated with skin 
tenderness
Target lesions covering 
> 30% BSA and associated 
with oral or genital erosions
Target lesions covering > 30% 
BSA; associated with fluid or 
electrolyte abnormalities; ICU 
care or burn unit indicated
Definition:  A disorder characterized by target lesions (a pink-red ring around a pale center).
Palmar-plantar 
erythrodysesthesia 
syndrome
Minimal skin changes or 
dermatitis (e.g., erythema, 
edema, or hyperkeratosis) 
without pain
Skin changes (e.g., peeling, 
blisters, bleeding, edema, or 
hyperkeratosis) with pain; 
limiting instrumental ADL
Severe skin changes 
(e.g., peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with pain; 
limiting self-care ADL
–
Definition:  A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
141
Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Skin (cont.)
Photosensitivity
Painless erythema and 
erythema covering < 10% BSA
Tender erythema covering 10 –
30% BSA
Erythema covering > 30% 
BSA and erythema with 
blistering; photosensitivity; 
oral corticosteroid therapy 
indicated; pain control 
indicated (e.g., narcotics or 
NSAIDs)
Life-threatening consequences; 
urgent intervention indicated
Definition:  A disorder characterized by an increase in sensitivity of the skin to light.
Rash maculo-papular
Macules/papules covering 
< 10% BSA with or without 
symptoms (e.g., pruritus, 
burning, tightness)
Macules/papules covering 10 –
30% BSA with or without 
symptoms (e.g., pruritus, burning, 
tightness); limiting instrumental 
ADL
Macules/papules covering 
> 30% BSA with or without 
associated symptoms; limiting 
self-care ADL
–
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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
142
Appendix J.
Fluid Retention Questionnaire
Fluid Retention Questionnaire for Study M16-289
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


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
143
4.
Please sign below to confirm that you have completed this questionnaire.
____________________________________ Date: __________________


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
144
Appendix K.
Adverse Events Expected Due to SCLC or Progression of SCLC
Preferred Term (MedDRA Version 19.1)
   Malignant pleural effusion
   Metastases to pleura
   Oesophageal obstruction
   Pneumonia bacterial
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
   Pulmonary embolism*
   Deep vein thrombosis*
   Lower respiratory tract infection*
   Respiratory tract infection*
   Upper respiratory tract infection*
   Opportunistic infection*
   Viral infection*
   Fungal infection*
   Bacterial infection*
   Lung abscess*


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
145
   Empyema*
   Lymphadenopathy
   Decreased appetite
   Malaise
   Weight decreased
   Pain 
*
Includes life threatening or fatal events.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
146
Appendix L.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.0  Title Page
"Sponsor/Emergency Contact:" 
Title previously read:
Medical Director
Has been changed to read:
Therapeutic Area Medical Director
Section 1.2  Synopsis
Subsection Methodology
Last paragraph previously read:
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.
Has been changed to read:
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to 
follow-up or withdraws consent, termination of the study by AbbVie, or until 12 February 
2020 whichever occurs first.
Section 1.2  Synopsis
Subsection Duration of Treatment:
Previously read:
Regimen of Arm A will be administered for 2 cycles unless earlier discontinuation is 
warranted due to disease progression, unacceptable toxicity or any other reason; up to two 
additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A who 
consent and satisfy all of the protocol defined criteria.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
147
Regimen of Arm B will be administered until disease progression, unacceptable toxicity 
or any other reason requiring treatment discontinuation.
Has been changed to read:
Regimen of Arm A will be administered for 2 cycles unless earlier discontinuation is 
warranted due to disease progression, unacceptable toxicity or any other reason; up to two 
additional cycles of rovalpituzumab tesirine may be permitted however the last dose on 
study must be administered no later than 04 December 2019 for subjects in Arm A who 
consent and satisfy all of the protocol defined criteria.  
Regimen of Arm B will be administered until disease progression, unacceptable toxicity, 
any other reason requiring treatment discontinuation, or no later than 04 December 2019, 
whichever comes first.
Follow up activities, including overall survival assessments, End of Treatment visits and 
AE/SAE reporting must occur no later than 12 February 2020.
Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
First paragraph previously read:
Overall Survival (OS):  After the End of treatment, survival information will be 
collected at approximately 6-week intervals (or as requested by sponsor to support data 
analysis) continuing until the endpoint of death, the subject becomes lost to follow-up, or 
AbbVie terminates the study.
Has been changed to read:
Overall Survival (OS):  After the End of treatment, survival information will be 
collected at approximately 6-week intervals (or as requested by sponsor to support data 
analysis) continuing until the endpoint of death, the subject becomes lost to follow-up, 
AbbVie terminates the study, or until 12 February 2020.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
148
Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
Add:  new first paragraph
Following the fourth safety review by the IDMC, on 04 December 2018, the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  For patients currently on treatment in Arm A, the IDMC 
recommends that sites and patients make individual decisions as to whether or not to 
continue treatment based on patient level response.  The data collection plan has been 
minimized given the status change of this study.  With all these changes, no statistical 
testing will be performed for the efficacy endpoints.  The efficacy endpoints will be 
analyzed using the original statistical methodologies as appropriate.  The efficacy 
endpoints for which there is not enough data to implement the statistical models will be 
summarized by treatment arms.  The statistical section remains unchanged to reflect the 
original analysis plan.
Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Sample Size:"
Add:  new first paragraph
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  444 subjects were enrolled in the study.  The following 
paragraph describes how the sample size was determined for the study.
Section 1.3  List of Abbreviations and Definition of Terms
Delete:  
CRAC
Central Radiographic Assessment Committee


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
149
Section 5.1  Overall Study Design and Plan:  Description
First bullet, last sentence previously read:
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in 
Arm A meeting certain criteria, as described in Section 5.3.1.1.
Has been changed to read:
Up to two additional cycles of rovalpituzumab tesirine may be permitted, however the last 
dose on study must be administered no later than 04 December 2019 for subjects in 
Arm A meeting certain criteria, as described in Section 5.3.1.1 .
Section 5.1  Overall Study Design and Plan:  Description
Last bullet, last sentence previously read:
The Arm B regimen will be administered until disease progression, unacceptable toxicity 
or any other reason requiring treatment discontinuation.
Has been changed to read:
The Arm B regimen will be administered until disease progression, unacceptable toxicity 
or any other reason requiring treatment discontinuation, or no later than 04 December 
2019, whichever comes first.
Section 5.1  Overall Study Design and Plan:  Description
Delete:  seventh paragraph
Disease assessments, for the purposes of efficacy assessments, will be performed by a 
Central Radiographic Assessment Committee (CRAC) blinded to study treatment 
information and independent of investigators and personnel who are involved in 
conducting the study (Section 5.3.1.1).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
150
Section 5.3.1.1  Study Procedures
Subsection Echocardiogram
Previously read:
Subjects will have echocardiograms performed per Appendix C and Appendix D, Study 
Activities Tables to assess any pericardial effusion during Screening, and prior to dosing 
at every cycle for subjects on Arm A, and prior to dosing at every other cycle for subjects 
on Arm B, if present, as well as cardiac function (left ventricular ejection fraction, LVEF).  
Additional echocardiograms may occur as clinically indicated during the study.
Has been changed to read:
Subjects will have echocardiograms performed per Appendix C and 0, Study Activities 
Tables to assess any pericardial effusion during Screening, and prior to dosing at every 
cycle for subjects on Arm A, if present, as well as cardiac function (left ventricular 
ejection fraction, LVEF).  Additional echocardiograms may occur as clinically indicated 
during the study.
Section 5.3.1.1  Study Procedures
Subsection Disease/Response Assessment (Radiographic Imaging)
First paragraph, sixth sentence previously read:
Disease response will be determined by the investigator at each assessment according to 
RECIST v1.1 (Appendix H, Response Evaluation Criteria for Solid Tumors (RECIST) v 
1.1)10 and independently reviewed by CRAC (described below).
Has been changed to read:
Disease response will be determined by the investigator at each assessment according to 
RECIST v1.1 (Appendix H, Response Evaluation Criteria for Solid Tumors (RECIST) 
v 1.1).10


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
151
Section 5.3.1.1  Study Procedures
Subsection Disease/Response Assessment (Radiographic Imaging)
Last paragraph
Delete:  last sentence
If so, all imaging should be submitted to the CRAC to be reviewed.  PET or PET/CT or 
X-rays, if performed with the purpose of disease status evaluation should be submitted for 
CRAC review.
Section 5.3.1.1  Study Procedures
Subsection Central Radiographic Assessment Committee (CRAC)
Delete:  Subsection title and text
Central Radiographic Assessment Committee (CRAC) 
In addition to being reviewed by the investigator and/or site staff, radiographic assessment 
scans will be assessed by a Central Radiographic Assessment Committee (CRAC), as 
outlined in the Appendix C and Appendix D, Study Activities Tables.  Sites will collect 
the appropriate scans and submit to the central facility at each subject's disease 
assessment.  In addition to baseline scans, on-study scans will be sent to the CRAC for 
review throughout the treatment period.  Scans will continue to occur as specified and be 
reviewed by the CRAC as long as the subject is receiving study treatment, including 
additional cycles post-progression in Arm A with rovalpituzumab tesirine.
Subject treatment management will be based on review by the local investigator and/or 
qualified medical staff.  The investigator should treat according to clinical judgment and 
the CRAC will make the definitive decision on tumor response or progression in regards 
to the PFS endpoint.
The CRAC will be blinded to subject treatment arm assignments.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
152
Section 5.3.1.1  Study Procedures
Subsection Health Resource Utilization
Delete:  Subsection title and text
Health Resource Utilization
Health Resource Utilization will be documented at each clinic visit per Appendix C and 
Appendix D, Study Activities.  Information regarding hospitalizations, emergency room 
visits, and physician office visits will be collected since the last study visit.
Section 5.3.1.1  Study Procedures
Subsection Fluid Retention Questionnaire (Including Subject Daily Weight)
First paragraph
Delete:  last sentence
The Arm B assessments will take place on Cycles 1 – 4 and Days 8 and 15 may take place 
by phone.
Section 5.3.1.1  Study Procedures
Subsection Fluid Retention Questionnaire (Including Subject Daily Weight)
Last paragraph, first sentence previously read:
Starting on Day 1 through the EOT visit, subjects will maintain a diary of daily weight 
(captured on the Fluid Retention Questionnaire).
Has been changed to read:
Starting on Day 1 through the EOT visit, subjects in Arm A will maintain a diary of daily 
weight (captured on the Fluid Retention Questionnaire).
Section 5.3.1.1  Study Procedures
Subsection Additional Two Cycles of Rovalpituzumab Tesirine (Arm A only)
First paragraph previously read:
Two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A 
who provide consent and who satisfy all of the following criteria:


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
153
Has been changed to read:
Up to two additional cycles of rovalpituzumab tesirine may be permitted, however the last 
dose on study must be administered no later than 04 December 2019 for subjects in 
Arm A who provide consent and who satisfy all of the following criteria:
Section 5.3.1.1  Study Procedures
Subsection End of Treatment (EOT) Visit
Last paragraph previously read:
Disease/Response assessment, including MRI/CT if clinically indicated, submission of 
scans to the CRAC, PRO assessments, blood for inflammatory markers, blood for tumor 
and soluble markers, and CTC may be omitted if performed within the last 6 weeks.
Has been changed to read:
Disease/Response assessment, including MRI/CT if clinically indicated, may be omitted if 
performed within the last 6 weeks.
Section 5.3.1.1  Study Procedures
Subsection Survival Follow Up (OS)
Last paragraph, second sentence previously read:
During this period, the subject will be followed every 6 weeks (± 1 week) for subsequent 
anti-cancer therapies (dates and responses), and survival status until the endpoint of death, 
the subject becomes lost to follow-up, termination of the study by AbbVie, whichever 
occurs first.
Has been changed to read:
During this period, the subject will be followed every 6 weeks (± 1 week) for subsequent 
anti-cancer therapies (dates and responses), and survival status until the endpoint of death, 
the subject becomes lost to follow-up, termination of the study by AbbVie, or until 
12 February 2020 whichever occurs first.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
154
Section 5.3.1.2  Collection and Handling of Biomarker and/or Optional Exploratory 
Research Samples
Subsection Blood (Plasma) for Inflammatory Markers and Circulating Tumor DNA 
(ctDNA)
Previously read:
At the indicated times noted in Appendix C, Study Activities, blood will be collected, 
processed to plasma for testing of inflammatory markers including erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), 
rheumatoid factor (RF) and ctDNA.  Samples will be collected on Day 1 of each cycle 
(pre-infusion) and at the EOT or at the time of disease progression.
Has been changed to read:
At the indicated times noted in Appendix C, Study Activities, blood will be collected, 
processed to plasma for testing of inflammatory markers including erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), 
rheumatoid factor (RF) and ctDNA.  Samples will be collected on Cycle 1 Day 1 (pre-
infusion).
Section 5.3.1.2  Collection and Handling of Biomarker and/or Optional Exploratory 
Research Samples
Subsection Blood (Serum) for Tumor and Soluble Markers
Last sentence previously read:
Samples will be collected on Day 1 of each cycle (pre-infusion) and at the EOT or at the 
time of disease progression.
Has been changed to read:
Samples will be collected on Cycle 1 Day 1 (pre-infusion).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
155
Section 5.3.1.2  Collection and Handling of Biomarker and/or Optional Exploratory 
Research Samples
Subsection Blood for Circulating Tumor Cells
Last sentence previously read:
Whole blood sample will be collected for CTC analysis during screening, pre-dose on 
Cycle 1 Day 1, Cycle 3 Day 1 (–3 business days window is permitted) and at the End of 
Treatment only at specific sites based on feasibility.
Has been changed to read:
Whole blood sample will be collected for CTC analysis during screening, and pre-dose on 
Cycle 1 Day 1.
Section 5.3.1.2  Collection and Handling of Biomarker and/or Optional Exploratory 
Research Samples
Subsection Pharmacogenetic Samples
First sentence previously read:
Whole blood samples for DNA and RNA isolation will be collected on Cycle 1 Day 1 
(pre-infusion) (–3 business days window is permitted) and EOT Visit from each subject.  
Has been changed to read:
Whole blood samples for DNA and RNA isolation will be collected on Cycle 1 Day 1 
(pre-infusion) (–3 business days window is permitted) from each subject.  
Section 5.4  Removal of Subjects from Therapy or Assessment
Add:  new last paragraph
All subjects will receive a final dose of study drug no later than 04 December 2019.  
Follow up activities, including Overall Survival assessments, End of Treatment visits and 
AE/SAE collection should occur no later than 12 February 2020.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
156
Section 5.4.1  Discontinuation of Individual Subjects
Fifth paragraph previously read:
Subjects no longer undergoing clinical assessments will have survival information 
collected at every 6 weeks (± 1 week) until the endpoint of death, the subject becomes lost 
to follow-up or termination of the study by AbbVie, whichever occurs first.
Has been changed to read:
Subjects no longer undergoing clinical assessments will have survival information 
collected at every 6 weeks (± 1 week) until the endpoint of death, the subject becomes lost 
to follow-up or termination of the study by AbbVie, whichever occurs first or until 
12 February 2020.
Section 5.5.2  Rovalpituzumab Tesirine (Arm A)
Fifth paragraph previously read:
All subjects assigned to Arm A will be administered 2 cycles of rovalpituzumab tesirine 
unless earlier discontinuation is warranted due to disease progression (see exception 
below), unacceptable toxicity or any other reason.
Has been changed to read:
All subjects assigned to Arm A will be administered 2 cycles of rovalpituzumab tesirine 
no later than 04 December 2019 unless earlier discontinuation is warranted due to disease 
progression (see exception below), unacceptable toxicity or any other reason.
Section 5.5.2  Rovalpituzumab Tesirine (Arm A)
Last paragraph previously read:
Two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A 
who provide consent and who satisfy all of the appropriate criteria as described in 
Section 5.3.1.1.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
157
Has been changed to read:
Up to two additional cycles of rovalpituzumab tesirine may be permitted, however the last 
dose on study must be administered no later than 04 December 2019 for subjects in 
Arm A who provide consent and who satisfy all of the appropriate criteria as described in 
Section 5.3.1.1.
Section 5.5.3  Topotecan (Arm B)
Last paragraph previously read:
All subjects assigned to Arm B will continue to receive topotecan until disease 
progression, unless earlier discontinuation is warranted due to unacceptable toxicity or 
any other reason.
Has been changed to read:
All subjects assigned to Arm B will continue to receive topotecan until disease 
progression or 04 December 2019 (whichever is later), unless earlier discontinuation is 
warranted due to unacceptable toxicity or any other reason.
Section 8.0  Statistical Methods and Determination of Sample Size
Add:  new text
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  For patients currently on treatment in Arm A, the IDMC 
recommends that sites and patients make individual decisions as to whether or not to 
continue treatment based on patient level response.  The data collection plan has been 
minimized given the status change of this study.  With all these changes, no statistical 
testing will be performed for the efficacy endpoints.  The efficacy endpoints will be 
analyzed using the original statistical methodologies as appropriate.  The efficacy 
endpoints for which there is not enough data to implement the statistical models will be 
summarized by treatment arms.  The statistical section remains unchanged to reflect the 
original analysis plan.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
158
Section 8.3  Type I Error Adjustment Procedure for Multiple Testing
Item H2, H4, H5, and H6 previously read:
H2:  Rovalpituzumab tesirine arm is not superior to topotecan arm in PFS per CRAC.
H4:  Rovalpituzumab tesirine arm is not superior to topotecan arm in ORR per CRAC.
H5:  Rovalpituzumab tesirine arm is not superior to topotecan arm in CBR per CRAC.
H6:  Rovalpituzumab tesirine arm is not superior to topotecan arm in DOR per CRAC.
Has been changed to read:
H2:  Rovalpituzumab tesirine arm is not superior to topotecan arm in PFS.
H4:  Rovalpituzumab tesirine arm is not superior to topotecan arm in ORR.
H5:  Rovalpituzumab tesirine arm is not superior to topotecan arm in CBR.
H6:  Rovalpituzumab tesirine arm is not superior to topotecan arm in DOR.
Section 8.4  Determination of Sample Size
Add:  new first paragraph
Following the fourth safety review by the IDMC, on 04 December 2018 the IDMC 
recommended that enrollment in the study is discontinued due to overall survival concerns 
associated with the study drug.  444 subjects were enrolled in the study.  The following 
paragraph describes how the sample size was determined for the study.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
159
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Pharmacokinetics
Clinical Drug Supply 
Management
Statistics
Bioanalysis
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Pharmacokinetics
Clinical Drug Supply 
Management
Statistics
Bioanalysis


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
160
Appendix C.  Study Activities for Arm A (Rovalpituzumab Tesirine)
Previously read:
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visitdd
X
X
X
X
X
Phone Contactdd
X
X
X
X
X
Safety 
Assessments
Informed Consentf
X
Inclusion/Exclusion Criteria
X
Medical and Surgical History 
Including Malignancy 
Historyg
X
Physical examinationh
X
X
X
X
Vital Signsi
X
X
X
X
Hematology and Serum 
Chemistryj
X
Xk
X
X
Coagulation Testsj
X
Xk
X
Urinalysisj
X
Xk
X
X
Pregnancy Test
X
X
X
Xl
Electrocardiogram (ECG)m
X
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
161
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Echocardiogramn
X
X
X
Performance Status (ECOG)
X
X
X
Fluid Retention 
Questionnaireo
X
X
X
X
X
X
X
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xp
Xp
Xp
Concomitant Medications
X
X
X
X
X
X
X
Xp
Xp
Treatment
Rovalpituzumab Tesirine
X
Dexamethasone
X
X
X
Response 
Assessment
Disease/Response 
Assessment (Radiographic 
Imaging)q
X
Xs
Xr
Xs
Xs
Central Radiographic 
Assessment Committee 
(CRAC) Reviewt
X
X
Xr
X
X
MRI/CT of the Brainu
X
Heath Resource Utilization
X
X
X
X
Patient Reported Outcome 
(PRO)v
X
X
X
X
X
Survival Status
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
162
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PK and PD/ 
Biomarker
Pharmacokinetics, Anti-
therapeutic Antibody (ATA) 
and Neutralizing Antibodies 
(nAb)w
X
X
Archived or Fresh Tumor 
Materialx
X
Tumor Material at Time of 
Disease Progressiony
X
X
Blood for Inflammatory 
Markers and ctDNA (10 mL)z
X
Xz
Xz
Blood for Tumor & Soluble 
Markers (5 mL)z
X
Xz
Xz
Circulating Tumor Cells 
(10 mL)aa
X
X
X
Pharmacogenetics 
(DNA/RNA)bb
Xbb
X
Serosal Fluidcc
Day 1 through 70 days after last study treatment
a.
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A meeting criteria as described in Section 5.3.1.1.  Subjects receiving additional 
doses of rovalpituzumab tesirine will follow the same study schedule as in Cycles 1 and 2. 
b.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.  Subjects in 
Arm A should be evaluated for eligibility of two additional doses of rovalpituzumab tesirine prior to proceeding with EOT procedures.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
163
c.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated. 
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits may be performed within 3 business days prior to the 
visit.  Disease/Response Assessment and CRAC Review may be performed within 7 days prior to the Day 1 visit unless otherwise indicated.
f.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window for DLL3 
testing.
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.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.
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 actual 
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 (including C1D1).
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 clinical laboratory tests performed at Screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1 of each cycle, at the EOT Visit, and during the PTFU period until 6 months 
after the last dose of study drug.  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 a 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
164
n.
Echocardiograms are required at Screening, Day 1 of each cycle starting C2D1, and EOT.  Screening echocardiogram will be performed within 3 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 J, 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 Day 1 (during the treatment period for Arm A) 
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 scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study.
r.
May be omitted if assessment was performed within the preceding 6 weeks.
s.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.  If the subject qualifies to 
receive 2 additional cycles of Rova-T, radiographic assessments will continue to occur every 6 weeks for the first 30 weeks and then every 9 weeks until second progression 
or death.
t
Site will collect the appropriate scans and submit to the central facility at each subject's disease assessment.  
u.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
v.
PRO assessments are required at Screening, before infusion on Day 1 of each cycle starting C2D1, Day 22 of each cycle, EOT, and PTFU (if applicable). 
w.
At each cycle, 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 business days window is permitted) and the second sample will be collected 30 minutes 
(± 10 minutes) post-infusion.  Only one collection will be required at the EOT visit.  The date and time of each sample collected will be recorded to the nearest minute.
x.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT. 
y.
An optional tumor biopsy may be obtained at the time of disease progression, from subjects who consent to undergo biopsy procedure.  Informed consent is 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


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
165
z.
On Day 1 (–3 business days window is permitted) of each cycle, the collection of blood for inflammatory markers, ctDNA, tumor and soluble markers will be pre-infusion.  A 
sample will also be collected once at the EOT or at the time of disease progression.
aa.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1 and Cycle 3 Day 1 (if applicable).  –3 business days window is 
permitted.  Sample will also be collected at the EOT.  CTCs implemented only at specific sites based on feasibility.
bb. Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogentic sample to be collected on Day 1 of Cycle 1 only and is 
collected pre-infusion (–3 business days window is permitted).
cc.
Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) must be procured 
for testing, for any AE starting from C1D1 through 70 days after the last study treatment.  Collected fluid must also be tested centrally and/or locally for cytology if disease 
progression due to appearance/worsening of effusion is suspected.
dd. Procedures for visits where no treatment is administered and phone contacts from Day 8 to Day 36 of each cycle may be performed within ± 3 day window relative to the due 
date.  Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and 
pericardial), peripheral edema, cutaneous reactions (e.g., photosensitivity).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
166
Has been changed to read:
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visitcc
X
X
X
X
X
Phone Contactcc
X
X
X
X
X
Safety 
Assessments
Informed Consentf
X
Inclusion/Exclusion Criteria
X
Medical and Surgical History 
Including Malignancy 
Historyg
X
Physical examinationh
X
X
X
X
Vital Signsi
X
X
X
X
Hematology and Serum 
Chemistryj
X
Xk
X
X
Coagulation Testsj
X
Xk
X
Urinalysisj
X
Xk
X
X
Pregnancy Test
X
X
X
Xl
Electrocardiogram (ECG)m
X
X
Echocardiogramn
X
X
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
167
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Performance Status (ECOG)
X
X
X
Fluid Retention 
Questionnaireo
X
X
X
X
X
X
X
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xp
Xp
Xp
Concomitant Medications
X
X
X
X
X
X
X
Xp
Xp
Treatment
Rovalpituzumab Tesirine
X
Dexamethasone
X
X
X
Response 
Assessment
Disease/Response 
Assessment (Radiographic 
Imaging)q
X
Xs
Xr
Xs
Xs
MRI/CT of the Braint
X
Patient Reported Outcome 
(PRO)u
X
X u
Survival Status
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
168
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to Day 
–1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
Day 
22 
(±3 
d)
Day 
29 
(± 3 
d)
Day 
36 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PK and PD/ 
Biomarker
Pharmacokinetics, Anti-
therapeutic Antibody (ATA) 
and Neutralizing Antibodies 
(nAb)v
X
X
Archived or Fresh Tumor 
Materialw
X
Tumor Material at Time of 
Disease Progressionx
X
X
Blood for Inflammatory 
Markers and ctDNA (10 mL)y
X y
Blood for Tumor & Soluble 
Markers (5 mL)y
X y
Circulating Tumor Cells 
(10 mL)z
X
X z
Pharmacogenetics 
(DNA/RNA)aa
Xaa
Serosal Fluidbb
Day 1 through 70 days after last study treatment
a.
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A meeting criteria as described in Section 5.3.1.1.  Subjects receiving additional 
doses of rovalpituzumab tesirine will follow the same study schedule as in Cycles 1 and 2. 
b.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.  Subjects in 
Arm A should be evaluated for eligibility of two additional doses of rovalpituzumab tesirine prior to proceeding with EOT procedures.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
169
c.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated.  
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits may be performed within 3 business days prior to the 
visit.  Disease/Response Assessment may be performed within 7 days prior to the Day 1 visit unless otherwise indicated.
f.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window for DLL3 
testing.
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.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.
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 actual 
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 (including C1D1).
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 clinical laboratory tests performed at Screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1 of each cycle, at the EOT Visit, and during the PTFU period until 6 months 
after the last dose of study drug.  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 a 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.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
170
n.
Echocardiograms are required at Screening, Day 1 of each cycle starting C2D1, and EOT.  Screening echocardiogram will be performed within 3 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 J, 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 Day 1 (during the treatment period for Arm A) 
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 scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study.
r.
May be omitted if assessment was performed within the preceding 6 weeks.
s.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.  If the subject qualifies to 
receive 2 additional cycles of Rova-T, radiographic assessments will continue to occur every 6 weeks for the first 30 weeks and then every 9 weeks until second progression 
or death.
t.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
u.
PRO assessments are required at Screening and before infusion on C1D1. 
v.
At each cycle, 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 business days window is permitted) and the second sample will be collected 30 minutes 
(± 10 minutes) post-infusion.  Only one collection will be required at the EOT visit.  The date and time of each sample collected will be recorded to the nearest minute.
w.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT. 
x.
An optional tumor biopsy may be obtained at the time of disease progression, from subjects who consent to undergo biopsy procedure.  Informed consent is 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
y.
On Cycle 1 Day 1 (–3 business days window is permitted), the collection of blood for inflammatory markers, ctDNA, tumor and soluble markers will be pre-infusion.  


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
171
z.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1.  –3 business days window is permitted.  CTCs implemented only at 
specific sites based on feasibility.
aa.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogentic sample to be collected on Day 1 of Cycle 1 only and is 
collected pre-infusion (–3 business days window is permitted).
bb. Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) must be procured 
for testing, for any AE starting from C1D1 through 70 days after the last study treatment.  Collected fluid must also be tested centrally and/or locally for cytology if disease 
progression due to appearance/worsening of effusion is suspected.
cc.
Procedures for visits where no treatment is administered and phone contacts from Day 8 to Day 36 of each cycle may be performed within ± 3 day window relative to the due 
date.  Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and 
pericardial), peripheral edema, cutaneous reactions (e.g., photosensitivity).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
172
Appendix D.  Study Activities for Arm B (Topotecan)
Previously read:
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visit
X
X
X
X
X
X
X
X
Phone Contacty
X
X
X
Screening, 
Baseline, 
and Safety 
Assessments
Informed Consente
X
Inclusion/Exclusion Criteria
X
Medical and Surgical 
History Including 
Malignancy Historyf
X
Physical examinationg
X
X
X
Vital Signsh
X
X
X
Hematology and Serum 
Chemistryi
X
Xj
X
Coagulation Testsi
X
Xj
Urinalysisi
X
Xj
Pregnancy Testk
X
X
X
X
Electrocardiogram (ECG)-l
X
X
Echocardiogram
X
Xm
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
173
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Performance Status 
(ECOG)
X
X
X
Fluid Retention 
Questionnairen
X
X
X
X
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xo
Xo
Xo
Concomitant Medications
X
X
X
X
X
X
X
Xo
Xo
Xo
Treatment
Topotecan
X
X
X
X
X
Response 
Assessment
Disease/Response 
Assessment (Radiographic 
Imaging)p
X
Xr
Xq
Xr
Xr
Central Radiographic 
Assessment Committee 
(CRAC) Reviews
X
X
Xq
X
X
MRI/CT of the Brain
Xt
Heath Resource Utilization
X
X
X
Patient Reported Outcome 
(PRO)u
X
X
X
X
Survival Status
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
174
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PD/ 
Biomarker
Archived or Fresh Tumor 
Materialv
X
Circulating Tumor Cells 
(10 mL)w
X
X
X
Pharmacogenetics 
(DNA/RNA)x
Xx
X
a.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.
b.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
c.
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).
d.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated.  
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits 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 unless otherwise indicated.
e.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window.  Informed 
consent is also required for the optional tumor biopsy at time of disease progression.
f.
Medical and Surgical History includes demographics and documentation of clinically significant medical condition, surgical history, and malignancy history.
g.
Height will be collected at the Screening visit only.  For height assessments, the subject should not wear shoes.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
175
h.
Vital sign determinations include weight, sitting blood pressure, heart rate and body temperature.  Weight will be collect prior to dosing at each cycle and recorded actual 
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 (including C1D1).
i.
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.
j.
The clinical laboratory tests performed at screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
k.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1, at the EOT visit, and during the PTFU period until 1 month after the last dose of 
study drug.  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 a FSH level > 40 IU/L and will have FSH performed at Screening and assessed by the investigator.
l.
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.
m.
Screening echocardiogram will be performed within 3 business days of randomization and results should be available prior to randomization to assess for the presence of any 
pericardial effusion as swell as cardiac function (left ventricular ejection fraction, LVEF).  Echocardiogram will then be performed every 6 weeks at alternating cycles starting 
C2D1 (–3 business days window is permitted).  Additional Echocardiogram monitoring may occur as clinically indicated during the study.
n.
Subjects will be asked about the development of any new or worsening peripheral edema or dyspnea (Appendix J, Fluid Retention Questionnaire).  Assessments will occur 
Cycles 1 – 4.  On Days 8 and 15, assessments may take place by phone, with the site contacting the subject and reviewing the questionnaire.  Starting Day 1 and through the 
EOT visit, subjects will maintain a diary of daily weights (captured on the Fluid Retention Questionnaire).
o.
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.
p.
Diagnostic quality, spiral CT scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study. 
q.
May be omitted if previous assessment was performed within the preceding 6 weeks.
r.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
176
s.
Site will collect the appropriate scans and or submit to the central facility at each subject's disease assessment. 
t.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
u.
PRO assessments are required at Screening, before infusion on Day 1 of each cycle, EOT, and PTFU (if applicable).
v.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT.
w.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1 and Cycle 3 Day 1 (if applicable).  –3 business day window is 
permitted.  Sample will also be collected at the EOT.  CTCs implemented only at specific sites based on feasibility.
x.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogenetic sample to be collected on Day 1 of Cycle 1 only and 
is collected pre-infusion (–3 business days window is permitted).
y.
Procedures for visits where no treatment is administered phone contacts for Day 8 and Day 15 of each cycle may be performed within ± 3 day window relative to the due date.  
Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and pericardial), 
peripheral edema, cutaneous reactions (e.g., photosensitivity).


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
177
Has been changed to read:
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visit
X
X
X
X
X
X
X
X
Phone Contactx
X
X
X
Screening, 
Baseline, 
and Safety 
Assessments
Informed Consente
X
Inclusion/Exclusion Criteria
X
Medical and Surgical 
History Including 
Malignancy Historyf
X
Physical examinationg
X
X
X
Vital Signsh
X
X
X
Hematology and Serum 
Chemistryi
X
Xj
X
Coagulation Testsi
X
Xj
Urinalysisi
X
Xj
Pregnancy Testk
X
X
X
X
Electrocardiogram (ECG)-l
X
Echocardiogram
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
178
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Performance Status 
(ECOG)
X
X
X
Fluid Retention 
Questionnairen
Xn
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xo
Xo
Xo
Concomitant Medications
X
X
X
X
X
X
X
Xo
Xo
Xo
Treatment
Topotecan
X
X
X
X
X
Response 
Assessment
Disease/Response 
Assessment (Radiographic 
Imaging)p
X
Xr
Xq
Xr
Xr
MRI/CT of the Brain
Xs
Patient Reported Outcome 
(PRO)t
X
Xt
Survival Status
X


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
179
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8 (± 
3 d)
Day 
15 
(± 3 
d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PD/ 
Biomarker
Archived or Fresh Tumor 
Materialu
X
Circulating Tumor Cells 
(10 mL)v
X
X v
Pharmacogenetics 
(DNA/RNA)w
Xw
a.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.
b.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
c.
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).
d.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated.  
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits may be performed within 3 days prior to the visit.  
Disease/Response Assessment may be performed within 7 days prior to the Day 1 visit unless otherwise indicated.
e.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window.  Informed 
consent is also required for the optional tumor biopsy at time of disease progression.
f.
Medical and Surgical History includes demographics and documentation of clinically significant medical condition, surgical history, and malignancy history.
g.
Height will be collected at the Screening visit only.  For height assessments, the subject should not wear shoes.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
180
h.
Vital sign determinations include weight, sitting blood pressure, heart rate and body temperature.  Weight will be collect prior to dosing at each cycle and recorded actual 
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 (including C1D1).
i.
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.
j.
The clinical laboratory tests performed at screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
k.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1, at the EOT visit, and during the PTFU period until 1 month after the last dose of 
study drug.  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 a FSH level > 40 IU/L and will have FSH performed at Screening and assessed by the investigator.
l.
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.
m.
Screening echocardiogram will be performed within 3 business days of randomization and results should be available prior to randomization to assess for the presence of any 
pericardial effusion as swell as cardiac function (left ventricular ejection fraction, LVEF).  Additional Echocardiogram monitoring may occur as clinically indicated during the 
study.
n.
Subjects will be asked about the development of any new or worsening peripheral edema or dyspnea (Appendix J, Fluid Retention Questionnaire).  Assessments will occur 
only in Cycle 1.  
o.
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.
p.
Diagnostic quality, spiral CT scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study. 
q.
May be omitted if previous assessment was performed within the preceding 6 weeks.
r.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.


Rovalpituzumab Tesirine
M16-289 Protocol Amendment 4
EudraCT 2016-003726-17
181
s.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
t.
PRO assessments are required at Screening and before infusion on C1D1.
u.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT.
v.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1.  –3 business day window is permitted.  CTCs implemented only at 
specific sites based on feasibility.
w.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogenetic sample to be collected on Day 1 of Cycle 1 only and 
is collected pre-infusion (–3 business days window is permitted).
x.
Procedures for visits where no treatment is administered phone contacts for Day 8 and Day 15 of each cycle may be performed within ± 3 day window relative to the due date.  
Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and pericardial), 
peripheral edema, cutaneous reactions (e.g., photosensitivity).

SAP_001.pdf: 
Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
1
1.0
Title Page
Statistical Analysis Plan
Study M16-289
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
Date:  13 Mar 2020
Version 1.0 
NCT03061812


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Abbreviation.............................................................................5
4.0
Introduction ...........................................................................10
5.0
Study Objectives and Design................................................10
5.1
Objectives ................................................................................................10
5.1.1
Primary Objective ....................................................................................10
5.1.2
Secondary Objectives...............................................................................10
5.1.3
Exploratory Objectives ............................................................................11
5.2
Design Diagram .......................................................................................11
5.3
Randomization and Stratification.............................................................13
5.4
Sample Size..............................................................................................14
5.5
Independent Data Monitoring Committee (IDMC) .................................14
5.6
Planned Analyses .....................................................................................15
5.6.1
Final Analysis ..........................................................................................15
5.6.2
Supportive Analysis .................................................................................15
5.6.3
Interim Analysis for Early Efficacy.........................................................15
5.7
Type I Error Adjustment Procedures .......................................................16
5.7.1
Type I Error Control for Supportive analysis ..........................................16
5.7.2
Type I Error Control for Interim Analysis...............................................16
5.7.3
Type I Error Adjustment Procedures for Multiple Testing......................16
6.0
Analysis Sets...........................................................................18
7.0
Analysis Conventions ............................................................19
7.1
Data Handling Convention at Database Level.........................................22
8.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies.....................................................22
8.1
Demographic and Baseline Characteristics .............................................23
8.2
Medical History .......................................................................................23
8.3
Prior and Concomitant Medications ........................................................24
9.0
Subject Disposition................................................................24


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
3
10.0
Study Drug .............................................................................25
10.1
Study Drug Exposure...............................................................................25
10.2
Relative Dose Intensity (RDI) of Rovalpituzumab Tesirine....................26
11.0
Efficacy Analysis....................................................................27
11.1
General Considerations............................................................................27
11.1.1
Analysis of Efficacy Endpoints by Variable Type...................................28
11.2
Efficacy Analyses ....................................................................................29
11.3
Sensitivity Analyses.................................................................................35
11.4
Subgroup Analyses ..................................................................................35
12.0
Safety Analysis.......................................................................36
12.1
General Considerations............................................................................36
12.2
Analysis of Adverse Events.....................................................................36
12.3
Adverse Events of Special Interest (AESIs) ............................................38
12.3.1
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................42
12.3.2
Listing of Adverse Events........................................................................42
12.3.3
Deaths ......................................................................................................42
12.4
Analysis of Laboratory, Vital Signs, and ECG Data ...............................43
12.5
Analysis of ECOG Performance Status ...................................................44
12.6
Analysis of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values...................................................................45
13.0
References...............................................................................45
List of Tables
Table 1.
Visit Window laboratory and vital sign analysis .....................................22
Table 2.
Visit Window for PRO analysis...............................................................22
Table 3.
Adverse Events of Special Interest ..........................................................39
Table 4.
Clinical Laboratory Tests.........................................................................44
List of Figures
Figure 1.
Study Schema...........................................................................................12


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
4
Figure 2.
Testing Procedure ....................................................................................18
List of Appendices
Appendix A.
Activities for Arm A (Rovalpituzumab Tesirine)....................................48
Appendix B.
Study Activities for Arm B (Topotecan)..................................................55


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
5
3.0
Abbreviation
ADC
Antibody-drug conjugate
AE
Adverse event
ALT
Alanine aminotransferase
ANA
Anti-nuclear antibodies
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASCL1
Achaete-scute homolog 1
ASTRO
American Society for Radiation Oncology
AST
Aspartate aminotransferase
AT
Aminotransferase
ATA
Anti-therapeutic antibody
ATC
Anatomical therapeutic chemical (codes)
ATEMS
AbbVie Temperature Excursion Management System
β-hCG
Beta-human chorionic gonadotropin
BUN
Blood urea nitrogen
CBR
Clinical benefit rate
CDSM
Clinical Drug Supply Management
CFR
Code of Federal Regulations
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
CR
Complete response
CRF
Case report forms
CRAC
Central Radiographic Assessment Committee
CRP
C-reactive protein
CS
Clinically significant
CSC
Cancer stem cell
CT
Computerized tomography
CTC
Circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CYP3A4
Cytochrome P450 3A4


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
6
DILI
Drug-induced liver injury
DLL3
Delta-like protein 3
DLL3high
DLL3 high expression in tumor
DNA
Deoxyribonucleic acid
DOR
Duration of response
DOT
US Department of Transportation
eCCR
Estimated creatinine clearance rate
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EFNS
European Federation of Neurological Societies
EGF
Epidermal growth factor
EMEA
European Agency for the Evaluation of Medicinal Products
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EQ-5D-5L
EuroQoL Five Dimensions Questionnaire
ESR
Erythrocyte sedimentation rate
EU
European Union
FDA
US Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
Gy
Gray
HIPPA
Health Insurance Portability and Accountability Act
HR
Hazard ratio
HRQOL
Health-related quality of life
IATA
International Air Transport Association
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IL
Interleukin
IMP
Investigational Medicinal Product


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
7
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous(ly)
KM
Kaplan-Meier
LCNEC
Large cell neuroendocrine cancer
LD
Longest diameter
LFT
Liver function tests
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
nAb
Neutralizing antibodies
NASH
Non-alcoholic steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCS
Not clinically significant
NEUROD1
Neurogenic differentiation 1
NSAID
Non-steroidal anti-inflammatory drug
NSE
Neuron-specific enolase
NYHA
New York Heart Association
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PBD
Pyrrolobenzodiazepine
PCI
Prophylactic cranial irradiation
PD
Progressive disease
PDX
Patient-derived xenografts
PET
Positron emission tomography
PET-CT
Positron emission tomography-computed tomography


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
8
PFS
Progression-free survival
PK
Pharmacokinetics
PO
Per os (by mouth)
POR
Proof of receipt
PR
Partial response
PRO
Patient reported outcome
PT
Prothrombin time
PTFU
Post-treatment follow up
q3wk
Every 3 weeks
q6wk
Every 6 weeks
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria in Solid Tumors
RF
Rheumatoid factor
Rova-T
Rovalpituzumab tesirine
ROVAT
AbbVie compound number for rovalpituzumab tesirine
RPTD
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SC-DR002
DNA cross-linking agent also known as D6.5
SC16
Humanized DLL3-specific IgG1 antibody
SCLC
Small cell lung cancer
SD
Stable disease
SGOT/AST
Serum glutamic-oxaloacetic transaminase
SGPT/ALT
Serum glutamic-pyruvic transaminase
SIADH
Syndrome of Inappropriate Anti-Diuretic Hormone
SMPC
Summary of product characteristics
SPF
Sun protection factor
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TIC
Tumor-initiating cells
ULN
Upper limit of normal
US
Ultrasound


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
9
VALG
Veterans Administration Lung Study Group
VAS
Visual analog scale
VEGF
Vascular endothelial growth factor
WBC
White Blood Cell
WHODRUG
World Health Organization Drug (Dictionary)
WOCBP
Women of Childbearing Potential


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
10
4.0
Introduction
This draft statistical analysis plan (SAP) describes the detailed statistical methods, 
including analysis conventions, for primary and secondary objectives as outlined in the 
protocol for Study M16-289 Amendment 4 (which is currently also in draft stage).
Efficacy and safety analyses will be performed using SAS Version 9.3 or higher (SAS 
Institute, Inc., Cary, NC  27513) under the UNIX operating system.  The SAP will be 
finalized prior to any comparative analysis of study data by treatment arm.
5.0
Study Objectives and Design
5.1
Objectives
5.1.1
Primary Objective
The primary objectives of the study are to assess if treatment with rovalpituzumab tesirine 
(Rova-T) improves overall survival (OS) compared to topotecan in subjects with 
advanced or metastatic Delta-like protein 3 high expression in tumor (DLL3high), small-
cell lung cancer (SCLC) who have first disease progression during or following front-line 
platinum based chemotherapy.
5.1.2
Secondary Objectives
The secondary objectives of the study are as follows:  
●
to demonstrate if the treatment with Rova-T improves progression free 
survival (PFS) assessed by Central Radiographic Assessment Committee 
(CRAC) compared to topotecan; 
●
to assess the effect on physical functioning scale in EORTC-QLQ-C15-PAL 
questionnaire at post-baseline Week 7 due to treatment with rovalpituzumab 
tesirine compared to topotecan; 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
11
●
to assess if treatment with rovalpituzumab tesirine improves clinical benefit 
rate (CBR) assessed by CRAC compared to topotecan;
in subjects with advanced or metastatic DLL3high SCLC who have first disease 
progression during or following front-line platinum based chemotherapy.
5.1.3
Exploratory Objectives
The exploratory objectives are
●
to determine if treatment with rovalpituzumab tesirine improves objective 
response rate (ORR); 
●
to compare the duration of objective response between two arms; 
●
to compare the safety and tolerability of rovalpituzumab tesirine to topotecan; 
in subjects with advanced or metastatic DLL3high SCLC who have first disease 
progression during or following front-line platinum based chemotherapy
5.2
Design Diagram
This is a Phase 3, randomized, open-label, multinational, and multicenter study comparing 
the efficacy, safety and tolerability of rovalpituzumab tesirine versus topotecan in subjects 
with advanced or metastatic DLL3high SCLC who have first disease progression during or 
following front-line platinum-based chemotherapy.  DLL3high is defined as ≥ 75% tumor 
cells staining positive according to the VENTANA DLL3 (SP347) IHC Assay.
Eligible subjects will be randomized in a 2:1 ratio to receive rovalpituzumab tesirine 
(Arm A) or topotecan (Arm B):
●
Subjects assigned to Arm A will receive 0.3 mg/kg rovalpituzumab tesirine 
(IV) on Day 1 of a 42-Day cycle for 2 cycles, along with 8 mg orally (PO) of 
dexamethasone twice daily on Day –1, Day 1, and Day 2.  Regimen of Arm A 
will be administered for the 2 cycles planned unless earlier discontinuation is 
warranted due to disease progression, unacceptable toxicity or any other 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
12
reason.  Up to two additional cycles of rovalpituzumab tesirine may be 
permitted for subjects in Arm A meeting certain criteria, as described in 
Section 5.3.1.1 of the study protocol.  
●
Arm B subjects will receive 1.5 mg/m2 topotecan (IV) on Days 1 – 5 of each 
21-Day cycle.  Topotecan may be administered at a lower dose if required by 
the local label. The Arm B regimen will be administered until disease 
progression, unacceptable toxicity or any other reason requiring treatment 
discontinuation.
A schematic of the study is provided in Figure 1 Study Schema.
Figure 1.
Study Schema
Empty arrowhead = Rovalpituzumab tesirine administration cycle; Dotted arrowhead = Additional Rovalpitizumab 
tesirine administration cycle; Filled arrowhead = Topotecan administration cycle; PTFU = post-treatment follow-up; 
OS = overall survival
1.
Tumor material collection and testing for DLL3 status may occur at any time after initial diagnosis, including 
outside of the Screening window, depending on completion of the appropriate consent process.
2.
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A meeting certain 
criteria, as described in Protocol Section 5.3.1.1.
3.
Topotecan will be administered until disease progression, unacceptable toxicity or any other reason requiring 
treatment discontinuation.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
13
The collection of tumor material for DLL3 testing may be done at any time after the 
informed consent is signed and prior to randomization.  Screening procedures and 
radiographic assessments (CT scan or MRI) must be performed within 28 days prior to 
randomization.  Post-baseline radiographic assessments will be performed every 6 weeks 
for the first 30 weeks and then every 9 weeks until radiographic progression or death.  
Radiographic information will be collected to determine response according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1.  For subjects receiving post-
progression doses of rovalpituzumab tesirine radiographic assessments will continue until 
the second event of disease progression as outlined in Section 5.3.1.1 of the study 
protocol.
Disease assessments, for the purposes of efficacy assessments, will be performed by a 
CRAC blinded to study treatment information and independent of investigators and 
personnel who are involved in conducting the study.
The study procedures for each visit are outlined in Appendix A and Appendix B.
5.3
Randomization and Stratification
All subjects in the study will be randomized using an Interactive Response Technology 
(IRT) system.  The site will contact the IRT to obtain a Screening (subject) number once 
the subject has signed the informed consent.  Once the screening number is assigned, if 
the subject is not randomized into the study, the reason for screen failure will be 
documented in the source document and in the eCRF.
The IRT will randomize subjects in a 2:1 ratio, with two-thirds of the subjects randomized 
to the rovalpituzumab tesirine treatment arm and the other one-third to the topotecan arm.  
Subjects who meet the eligibility criteria will be stratified according to the following 
4 factors: 
●
prior history of brain metastases and Prophylactic cranial irradiation (PCI) 
(brain metastases, no brain metastases and PCI, no brain metastases nor PCI,), 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
14
●
sensitivity to first line platinum-based regimen [sensitive (OR/SD after 
first line therapy and progression/recurrence-free interval ≥ 90 days) versus 
refractory/resistant (PD as best response to or < 90 days 
progression/recurrence-free interval after first line therapy)],
●
LDH level (> ULN versus ≤ ULN) at screening.
5.4
Sample Size
The sample size of the study is determined by analysis of OS.  Approximately 
600 subjects in total will be randomized to rovalpituzumab tesirine (Arm A) or topotecan 
(Arm B) in a 2:1 ratio.  It is assumed that median overall survival in the topotecan arm 
(Arm B) will be around 6.5 months.  Based on a log-rank test, at a one-sided significance 
level of 0.025 and a power of 85%, a total of 497 deaths are needed to detect a hazard 
ratio of 0.75 (i.e., a reduction in the hazard death of 25%) which corresponds to an 
increase in median OS to 8.67 months in rovalpituzumab tesirine arm (Arm A) assuming, 
an exponential survival time distribution.  It is projected that an observed hazard ratio of 
0.826 or less would result in statistically significance in the final analysis of OS.
5.5
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will be formed and constituted 
according to appropriate regulatory guidelines.  The IDMC will be scheduled to review 
safety data approximately every 3 months after the first IDMC meeting, or at any time 
requested by the IDMC.  Detailed information regarding the composition of the 
committee and detailed procedures will be documented in a separate charter.
Data will be analyzed by the Statistical and Data Analysis Center (SDAC), an external 
vendor outside of the Sponsor, and the results from analyses will be reviewed by the 
IDMC.  Details will be provided in the IDMC charter. 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
15
5.6
Planned Analyses
5.6.1
Final Analysis
Final analysis will be performed when at least 497 deaths have occurred, which is 
projected to be approximately 38 months the first subject randomized.
5.6.2
Supportive Analysis
A supportive analysis is planned to support activities in Rova-T program that are not 
related to TAHOE study, specifically potential regulatory submission of data from 
Phase I/II for consideration of early registration.  The supportive analysis will be 
conducted during 2Q 2019 and will include approximately the first 190 enrolled subjects.  
The result of the analysis will not impact the study conduct in any way unless it is 
warranted based on a review of safety data.  There is no intent to stop the trial early to 
claim efficacy based on this supportive analysis.  Nevertheless, one sided alpha of 10–6
will be spent at the supportive analysis per regulatory agency feedback since efficacy data 
will be analyzed.  The supportive analysis will be conducted by SDAC which is an 
independent group external to the Sponsor.  The study team that is involved in the conduct 
of this trial will not have access to, or any knowledge of, the results that would be 
generated during the supportive analysis.  The details of the conduct of the supportive 
analysis are documented in the Trial integrity plan (TIP).
5.6.3
Interim Analysis for Early Efficacy
An interim efficacy analyses of OS will be performed after observing about 373 deaths 
(i.e., 75% of the 497 deaths required at final analysis).  At the interim analysis, OS will be 
tested at the significance level determined based on the actual number of deaths using the 
Lan-DeMets alpha spending function with O'Brien and Fleming boundary so that the 
overall 1-sided significance level is maintained at 0.025.  When 373 deaths are observed, 
an alpha spending of 0.0097 for the interim OS analysis will be allocated to test for 
superiority.  The final OS analysis will be performed at a one-sided nominal alpha level of 
0.0221, adjusting for the interim look at OS data.  If the interim analysis is performed at 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
16
373 deaths, the HR boundary for demonstrating superiority in OS at the interim will be 
0.773.  The HR boundary for demonstrating superiority at the final analysis with 
497 deaths will be 0.826.
The trial will be considered for early stopping for efficacy if the Independent Data 
Monitoring Committee (IDMC) makes such a recommendation after consideration of the 
OS results and all supportive evidence including other efficacy endpoints and safety. 
5.7
Type I Error Adjustment Procedures
5.7.1
Type I Error Control for Supportive analysis
The one-sided alpha of 10–6 will be spent for the early look at the efficacy data for 
supportive analysis.  However, there is no provision to stop the trial early to claim 
efficacy based on this interim analysis.
5.7.2
Type I Error Control for Interim Analysis
O'Brien-Fleming method will be used to adjust for multiple testing to maintain one-sided 
type I error level at 2.5% for the whole study.  As described in Section 11.2, stratified log-
rank test would be used for primary efficacy analyses.  With interim analysis planned at 
373 events and final analysis planned at 497 events, the simulation results suggest that the 
information fraction (IF) at interim analysis is estimated to be approximately 75%.  With 
this IF at interim analyses, a one-sided type I error of 0.0097 will be used for interim 
analysis with 373 events for early efficacy, and final analysis will be carried out at 
one-sided type I error of 0.0221 to preserve type I error at one-sided 2.5% for the whole 
study.
5.7.3
Type I Error Adjustment Procedures for Multiple Testing
As mentioned above, the overall one-sided type I error for testing the primary and all 
secondary endpoints will be preserved at 2.5%.  The primary and secondary endpoints 
will be tested using a fixed-sequence hierarchical testing strategy.  At each analysis 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
17
timepoints (i.e., interim and final analyses), the treatment effects on primary and 
secondary endpoints will be tested in the following order
Testing Order
Endpoint
1
OS
2
PFS, assessed by CRAC
3
Change from baseline in physical functioning scale on EORTC-QLQ C15-PAL 
questionnaire at post-baseline Week 7
4
clinical benefit rate assessed by CRAC
To protect overall Type I error across primary and all the secondary endpoints, we will 
follow "overall hierarchical" testing strategy.10  The O'Brien Fleming alpha spending 
function will be used for the OS endpoint.  For all the secondary endpoints one-sided 
alpha of 0.02 will be allocated for the interim analysis; the alpha spend in the final 
analysis will be calculated using the group sequential design methodology and estimated 
information fraction at interim analysis.  For example, the one-sided alpha for the PFS 
endpoint in the final analysis would be 0.014 and 0.018 if the information fraction at the 
interim analysis is 0.8 and 0.9, respectively.  The interim analysis will be driven by the 
timing of observing 373 OS events. 
The testing procedure is displayed in Figure 2.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
18
Figure 2.
Testing Procedure
*
The alpha for the final analysis will be calculated using the group sequential design methodology and estimated 
information fraction at interim analysis.
6.0
Analysis Sets
The following analysis sets will be used for analysis of safety and efficacy endpoints of 
the study.
Randomized Set will comprise all randomized subjects regardless of whether they 
received study treatment.  Subjects will be classified in the treatment groups, 
"rovalpituzumab tesirine" or "Topotecan," according to the treatment they were assigned 
at the time of randomization.  Unless otherwise specified (and except for subgroup and 
sensitivity analyses), the Randomized Set will be the default dataset for analysis of 
efficacy data.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
19
Per-protocol Set (PPS) will be comprised of a subset of patients in the Randomized Set 
excluding those with deviation(s) from study inclusion and exclusion criteria.  Subjects 
meeting any of the following criteria will be excluded from PPS:
●
Those entered into the study even though did not satisfy the entry criteria
●
Those who developed withdrawal criteria during the study but were not 
withdrawn
●
Those who received the wrong treatment
●
Those who received an excluded concomitant treatment
●
Those who were randomized but did not receive any dose of study medication
Subjects will be classified according to treatment assigned. 
Safety Set will be comprised of a subset of subjects who receive at least one dose of study 
treatment (either rovalpituzumab tesirine or topotecan).  Subjects will be classified 
according to the treatment they had received (as-treated).
7.0
Analysis Conventions
This section provides general considerations for data handling, summary, and analysis.  
This also includes general definitions of certain kinds of endpoints.
Continuous variables will be summarized by sample size (N), mean, standard deviation 
(St. Dev.), median, minimum, and maximum.  Frequency and percentage will be provided 
for categorical variables and 95% confidence intervals (CIs) will be generated for 
parameter estimates of interest, unless specified otherwise.
For the analysis of efficacy endpoints, the Randomized Set will be the primary analysis 
set whereas the Per Protocol Set (PPS) will be used for supportive analysis only.  Analysis 
for the sub-groups will be carried out in the subset of Randomized Set meeting the sub-
group selection criteria at the enrollment.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
20
The change from baseline analysis for the QOL measures, patients with missing baseline 
values will be excluded.  Descriptive summaries for the efficacy endpoints will be 
reported by treatment groups.  These summaries will also be reported at the individual 
levels of each stratification factors. 
The statistical comparisons for the primary and secondary endpoints will be made 
according to the multiplicity adjustment plan described in Section 5.7.2 to preserve the 
familywise one-sided type 1 error rate at 0.025.  The statistical comparisons for all the 
other exploratory efficacy endpoints will be performed at a nominal one-sided 
2.5% significance level.  Confidence intervals for parameters (e.g., median survival times, 
HR) will be constructed with 2-sided 95% confidence level, whenever applicable.  No 
type I error adjustment for multiple comparisons will be carried out for these exploratory 
endpoints. 
Dealing with Multiple Values on the Same Day
In case multiple values are collected on the same day at a baseline or post-baseline visit, 
the arithmetic average (for continuous summary) will be used for analyses unless 
otherwise specified. 
Definition of Baseline Observation
Unless otherwise specified, the baseline observation is defined as the last non-missing 
measurement collected prior to the first dose date of any study drug (rovalpituzumab 
tesirine or dexamethasone) for Arm A; topotecan for Arm B).
Definition of Final Observation for Laboratory and Vital Sign Parameters
For lab and vital sign parameters, the final observation is defined as the last non-missing 
post-baseline measurement collected not more than 70 days after the last dose of 
investigational product. 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
21
Missing Data
No missing data imputation will be implemented, unless specified otherwise.
Definition of Study Day (Day Relative to the day of Randomization) and Rx Day 
(Day Relative to the First Dose of Study Drug)
Study Day of any observation is defined for post-randomization observations as: 
Study Day = Date of observation – Date of randomization + 1,
and for observations pre-dating randomization as:
Study Day = Date of observation – Date of randomization.
Thus, the day of randomization is defined as Study Day 1, while the day prior to the 
randomization is defined as Study Day –1 (there is no Study Day 0).
Study Rx Day of any post-baseline observation is defined as the number of days from the 
day of the first dose of any study drug (rovalpituzumab tesirine or topotecan) to the date 
of observation.  It is calculated for each observation as follows:
●
Study Rx Day = Date of observation – Date of first dose of any study drug + 1
Definition of Analysis Windows
All time points and corresponding time windows are based on Study Rx Days, unless 
specified otherwise.  For analysis at visit, especially for the laboratory data (hematology, 
chemistry, and urinalysis), nominal days and visit windows for the 2 treatment arms 
(Arm A and Arm B) are given in the table below.  If more than one observation is 
included in a time window, the observation closest to the nominal day should be used.  If 
there are two observations equally distant to the nominal day, the later one will be used in 
analyses.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
22
Table 1.
Visit Window laboratory and vital sign analysis
Study Visit (Week)
Nominal Study Rx Day
Time Window (Study Rx Days Range)
Baseline
Baseline definition
3
22
2 to ≤ 32
6
43
33 to ≤ 53
…
…
…
3•X
7•3•X + 1
7•3•X - 9 to ≤ 7•3•X + 11
The endpoints based on subject self-reported health related quality of life (QoL) and 
symptom assessments will be analyzed for post-treatment Week 3, Week 7 and 
subsequently with the increment of 6 weeks (i.e., Week 13, Week 19, and Week 24). The 
visit windows for the PRO endpoints are defined in Table 2 below.
Table 2.
Visit Window for PRO analysis
Study Visit (Week)
Nominal Study Rx Day
Time Window (Study Rx Days Range)
Baseline
Baseline definition
3
22
2 to ≤ 28
7
50
29 to ≤ 70
13
92
71 to ≤ 112
…
…
…
7 + 6•X
(7+6•X) 7 + 1
(7+6•X) 7 - 20 to ≤ (7 + 6•X) 7 + 21
7.1
Data Handling Convention at Database Level
There is no applicable data handling convention at database level.
8.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies
Data for demographic, baseline characteristics, medical history, prior/concomitant 
medications, prior systemic therapies, and prior procedures will be summarized by 
treatment groups using the Randomized Set population.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
23
8.1
Demographic and Baseline Characteristics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
N, mean, standard deviation (St. Dev.), median, minimum, and maximum.  Frequencies 
and percentages will be computed for the following categorical parameters (but not 
limited to):  sex, race, ethnicity, age group (< 55, 55 to < 65, 65 to < 75, 75 to < 85, and 
≥85 years old), tobacco and alcohol use (unknown, never, current, former), and ECOG 
performance status (0, 1, ≥ 2).
Subject's baseline characteristics will be summarized, including (but not limited to) 
stratification factors, small cell lung cancer history (overall VALG stage at study 
entry/initial diagnosis, overall TNM at study entry/initial diagnosis, TNM staging (T, N, 
M) at study entry, weeks from initial diagnosis to randomization, DLL3 status, DLL3 
expression in percentage), prior systemic therapies (sensitivity to first line platinum-based 
regimen, number of subjects who progressed prior to completion of platinum-based 
regimen, days from completion of prior regimen to progression for those who completed 
it, treatment received, reason for discontinuation of prior treatment), prior radiation 
therapy (number of subjects with any prior radiation, type of radiation, treatment intent, 
best outcome), prior procedures, electrocardiogram, and echocardiogram. 
There will be no statistical comparison of demographic and baseline measurements 
between treatment arms.
8.2
Medical History
Medical history data will be summarized and presented using conditions/diagnoses as 
captured on the eCRF.  The conditions/diagnoses will be presented in alphabetical order.  
The number and percentage of subjects with a particular condition/diagnosis will be 
summarized for each treatment arm.  Subjects reporting more than 
one condition/diagnosis will be counted only once for that condition/diagnosis.  There 
will be no statistical comparison of the medical history between treatment arms.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
24
8.3
Prior and Concomitant Medications 
A prior medication is defined as any medication with an end date prior to the date of 
randomization and collected on the electronic case report forms (eCRFs).  A concomitant 
medication is defined as any drug that started on the day of or after randomization, but not 
more than 70 days after the last study drug administration.  Medications with a start date 
prior to the date of randomization and continuing after randomization are also classified as 
concomitant medications.  A medication will also be considered a concomitant medication 
if one of the following three cases occur:  (1) the start date is missing and the end date is 
either after or on the day of randomization; (2) the start date is not missing but not more 
than 70 days after the last study drug administration and the end date is missing; (3) both 
the start date and the end date are missing.
Prior and concomitant medications will be summarized separately by the anatomical 
therapeutic chemical (ATC) codes in the World Health Organization (WHO) dictionary.  
Subjects reporting the same medication generic name two or more times will be counted 
only once for that generic name.  Subjects reporting more than one medication will be 
counted only once in the total number of subjects taking a concomitant medication.  In 
addition, the number of prior and concomitant medications will also be presented for each 
treatment arm. 
There will be no statistical comparison of prior and concomitant medications between 
treatment arms.
9.0
Subject Disposition
Subject disposition summary will be presented on all the screened subjects by investigator 
site and overall.  The following information will be presented:
●
Subjects who were screened
●
Subjects who screen failed
●
Subjects who were randomized
●
Subjects who were randomized without any major protocol violations


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
25
●
Subjects who took at least one dose of study drug (rovalpituzumab tesirine; 
topotecan)
●
Subjects who completed/discontinued the study drug 
In addition, a subject disposition summary will be presented for the Randomized Set by 
treatment arm assigned at randomization – the numbers and percentages of subjects who 
were randomized, and discontinued the study. 
In addition, treatment disposition summary will be presented for the safety set, classifying 
subjects according to actual treatment received.  The numbers and percentages of subjects 
who discontinued the study drug and primary reason for study drug discontinuation will 
be provided.  No statistical tests will be performed.
10.0
Study Drug 
10.1
Study Drug Exposure
Summary of study drug exposure will be presented on the safety set.  
The following summaries will be presented by treatment group:
●
The number and percentage of subjects with total number of cycles of 
rovalpituzumab tesirine and topotecan received,
●
Descriptive summary of average dose level per cycle (mg/kg for 
rovalpituzumab tesirine; mg for dexamethasone; mg/m2 for topotecan),
An overview of interruption and dose reduction will be presented for each of 
rovalpituzumab tesirine, dexamethasone, and topotecan treatments as following: 
●
The number and percentage of subjects who had at least one interruption of 
study drug (rovalpituzumab tesirine/dexamethasone/topotecan) administration, 
and further breakdowns by the number of interruptions and by reason,
●
The number and percentage of subjects who had at least one dose reduction, 
and further breakdowns by the number of dose reductions and by reason.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
26
For each cycle, the number and percentages of subjects with interruption and reason will 
be presented (42-day cycle for rovalpituzumab tesirine; 21-day cycle for topotecan).  
Similarly, the number and percentages of subjects with dose reduction and reason will be 
presented at each cycle.
10.2
Relative Dose Intensity (RDI) of Rovalpituzumab Tesirine 
Dose intensity of rovalpituzumab tesirine will be summarized for the safety set (Arm A 
only).
For a subject, the total dose is defined as the sum of rovalpituzumab tesirine doses 
(mg/kg) administered during the study.  Treatment duration of rovalpituzumab tesirine is 
defined as total number of weeks rovalpituzumab tesirine treated, i.e., (date of last 
injection – date of first injection + 42)/7, by adding the appropriate number of days to 
complete the last cycle.  
The observed dose intensity (DIobserved), expressed in units of dose level divided by unit of 
treatment duration, i.e., mg/kg/week, is the ratio of the total dose (mg/kg) received to the 
total duration of treatment (weeks);
)
(
)
/
(
weeks
duration
treatment
total
Actual
kg
mg
dose
Total
DIobserved !
The theoretical dose intensity (DIprotocol) will be expressed in the same unit as those used 
for the observed dose intensity;
)
(
)
/
(
weeks
cycle
one
of
duration
l
Theoretica
kg
mg
cycle
per
Dose
DI protocol !
The relative dose intensity (RDI), expressed in percentage (%), is calculated as the ratio of 
the observed dose intensity to the dose intensity indicated in the protocol;


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
27
100
∀
!
protocol
observed
DI
DI
RDI
.
Simple continuous summary statistics for the observed dose intensity will be presented.  
The number and percentages of subjects will be presented for the following categories of 
RDI < 70%, 70% to < 90%, 90% to < 110%, 110% to < 120%, and 120% or higher.
11.0
Efficacy Analysis
11.1
General Considerations
Unless otherwise specified, all efficacy analyses described below will be performed on the 
Randomized Set.  Efficacy endpoints of response and progression used in analyses will be 
based on Central Radiographic Assessment Committee (CRAC).  Disease progression 
will be defined as progression of disease according to RECIST v1.1.  For subjects whose 
tumors meet the criteria of partial or complete response (PR or CR), tumor response must 
be confirmed by repeat measurements performed no less than 4 and no more than 8 weeks 
after the criteria for response are first met. 
For change from baseline analysis of QOL measures, patients with missing baseline value 
will be excluded.  Descriptive summaries for the efficacy endpoints will be reported by 
treatment groups.  These summaries will also be reported at the individual levels of each 
stratification factors. 
The statistical comparisons for the primary and secondary endpoints will be done 
according to the multiplicity adjustment plan described in Section 5.7.2 to preserve the 
familywise one-sided type 1 error rate to 0.025.  The statistical comparisons for all the 
other exploratory efficacy endpoints will be performed at a nominal one-sided 
2.5% significance level.  Confidence intervals for parameters (e.g., median survival times, 
HR) will be constructed with 2-sided 95% confidence level, whenever applicable.  No 
type I error adjustment for multiple comparisons will be carried out for these exploratory 
endpoints. 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
28
11.1.1
Analysis of Efficacy Endpoints by Variable Type
Time to events (TTE) variables
All TTE endpoints defined in this study are concerned with only the first incidence of an 
event of interest, and recurrence of the same event is not considered for endpoint 
derivation.  An event however may be defined in a composite manner, i.e., as the 
occurrence of one among several different outcomes.  The composite event is observed 
when at least one of the component events occurs, and the time to the earliest among the 
occurring component events is considered to be the TTE for the composite event.
Time to events (TTE) endpoints will be derived as follows: 
TTE = Date of first occurrence of an event or censoring – date of randomization + 1.
TTE endpoints will be computed in days and converted into months 
(1 month = 30.4375 days) for analysis.  Thus, for subjects who experience the event of 
interest, time to event will be defined as the time from randomization to the 
first occurrence of the event.  When multiple assessments are needed to ascertain the 
occurrence of an event, the earliest date among all of these assessments is taken to be date 
of the event or censoring.  For a subject who does not experience an event on the study, 
time will be right censored at the time of his/her last available adequate post-baseline 
assessment that rules out the occurrence of the event.  If a subject had no post-baseline 
assessment and did not experience the event of interest, then TTE will be censored at the 
date of randomization and we will set TTE = 1 day, by convention. 
TTE endpoints will be summarized by number of events observed, number of subjects 
censored, and times corresponding to 25% (1st quartile), 50% (median) and 75% 
(3rd quartile) event probabilities.  Kaplan-Meier (KM) estimates will be calculated and 
plotted.  Comparison between treatment arms will be based on stratified log-rank tests as 
specified. 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
29
A Cox proportional-hazards regression model4 with the treatment and stratification factors 
as covariates will be used to estimate the HR of rovalpituzumab tesirine to topotecan and 
its two-sided 95% CI.  Only the main effects of the stratification variables will be fitted.  
Measure of treatment effects will be provided in term of HR (rovalpituzumab tesirine to 
Topotecan) from the above model with HR value less than 1 representing treatment 
benefit.  For all of the above time-to-deterioration endpoints, death will be considered as 
event.
Continuous variables
Summary of continuous endpoints at baseline, post-baseline and change from baseline (as 
available) will be provided.  Change from baseline values will be analyzed using an 
analysis of covariance (ANCOVA) model including stratification factors and baseline as 
covariates and 95% CI for treatment group difference will be provided. 
11.2
Efficacy Analyses
Overall Survival (OS)
All events of death available at the time of analysis will be included, regardless of 
whether the event occurred while the subject was still taking study drug or after the 
subject discontinued study drug.
The primary endpoint OS will be compared between treatment Arms rovalpituzumab 
tesirine and topotecan at both interim and final analysis.  Superiority of rovalpituzumab 
tesirine (Arm A) to topotecan (Arm B) in terms of OS will be evaluated using stratified 
log-rank test, adjusting for the study stratification factors. 
This stratified log rank test will be implemented in SAS using LIFETEST procedure as 
follows:


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
30
proc lifetest method=km; 
   time <follow-up time>*<Censoring status>(<censoring codes>);
   strata <stratification factors> / group=<treatment> 
test = logrank;   
run;
The OS curves for each arm will be estimated using the Kaplan-Meier (KM) product-limit 
method.  Two-sided, 95% confidence interval for median OS will be computed, using the 
Brookmeyer and Crowley method.  Landmark survival rate, defined as the survival rate 
estimated using the Kaplan-Meier approach at pre-defined time points from 
randomization (e.g., 6, 12, 18, and 24 months), will be presented with two-sided 95% CIs, 
using Greenwood's method for calculating standard errors.
Estimation of HR
A Cox proportional-hazards regression model4 with the treatment and stratification factors 
as covariates will be used to estimate the HR of rovalpituzumab tesirine to topotecan and 
its two-sided 95% CI.  Only the main effects of the stratification variables will be fitted.
Where, treatment takes value 1, if treated with rovalpituzumab tesirine, otherwise 0, for 
topotecan.  Effron's approximate method (1977) will be used for handling ties.  In SAS, 
estimate of HR will be estimated using PHREG procedure and Effron's method5 will be 
employed by using TIES = EFFRON option in MODEL statement.19  Following SAS 
code will be used
PROC PHREG;
  CLASS <treatment>;
  MODEL <follow-up time>*<Censoring status>(<censoring codes>)= 
<strata variables> <treatment> /TIES=EFFRON RL;
RUN;
Progression-free Survival (PFS)
All disease progression assessed by CRAC per RECIST v1.1 will be included, regardless 
of whether the event occurred while subject was taking the study drug or had previously 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
31
discontinued the study drug.  Data from subjects who are lost to follow-up will be 
included in the analysis as censored observations on the last date of radiographic 
assessment that the subject was documented to be progression free.
Analysis methods for PFS endpoint are similar to those described for the OS endpoint.  
The PFS rates at 6, 9 and 12 months and corresponding 95% CIs will also be estimated 
using KM estimates on the PFS curve for each arm.  
Clinical Benefit Rate (CBR)
Subjects with clinical benefit includes those who achieve confirmed complete or partial 
response (CR or PR), or stable disease (SD) for at least 12 weeks (2 tumor assessments) 
as adjudged by the CRAC based on RECIST v1.1. 
The clinical benefit rate (CR, PR, and SD) rate will be reported with exact (binomial) 
two-sided 95% CI for each treatment arm. 
CBR will be compared between treatment arms using a Cochran-Mantel-Haenszel (CMH) 
test, stratified by the randomization stratification factors.  The difference in CBR will be 
summarized with two-sided 95% CI.  Rates and corresponding 95% exact CIs will be 
calculated by Clopper-Pearson method for each arm.  Sensitivity analysis based on 
investigator-determined CBR will also be performed.
Objective Response Rate (ORR)
Analysis of ORR will be performed for the randomized subjects with measureable disease 
at baseline.
Objective response includes complete response (CR) and partial response (PR) assessed 
by the CRAC based on RECIST v1.1 Subjects who do not achieve CR or PR, including 
those who do not have post-baseline radiological assessments will be considered as non-
responders.  
The same statistical methodology will be used as that for CBR endpoint.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
32
Duration of Response (DOR)
Only subjects with a confirmed objective response will be included in the analysis of 
duration of response (DOR).
DOR is defined as the time between the date of first response (CR or PR by CRAC, 
whichever is recorded first) to the date of the first documented tumor progression 
(assessed by CRAC) or death due to any cause, 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.  Due to the non-randomization nature of 
the analysis set for DOR, the analysis of DOR will be considered descriptive and will not 
be compared between treatment arms.
Patients Reported Outcomes (PRO)
The endpoints based on subject self-reported health related quality of life (QoL) and 
symptom assessments will be analyzed for post-treatment Week 3, Week 7 and 
subsequently with the increment of 6 weeks (i.e., Week 13, Week 19, and Week 24).  The 
EORTC QLQ-C15-PAL/LC13 and the European Quality of Life-5 Dimensions 
(EQ-5D-5L) are used to measure the QoL and symptom assessments.
QLQ-C15-PAL & QLQ-LC13
The QLQ-C15-PAL is an abbreviated 15-item version of the EORTC QLQ-C30 for 
palliative care.  The QLQ-C15-PAL questionnaire has four abbreviated scales measuring 
physical functioning, emotional functioning, nausea and vomiting, and fatigue.  These 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
33
scales are estimated using the algorithm specified in Addendum to the EORTC QLQ-C30 
Scoring Manual: Scoring of the EORTC QLQ-C15-PAL (July, 2006).
For each scale in QLQ-C15-PAL questionnaire, the raw score (RS) is computed as the 
mean of component items over the number of items answered for that scale if at least 
50% of the items are answered, and set as missing otherwise.  Then the scale score (SS) 
will be computed as:
SS = {(RS - 1)/range} · 100.
The lung cancer module (QLQ-LC13) is composed of one multi-item scale to assess 
dyspnea, and a series of single items assessing coughing, sore mouth, dysphagia, 
peripheral neuropathy, alopecia, hemoptysis, and pain. 
All scales and single items are reported on categorical responses, and will be linearly 
converted to 0 through 100 numeric values.  Given a scale, the raw score (RS) is 
computed as the mean of component items over the number of items answered for that 
scale if at least 50% of the items are answered.  It will be set as missing otherwise.  Then 
the scale score, SS = {(RS - 1)/range} · 100, will be computed.
For single-item measures (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties), none of the single-item measures can be computed if not answered.  
If a scale score cannot be computed, the outcome for that score is left blank.
The analysis of continuous endpoint of EORTC QLQ-C15-PAL PF scale score will be 
performed by analyzing the change in scale score from baseline to the given time point, 
using an analysis of covariance (ANCOVA) model including stratification factors and 
baseline as covariates, and 95% CI for treatment group difference will be provided.
Change from baseline at post-baseline Week 7 in the physical function scale is one of the 
secondary efficacy endpoints, and other scales and items are considered exploratory.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
34
For each scale, the treatment group differences will be evaluated by analyzing the change 
from baseline to each of the post-baseline time-points and to the final measurement (last 
QoL assessment per subject) using a one-way analysis of variance (ANOVA) model 
including stratification factors and baseline as covariates.  Simple summary statistics for 
QoL assessments at each timepoint will also be presented.  
EQ-5D-5L
The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) is a preference based measure of health 
status that consists of EQ-5D descriptive system and EQ visual analogue scale (VAS).  
The EQ-5D descriptive system comprises the following 5 dimensions:  mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression.  Each of the dimensions is 
divided into 5 levels of perceived problems:  Level 1 (indicating no problem), Level 2 
(indicating slight problems), Level 3 (indicating moderate problems), Level 4 (indicating 
severe problems), and Level 5 (indicating extreme problems).  EQ-5D-5L health status, 
defined by the EQ-5D-5L descriptive system, will be converted into a single
preference –weighted health status or "utility" index score by applying country-specific 
weights (if available) or U.S. weights (if not available).
The EQ VAS records the respondent's self-rated health on a visual analogue scale (0 to 
100).  The VAS score will be measured separately.
Mean change from baseline in EQ-5D-5L "utility" index score to each applicable post-
baseline time point, and to the final measurement will be presented by treatment arm.  The 
treatment group difference will be evaluated by analyzing the change from baseline using 
a one-way analysis of variance (ANOVA) model including stratification factors and 
baseline as covariates.  The same methodology will apply to the mean change from 
baseline in VAS score.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
35
11.3
Sensitivity Analyses
Sensitivity analyses will be conducted to evaluate the robustness of efficacy results.  OS 
and PFS (by CRAC) will be analyzed in the PPS. 
A sensitivity analysis of PFS will be performed based on investigator-assessed disease 
progression or death from any cause using the Randomized Set.  The statistical 
methodology described in Section 11.1.1 for TTE endpoints will be used.
Sensitivity analyses of investigator-determined ORR will also be performed based on the 
Randomized Set (ORR analysis will only include the randomized subjects with 
measureable disease at baseline).
11.4
Subgroup Analyses
For randomized subjects, analysis of OS will be performed in the following subgroups on 
an as-stratified basis according to stratification data collected at randomization:
●
Prior history of brain metastases and PCI (brain metastases, no brain 
metastases and PCI, no brain metastases nor PCI)
●
Sensitivity to first line platinum-based regimen (sensitive [OR/SD after 
first line therapy and progression/recurrence-free interval ≥ 90 days] versus 
refractory/resistant [PD as best response to or < 90 days 
progression/recurrence-free interval after first line therapy])
●
Lactate dehydrogenase (LDH) (> Upper Limit of Normal (ULN) vs. ≤ ULN) at 
Screening
●
Overall Veterans Administration Lung Study Group (VALG) stage (Limited 
Disease vs Extensive Disease) at initial diagnosis
●
Gender
●
Race
Difference in OS between rovalpituzumab tesirine and topotecan arms will be assessed by 
an unstratified log-rank test for each subgroup.  Hazard ratios will be calculated by a 
Cox's model.  


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
36
12.0
Safety Analysis
12.1
General Considerations
Unless otherwise specified, safety analyses will be performed on the safety set.
Unless specified, all summaries/analyses involving AEs will only include treatment-
emergent adverse events (TEAEs).  TEAEs are defined as any adverse event with onset or 
increase in severity after the first dose of study drug (rovalpituzumab tesirine or 
topotecan) but no more than 70 days after the last dose of study drug administration.
A summary of continuous safety endpoints (e.g., change from baseline values in 
laboratory values, vital signs parameters) will include the mean, standard deviation, 
median and range.  In the context of change from baseline analyses, summary of baseline 
and post-baseline data will also be provided.  Categorical safety endpoints (e.g., incidence 
of AEs or clinically significant ECG values) will be summarized using frequencies and 
percentages.  All the analyses will be carried out by treatment group. 
Unscheduled assessment will not be included in the summary of change from baseline, 
but will be included in producing shift tables and summary of lab abnormalities. 
12.2
Analysis of Adverse Events
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs between the treatment 
groups will be summarized for the following adverse event categories.  
●
TEAEs
●
NCI toxicity (maximum) grade 3 or 4 TEAEs
●
Drug-related TEAEs
●
NCI toxicity (maximum) grade 3 or 4 drug-related TEAEs
●
Serious TEAEs 
●
NCI toxicity (maximum) grade 3 or 4 serious TEAEs


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
37
●
Drug-related serious TEAEs
●
TEAEs leading to discontinuation/reduction/interruption of study drug, 
●
Drug-related TEAEs leading to discontinuation/reduction/interruption of study 
drug 
●
TEAEs leading to death
●
Drug-related TEAEs leading to death
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing TEAEs will be tabulated according 
to the primary MedDRA system organ class (SOC) and MedDRA preferred term (PT) for 
each treatment group.  Subjects reporting more than one adverse event for a given 
MedDRA PT will be counted only once for that term.  Subjects reporting more than 
one type of adverse event within a MedDRA SOC will be counted only once for that 
SOC.  Subjects reporting more than one type of adverse event will be counted only 
once in the overall total. 
AEs by Preferred Term
The number and percentage of subjects experiencing adverse events will be tabulated 
according to the MedDRA PT for each treatment group.  Subjects reporting more than 
one AE for a given MedDRA PT will be counted only once for that term.
AEs by Maximum Severity
Adverse events will be summarized by SOC, PT and maximum severity per NCI CTCAE 
v.4 grading in each treatment arm.  If a subject has an AE with unknown severity, then the 
subject will be counted in the severity category of "unknown," unless the subject does not 
have another occurrence of the same AE with a severity present.  In addition, Grade 3 or 
higher AE will also be summarized by SOC and PT.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
38
AEs by Relationship
Adverse events possibly related to rovalpituzumab tesirine, dexamethasone, topotecan, as 
assessed by the investigator, will be summarized separately in each treatment arm.  
Following summaries will be presented for the AEs possibly related to rovalpituzumab 
tesirine, dexamethasone, topotecan, separately:
●
Summary of AE by PT
●
Summary of AE by SOC and PT
●
Summary of Grade 3 or higher AE by SOC and PT
●
Summary of SAE by SOC and PT
●
Summary of rovalpituzumab tesirine discontinuation by SOC and PT (possibly 
related to rovalpituzumab tesirine only)
●
Summary of topotecan discontinuation by SOC and PT (possibly related to 
topotecan only)
If a subject has an AE with unknown relationship, then the subject will be counted in the 
relationship category of "unknown," unless the subject does not have another occurrence 
of the same AE with a relationship present.
12.3
Adverse Events of Special Interest (AESIs)
Specific treatment-emergent AESIs, including important identified risks, will be identified 
by the search criteria provided in Table 3.




Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
40
Table 3.
Adverse Events of Special Interest (Continued)
Adverse Event of Special Interest
MedDRA Search Criteria/Codes
Cutaneous Reaction 
SOC 10040785 Skin and Subcutaneous Tissue Disorders
The observed TEAEs under this SOC will be medically 
adjudicated to maintain a list of PTs that are not medically 
relevant and that will be excluded from the analysis. 
Current list of PTs to exclude:
10001760 Alopecia
10002424 Angioedema
10011985 Decubitus Ulcer
10014080 Ecchymosis
10020642 Hyperhidrosis
10051235 Madarosis
10070533 Nail Bed Disorder
10028694 Nail Disorder
10062283 Nail Ridging
10028692 Nail Discolouration
10029410 Night Sweats
10034754 Petechiae
10037087 Pruritus
10052576 Pruritus generalised
10037549 Purpura
10042682 Swelling Face
Thrombocytopenia 
SMQ 20000031 Haematopoietic Thrombocytopenia (broad)
Haemorrhages 
SMQ 20000039 Haemorrhage Terms (Excluding Laboratory 
Terms; narrow)
Edema
PTs:
10030095 Oedema
10030124 Oedema Peripheral
10048961 Localised Oedema
10018092 Generalised Oedema
10042674 Swelling
10016807 Fluid Retention
10016803 Fluid Overload
10024770 Local Swelling
10048959 Peripheral Swelling
10007196 Capillary Leak Syndrome
10015993 Eyelid Oedema
10016029 Face Oedema
10052139 Eye Oedema
10034545 Periorbital Oedema


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
41
Table 3.
Adverse Events of Special Interest (Continued)
Adverse Event of Special Interest
MedDRA Search Criteria/Codes
Hypoalbuminemia  
PTs: 
10020942 Hypoalbuminaemia
10005287 Blood Albumin Decreased
10005286 Blood Albumin Abnormal
Hepatotoxicity 
SMQs:
20000007 Drug-Related Hepatic Disorders (severe events only;
broad)
20000009 Cholestastis and Jaundice of Hepatic Origin (broad)
20000008 Liver Related Investigations, Signs and Symptoms
(broad)
Exclude PT 10020942 Hypoalbuminaemia from this search
since hypoalbuminemia is associated with chronic liver disease
and therefore not included in AESI
Anemia
SMQ 20000029: Haematopoietic Erythropenia (broad)
Neutropenia
SMQ 20000030: Haematopoietic Leukopenia (broad)
Infusion-Related Reaction
PT 10051792 Infusion related reaction
Nephrotoxicity
SMQ 20000003 Acute Renal Failure (broad)
Teratogenicity/Embryotoxicity
SMQ 20000185: Pregnancy and Neonatal Topics (broad)
Abuse Liability*
CMQ:  80000120 Abuse Liability
Febrile Neutropenia (Symptomatic
Neutropenia)**
PTs:
10016288 Febrile Neutropenia
10049151 Neutropenic Sepsis
10059482 Neutropenic Infection
*
Search performed as needed for the Drug Abuse Liability Assessment (DALA) report.
**
Search performed for only patient narratives for specific safety assessments.
Time to onset
Time to onset is the Rx Day of the start date of the first occurrence of AESI.  If a subject 
has not experienced an AESI, the subject will be censored on the day of the subject's last 
assessment (i.e., the day of the subject's last known laboratory assessment, last known 
vital sign assessment, last known physical exam, last known tumor assessment, or last 
known follow-up visit, whichever is the latest) or 70 days from the last study drug 
administered, whichever is earliest; if the subject has not experienced an AESI and had no 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
42
post-baseline assessment (i.e., none of laboratory assessment, vital sign assessment, 
physical exam, or tumor assessment), the subject will be censored on the day of the 
subject's first study drug.
Median onset time will be estimated using a Kaplan-Meier method with corresponding 
95% CI for the median for each treatment arm.
12.3.1
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs and AEs leading to rovalpituzumab tesirine, dexamethasone, topotecan, dose 
reduction and dose interruption will be summarized separately by SOC and PT in each 
treatment arm.  Separate listings for SAEs, AEs leading to death and AEs leading to 
treatment discontinuation will also be provided.
12.3.2
Listing of Adverse Events
The following additional summaries of adverse events will be prepared.
●
Listing of treatment-emergent serious adverse events
●
Listing of treatment-emergent adverse events that lead to discontinuation of 
study drug
●
Listing of treatment-emergent fatal adverse events
●
Listing of Grade 3 or higher adverse events
12.3.3
Deaths 
The number and percentage of subject deaths will be summarized by treatment Arm 1) for 
deaths occurring while the subject was still receiving study drug (rovalpituzumab tesirine, 
dexamethasone, topotecan); 2) for deaths occurring off-treatment; 3) for deaths occurring 
≤ 70 days after treatment stopped; 4) for deaths occurring > 70 days after treatment 
stopped.  Primary cause of death will also be presented.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
43
12.4
Analysis of Laboratory, Vital Signs, and ECG Data
Clinical laboratory variables are listed in Table 4.
For laboratory (hematology, chemistry, urinalysis, and coagulation), vital signs, and ECG 
parameters, changes from baseline are analyzed for each post-baseline visit (as specified 
in Section 7.0 Analysis of Conventions) and the final visit.  If more than one measurement 
exists for a subject on a particular day, an arithmetic average will be calculated.  The 
average will be considered to be the subject's measurement of that day.  
Descriptive statistics will be presented for baseline, each post-baseline, and the final visit 
by each treatment arm.  Mean change from baseline to each post-baseline visit and the 
final visit within each treatment arm will also be presented.  The highest and lowest 
values of each parameter will be identified for each subject, and descriptive statistics for 
mean change from baseline within each treatment arm will be presented.
Laboratory grade determinations will be categorized according to NCI CTCAE 
version 4.0 grades, and shifts from baseline grades to maximum and final post-baseline 
grades will be assessed.  The baseline and final grades will be defined respectively as the 
grade of the last measurement collected prior to or on the first dose of study drug, and as 
the grade of the last post-baseline measurement collected no more than 70 days after the 
last dose of study drug.  Frequency and percentage of subjects will be presented by 
treatment arm:  1) baseline grade vs. maximum post-baseline grades, and 2) baseline 
grade vs. final post-baseline grade.  Frequency and percentage of subjects experiencing a 
shift from baseline grades of 0 to 2 to maximum post-baseline grades of 3 to 4, and from 
baseline grades of 0 to 2 to final post-baseline grades of 3 to 4 will be presented by 
treatment arm.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 biochemistry 
and hematology values will be provided.  All measurements collected, regardless of the 
number of days after the last dose of study drug, will be included in these listings.  A 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
44
listing will be provided for out-of-normal range as well as clinically significant abnormal 
lab values.
Descriptive summary statistics for categorical ECG data will be presented for baseline and 
post-baseline visits; change from baseline in ECG measurements (eg QTcF) will also be 
summarized.  Shift tables will also be provided.
Table 4.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis – Dipstick Only
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands (if indicated)
Lymphocytes
Monocytes
Basophils (if indicated)
Eosinophils (if indicated)
Platelet count (estimate not 
acceptable)
Mean corpuscular volume
Mean corpuscular hemoglobin 
concentration
RBC distribution width
Blood Urea Nitrogen (BUN)
Serum Creatinine
Total bilirubin
Albumin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Total protein
Glucose
Chloride
Magnesium
Amylase
Lipase
Lactate dehydrogenase (LDH)
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Urobilinogen
Bilirubin
Leukocyte esterase
Coagulation
Serum Pregnancy Test
Activated Partial
Thromboplastin Time
(aPTT)
Prothrombin time (PT)
International Normalized Ratio
(INR)
Beta-Human Chorionic 
Gonadotropin (β-hCG) (if 
applicable)
Follicle-stimulating hormone 
(FSH) (if applicable)
12.5
Analysis of 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 will be tabulated.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
45
12.6
Analysis of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Vital signs values will be assessed for potential clinical significance through the 
application of criteria developed by the sponsor as detailed in the table below.
Systolic Blood Pressure
> 150 mmHg and > 20 mmHg higher than baseline 
< 70 mmHg and a decrease of ≥ 30 mmHg from baseline
Diastolic Blood Pressure
> 100 mmHg and higher than baseline 
< 50 mmHg and a decrease of ≥ 20 mmHg from baseline
Pulse Rate
> 120 bpm and an increase of ≥ 30 bpm from baseline 
< 50 bpm and a decrease of ≥ 30 bpm from baseline
Temperature
≥ 38.9°C 
≤ 35.6°C
The number and percentage of subjects with post baseline values meeting Criteria for 
Potentially Clinically Significant Vital Signs values will be summarized.  Except for the 
temperature, subjects who have a baseline measurement and at least one post-baseline 
measurement will be included in the summary.  A separate listing will be provided that 
presents all of the subjects and values that meeting the criteria.  No comparisons of the 
rates of subjects met the above criteria between the treatment arms will be performed.
13.0
References
1.
Armstrong TS, Gning I, Mendoza TR, et al. Clinical utility of the MDASI-BT in 
patients with brain metastases.  J Pain Symptom Manage.  2009;37(3):331-40.
2.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
3.
Brookmeyer R. Crowley J.  A Confidence Interval for the Median Survival Time.  
Biometrics.  1982;38:29-41.
4.
Cox DR.  Regression Models and Life Tables.  Journal of the Royal Statistical 
Society.  Series B.  1972;20:187-220.  With discussion.
5.
Efron B.  The Efficiency of Cox's Likelihood Function for Censored Data.  Journal 
of the American Statistical Association.  1977;72:557-65.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
46
6.
Food and Drug Administration.  Multiple endpoints in clinical trials:  guidance for 
industry.  Food and Drug Administration, College Park, Maryland.  2017.
7.
Fine GD.  Consequences of delayed treatment effects on analysis of time-to-event 
endpoints.  Drug Information Journal.  2007;41(4):535-9.
8.
Fleming TR, Harrington DP.  Counting processes and survival analysis.  
New York:  NY Wiley; 1991.
9.
Major Greenwood, Jr.  The Natural Duration of Cancer.  Reports of Public Health 
and Related Subjects.  Vol. 33, HMSO, London.  1926.
10.
Glimm E, Maurer W, Bretz F. (2010). Hierarchical testing of multiple endpoints in 
group-sequential trials. Stat Med. 2010;29(2):219-28.
11.
Harrington DP, Fleming TR.  A class of rank test procedures for censored survival 
data.  Biometrika.  1982;69(3):553-66.
12.
Hasegawa T. Group sequential monitoring based on the weighted log-rank test 
statistic with the Fleming-Harrington class of weights in cancer vaccine studies. 
Pharm Stat.  2016;15(5):412-9.
13.
Jacobson NS, Truax P.  Clinical significance:  a statistical approach to defining 
meaningful change in psychotherapy research.  J Consult Clin Psychol.  
1991;59(1):12.
14.
Klein JP, Moeschberger ML.  Survival Analysis:  Techniques for Censored and 
Truncated Data.  2nd ed.  New York:  Springer-Verlag; 2003.
15.
Klein JP, Van Houwelingen HC, Ibrahim, JG, Scheike TH, editors.  Handbook of 
Survival Analysis.  CRC Press.  2016
16.
Maurer W.  Multiple comparisons in drug clinical trials and preclinical assays:  a-
priori ordered hypothesis.  Biomed.  Chem.-Pharm. Ind.  1995;6:3-18.
17.
McNair DM, Lorr M, Droppleman LF.  Manual for the Profile of Mood States.  
San Diego, CA:  Educational and Industrial Testing Service, 1992.
18.
Powell TM, Bagnell ME.  Your "survival" guide to using time-dependent 
covariates.  In:  Proceedings of the SAS Global Forum (Vol. 2012, pp. 22 - 25).  
2012.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
47
19.
SAS/STAT® 13.1 User's Guide.  Cary, NC:  SAS Institute Inc; 2013.
20.
Study Protocol M13-813, Amendment 7, dated 29-May-2018.
21.
Su Z, Zhu M.  Is it time for the weighted log-rank test to play a more important role 
in confirmatory trials?.  Contemp Clin Trials Commun.  2018;10:A1-2.
22.
Xu T, Qin Q, Wang X.  Defining information fractions in group sequential clinical 
trials with multiple endpoints.  Contemp Clin Trials Commun.  2018;10:77-9.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
48
Appendix A.
Activities for Arm A (Rovalpituzumab Tesirine)
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to
Day –1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 8 
(± 3 d)
Day 
15
(± 3 d)
Day
22
(± 3 d)
Day
29
(± 
3 d)
Day 
36 
(± 
3 d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visitdd
X
X
X
X
X
Phone Contactdd
X
X
X
X
X
Safety 
Assessments
Informed Consentf
X
Inclusion/Exclusion 
Criteria
X
Medical and 
Surgical History 
Including 
Malignancy 
Historyg
X
Physical 
examinationh
X
X
X
X
Vital Signsi
X
X
X
X
Hematology and 
Serum Chemistryj
X
Xk
X
X


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
49
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to
Day –1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 8 
(± 3 d)
Day 
15
(± 3 d)
Day
22
(± 3 d)
Day
29
(± 
3 d)
Day 
36 
(± 
3 d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Coagulation Testsj
X
Xk
X
Urinalysisj
X
Xk
X
X
Pregnancy Test
X
X
X
Xl
Electrocardiogram 
(ECG)m
X
X
Echocardiogramn
X
X
X
Performance Status 
(ECOG)
X
X
X
Fluid Retention 
Questionnaireo
X
X
X
X
X
X
X
SAE/Adverse 
Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xp
Xp
Xp
Concomitant 
Medications
X
X
X
X
X
X
X
Xp
Xp
Treatment
Rovalpituzumab 
Tesirine
X
Dexamethasone
X
X
X


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
50
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to
Day –1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 8 
(± 3 d)
Day 
15
(± 3 d)
Day
22
(± 3 d)
Day
29
(± 
3 d)
Day 
36 
(± 
3 d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Response 
Assessment
Disease/Response 
Assessment 
(Radiographic 
Imaging)q
X
Xs
Xr
Xs
Xs
Central 
Radiographic 
Assessment 
Committee 
(CRAC) Reviewt
X
X
Xr
X
X
MRI/CT of the 
Brainu
X
Heath Resource 
Utilization
X
X
X
X
Patient Reported 
Outcome (PRO)v
X
X
X
X
X
Survival Status
X


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
51
Screening
Treatment (Cycle 1 and Cycle 2)a
End of 
Treatment 
(EOT)b
PTFUc
Survival 
FU 
(OS)d
Category
Description
Day –28 to
Day –1
Day 
–1
Day 1e
(–3 d)
Day 
2
Day 8 
(± 3 d)
Day 
15
(± 3 d)
Day
22
(± 3 d)
Day
29
(± 
3 d)
Day 
36 
(± 
3 d)
q6/q9 
Weeks 
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
Treatment
q6 
Weeks 
(± 1 
wk)
q9 
Weeks 
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
PK and PD/ 
Biomarker
Pharmacokinetics, 
Anti-therapeutic 
Antibody (ATA) 
and Neutralizing 
Antibodies (nAb)w
X
X
Archived or Fresh 
Tumor Materialx
X
Tumor Material at 
Time of Disease 
Progressiony
X
X
Blood for 
Inflammatory 
Markers and 
ctDNA (10 mL)z
X
Xz
Xz
Blood for Tumor & 
Soluble Markers
(5 mL)z
X
Xz
Xz
Circulating Tumor 
Cells (10 mL)aa
X
X
X
Pharmacogenetics 
(DNA/RNA)bb
Xbb
X
Serosal Fluidcc
Day 1 through 70 days after last study treatment


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
52
a.
Up to two additional cycles of rovalpituzumab tesirine may be permitted for subjects in Arm A meeting criteria as described in Protocol Section 5.3.1.1.  Subjects receiving 
additional doses of rovalpituzumab tesirine will follow the same study schedule as in Cycles 1 and 2. 
b.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.  Subjects in 
Arm A should be evaluated for eligibility of two additional doses of rovalpituzumab tesirine prior to proceeding with EOT procedures.
c.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated.  
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits may be performed within 3 business days prior to the 
visit.  Disease/Response Assessment and CRAC Review may be performed within 7 days prior to the Day 1 visit unless otherwise indicated.
f.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window for 
DLL3 testing.
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.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.
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 actual 
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 (including C1D1).
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 in the Protocol for details.
k.
The clinical laboratory tests performed at Screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1 of each cycle, at the EOT Visit, and during the PTFU period until 6 months 
after the last dose of study drug.  Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined in Protocol Section 5.2.4 at 
Screening do not require pregnancy testing.  Post-menopausal female subjects ≤ 55 years of age must have a FSH level > 40 IU/L and will have FSH performed at Screening 
and assessed by the investigator.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
53
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 3 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 J, Fluid Retention Questionnaire in the Protocol).  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 Day 1 (during the treatment 
period for Arm A) 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 scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study.
r.
May be omitted if assessment was performed within the preceding 6 weeks.
s.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.  If the subject qualifies to 
receive 2 additional cycles of Rova-T, radiographic assessments will continue to occur every 6 weeks for the first 30 weeks and then every 9 weeks until second progression 
or death.
t
Site will collect the appropriate scans and submit to the central facility at each subject's disease assessment.  
u.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
v.
PRO assessments are required at Screening, before infusion on Day 1 of each cycle starting C2D1, Day 22 of each cycle, EOT, and PTFU (if applicable). 
w.
At each cycle, 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 business days window is permitted) and the second sample will be collected 30 minutes 
(± 10 minutes) post-infusion.  Only one collection will be required at the EOT visit.  The date and time of each sample collected will be recorded to the nearest minute.
x.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT. 


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
54
y.
An optional tumor biopsy may be obtained at the time of disease progression, from subjects who consent to undergo biopsy procedure.  Informed consent is 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.
z.
On Day 1 (–3 business days window is permitted) of each cycle, the collection of blood for inflammatory markers, ctDNA, tumor and soluble markers will be pre-infusion.  A 
sample will also be collected once at the EOT or at the time of disease progression.
aa.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1 and Cycle 3 Day 1 (if applicable).  –3 business days window is 
permitted.  Sample will also be collected at the EOT.  CTCs implemented only at specific sites based on feasibility.
bb. Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogentic sample to be collected on Day 1 of Cycle 1 only and is 
collected pre-infusion (–3 business days window is permitted).
cc.
Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) must be procured 
for testing, for any AE starting from C1D1 through 70 days after the last study treatment.  Collected fluid must also be tested centrally and/or locally for cytology if disease 
progression due to appearance/worsening of effusion is suspected.
dd. Procedures for visits where no treatment is administered and phone contacts from Day 8 to Day 36 of each cycle may be performed within ± 3 day window relative to the due 
date.  Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and 
pericardial), peripheral edema, cutaneous reactions (e.g., photosensitivity).


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
55
Appendix B.
Study Activities for Arm B (Topotecan)
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 
1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 8
(± 3 d)
Day 
15
(± 3 d)
q6/q9 
Weeks
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks
(± 1 
wk)
q9 
Weeks
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Location
Clinic Visit
X
X
X
X
X
X
X
X
Phone Contacty
X
X
X
Screening, 
Baseline, 
and Safety 
Assessments
Informed Consente
X
Inclusion/Exclusion 
Criteria
X
Medical and Surgical 
History Including 
Malignancy Historyf
X
Physical 
examinationg
X
X
X
Vital Signsh
X
X
X
Hematology and 
Serum Chemistryi
X
Xj
X
Coagulation Testsi
X
Xj


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
56
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 
1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 8
(± 3 d)
Day 
15
(± 3 d)
q6/q9 
Weeks
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks
(± 1 
wk)
q9 
Weeks
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Urinalysisi
X
Xj
Pregnancy Testk
X
X
X
X
Electrocardiogram 
(ECG)–l
X
X
Echocardiogram
X
Xm
X
Performance Status 
(ECOG)
X
X
X
Fluid Retention 
Questionnairen
X
X
X
X
SAE/Adverse Events
SAE/Procedure-
related only
X
X
X
X
X
X
X
Xo
Xo
Xo
Concomitant 
Medications
X
X
X
X
X
X
X
Xo
Xo
Xo
Treatment
Topotecan
X
X
X
X
X


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
57
Screening
Treatment (Each Cycle)
End of 
Treatment 
(EOT)a
PTFUb
Survival 
FU 
(OS)c
Category
Description
Day –28 to 
Day –1
Day 
1d
(–3 d)
Day 
2
Day 
3
Day 
4
Day 
5
Day 8
(± 3 d)
Day 
15
(± 3 d)
q6/q9 
Weeks
(± 1 
wk)
Within 
7 Days of 
Decision to 
Discontinue 
tx
q6 
Weeks
(± 1 
wk)
q9 
Weeks
(± 1 
wk)
q6 
Weeks 
(± 1 wk)
Response 
Assessment
Disease/Response 
Assessment 
(Radiographic 
Imaging)p
X
Xr
Xq
Xr
Xr
Central Radiographic 
Assessment 
Committee (CRAC) 
Reviews
X
X
Xq
X
X
MRI/CT of the Brain
Xt
Heath Resource 
Utilization
X
X
X
Patient Reported 
Outcome (PRO)u
X
X
X
X
Survival Status
X
PD/ 
Biomarker
Archived or Fresh 
Tumor Materialv
X
Circulating Tumor 
Cells (10 mL)w
X
X
X
Pharmacogenetics 
(DNA/RNA)x
Xx
X
a.
EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-cancer therapy if possible.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
58
b.
For subjects who discontinue investigational product for reasons other than disease progression, the first PTFU 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.
c.
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).
d.
Procedures performed at Screening (with the exception of vital signs) do not need to be repeated if performed within 28 days of randomization unless clinically indicated.  
Randomization may occur within 3 calendar days prior to C1D1.  Starting at C2D1, study assessments for Day 1 visits 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 unless otherwise indicated.
e.
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 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 28-day screening window.  Informed 
consent is also required for the optional tumor biopsy at time of disease progression.
f.
Medical and Surgical History includes demographics and documentation of clinically significant medical condition, surgical history, and malignancy history.
g.
Height will be collected at the Screening visit only.  For height assessments, the subject should not wear shoes.  The physical examination performed at screening does not 
need to be repeated on CID1 if performed within 7 days of C1D1.
h.
Vital sign determinations include weight, sitting blood pressure, heart rate and body temperature.  Weight will be collect prior to dosing at each cycle and recorded actual 
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 (including C1D1).
i.
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 in the Protocol for details.
j.
The clinical laboratory tests performed at screening do not need to be repeated on C1D1 if performed within 7 days of C1D1 and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 business days prior to Day 1 visits.
k.
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 investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1, at the EOT visit, and during the PTFU period until 1 month after the last 
dose of study drug.  Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined in Protocol Section 5.2.4) at Screening do not 
require pregnancy testing.  Post-menopausal female subjects ≤ 55 years of age must have a FSH level > 40 IU/L and will have FSH performed at Screening and assessed by 
the investigator.
l.
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.


Rovalpituzumab Tesirine
M16-289 (TAHOE) – Statistical Analysis Plan
Version 1.0 – 13 Mar 2020
59
m.
Screening echocardiogram will be performed within 3 business days of randomization and results should be available prior to randomization to assess for the presence of any 
pericardial effusion as swell as cardiac function (left ventricular ejection fraction, LVEF).  Echocardiogram will then be performed every 6 weeks at alternating cycles starting 
C2D1 (–3 business days window is permitted).  Additional Echocardiogram monitoring may occur as clinically indicated during the study.
n.
Subjects will be asked about the development of any new or worsening peripheral edema or dyspnea (Appendix J, Fluid Retention Questionnaire in the Protocol).  
Assessments will occur Cycles 1 – 4.  On Days 8 and 15, assessments may take place by phone, with the site contacting the subject and reviewing the questionnaire.  Starting 
Day 1 and through the EOT visit, subjects will maintain a diary of daily weights (captured on the Fluid Retention Questionnaire).
o.
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.
p.
Diagnostic quality, spiral CT scans are recommended; other CT methods or MRI may be used if performed consistently throughout the study for each individual subject.  
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 radiographical assessment and any new findings communicated to the 
Investigator prior to the next dose of investigational product.  Effusions should contribute to disease status only if confirmed malignant by cytology.  Scheduled tumor 
assessments will not be affected by delays in therapy and/or drug holidays.  Subjects will continue to be monitored by the same diagnostic method throughout the study. 
q.
May be omitted if previous assessment was performed within the preceding 6 weeks.
r.
Radiographic assessments will occur every 6 weeks (± 1 week) for the first 30 weeks then every 9 weeks (± 1 week) until progression or death.
s.
Site will collect the appropriate scans and or submit to the central facility at each subject's disease assessment.  
t.
MRI/CT of the brain is required at screening.  Subsequent MRI/CT of the brain post screening is required only when clinically indicated (e.g., CNS metastasis history and if 
CNS progression is suspected).
u.
PRO assessments are required at Screening, before infusion on Day 1 of each cycle, EOT, and PTFU (if applicable).
v.
Tumor material must be collected to confirm DLL3 expression.  Subjects that provide consent for DLL3 testing at any time after initial diagnosis must be registered in IRT.
w.
Whole blood sample will be collected for CTC analysis during screening and pre-dose on Cycle 1 Day 1 and Cycle 3 Day 1 (if applicable).  –3 business day window is 
permitted.  Sample will also be collected at the EOT.  CTCs implemented only at specific sites based on feasibility.
x.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogenetic sample to be collected on Day 1 of Cycle 1 only and 
is collected pre-infusion (–3 business days window is permitted).
y.
Procedures for visits where no treatment is administered phone contacts for Day 8 and Day 15 of each cycle may be performed within ± 3 day window relative to the due date.  
Procedures will include symptom review for presence of neurotoxicity, neutropenic colitis, fever, interstitial lung disease, serosal effusions (including pleural and pericardial), 
peripheral edema, cutaneous reactions (e.g., photosensitivity).