Clinical trial NCT02963090
Conditions: Small Cell Lung Cancer
Keywords: SCLC small cell lung cancer lung cancer topotecan pembrolizumab
Sponsor: Alliance Foundation Trials, LLC.
Start date: 2017-05-20; Completion date: 2019-08-20
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multi-institutional, randomized, open-label phase II study of pembrolizumab compared to topotecan, administered to patients with SCLC who have progressed or relapsed after first-line treatment with etoposide and platinum. Patients will be randomized in a 2:1 fashion to receive pembrolizumab or topotecan. Participants in the topotecan arm that progress will be allowed to cross-over to the pembrolizumab arm.

Detailed description:
Patients who meet the eligibility criteria and are randomized to one of the treatment arms, will receive either topotecan alone intravenously at 1.25 mg/m2 on days 1 to 5 of a 21-day cycle or pembrolizumab alone administered intravenously at 200mg every 21 days.

During the study period, patients will be evaluated clinically by physical exam and with routine blood work every 21 days. Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. Pre-specified adverse events of clinical interest include: 1) Grade ≥ 2 diarrhea, 2) Grade ≥ 2 colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 2 hepatitis 5) Grade ≥ 3 hypo- or hyperthyroidism.

Patients will be evaluated every 6 weeks (42 ± 7 days) with radiographic imaging to assess response to treatment. Investigators will make all treatment-based decisions using RECIST 1.1. Patients will continue to receive topotecan or pembrolizumab every three weeks until documented disease progression, unacceptable side effects, intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the patient, patient withdraws consent, pregnancy of the patient, non-compliance with trial treatment or procedure requirements or administrative reasons. Patients on the topotecan arm who progress on study will be allowed to cross-over to the pembrolizumab arm.

After the end of treatment, each patient will be followed for a minimum of 30 days for adverse event monitoring. Serious adverse events will be collected for up to 90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier. Immune related serious adverse events will be followed for 90 days after end of treatment. Subjects who discontinue treatment for reasons other than disease progression will have posttreatment follow-up every 6 weeks for disease status until progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed by telephone contact every 3 months for overall survival until death or withdrawal of consent.

Although subjects will be enrolled regardless of PD-L1 status, subjects will be required to provide tissue of a tumor lesion (either archived tissue or a new biopsy before initiating therapy). Tumor samples will be required before initiating therapy (preferably a new specimen) and a repeat biopsy will be performed, if clinically feasible, on-treatment (during weeks 4 to 6) for those in the pembrolizumab arm and at the time of disease progression for those in the topotecan arm. PD-L1 expression status by immunohistochemistry will be determined on tumors at baseline, on treatment and at the time of topotecan progression. Numerous other correlative studies also will be performed, as outlined below. Peripheral blood mononuclear cell samples will be collected at screening, at day 1 of cycles 1, 2 and 3, and at the time of each imaging study (while on study), for characterization of T-cell phenotypes to understand how changes may correlate with clinical response.

Arms: arm 1: Topotecan IV at 1265mg/m\^2 Days 1-5 of every 21 day cycle arm 2: Pembrolizumab IV 200mg infusion Day 1 of every 21 day cycle
Interventions: intervention 1: Topotecan intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Topotecan at 1.25mg/m2 on days 1 to 5 every 21-days until progression of disease or unacceptable toxicities.

Patients with progression of disease by RECIST 1.1 will be allowed cross over to receive pembrolizumab 200 mg IV every 21-days for up to 1 year until progression of disease or unacceptable toxicities. intervention 2: 200 mg IV every 21-days until progression of disease or unacceptable toxicities.

Protocol documents:
Prot_SAP_001.pdf: 
 
Version Date 01/26/2017 
 
 
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1 
ALLIANCE FOUNDATION TRIALS (AFT) 
 
PROTOCOL NUMBER 
AFT – 17  
 
A Randomized Phase II Study Evaluating Pembrolizumab vs Topotecan in the Second-
line Treatment of Patients with Small Cell Lung Cancer   
Protocol Version: # 4.0 
 
Protocol Version Date: 01/26/2017 
 
Investigational Agent: Pembrolizumab 
IND Sponsor: Alliance for Clinical Trials in Oncology 
IND#: 131442 
Investigational Agent Supplier: Merck 
 
ClinicalTrials.gov Identifier: NCT02963090 
 
Study Chair 
Thomas Stinchcombe, MD 
Duke University Medical Center 3476 
30 Medical Center Circle 
25177 Morris Building 
Durham, NC 27710 
Tel: 
  
 
 
Sponsor Principal Investigator  
 Monica M. Bertagnolli, MD  
Alliance Foundation Trials 
221 Longwood Avenue Room 108 
Boston, MA 02115 
Tel: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Study Resources 
 
Adverse Event Reporting 
via Medidata Rave iMedidata Portal  
accessible via the AFT website, https://alliancefoundationtrials.org/ 
IRT – Randomization System 
accessible via the AFT website, https://alliancefoundationtrials.org/ 
Site Zone 
https://sitezone.mywingspan.com/sitezone/trials 
accessible via the AFT website, https://alliancefoundationtrials.org/ 
For Site Zone Help:
 
BiOMS AFT Resource Site 
https://cbmiapps.wustl.edu/confluence/x/TaETAO 
 
 
Protocol Contacts 
 
Alliance Foundation Trials Project Manager 
Andrew Morrison 
221 Longwood Avenue 
Boston, MA 02115 
Tel: 
 
 
Alliance Foundation Trials Biorepository at 
Washington University 
c/o Siteman Cancer Center Tissue 
Procurement Core 
425 S. Euclid Avenue 
BJCIH Building, Room 5120 
St. Louis, MO 63110-1005 
Tel: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document contains confidential information of Alliance Foundation Trials, LLC. The information in this document cannot be 
used for any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of Alliance 
Foundation Trials, LLC.  


 
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1. SYNOPSIS 
1.1. STUDY SUMMARY 
Abbreviated Title 
Pembrolizumab vs Topotecan in the Second-line Treatment of 
Patients with Small Cell Lung Cancer 
Study Phase 
Randomized Phase II 
Clinical Indication 
Small cell lung cancer (SCLC) patients in need of second-line 
therapy after standard platinum/etoposide chemotherapy.  
Study Type 
Interventional 
Type of Control 
Active control without placebo 
Route of Administration 
Intravenous 
Study Blinding 
Unblinded open-label 
Treatment Groups  
Topotecan every 3 weeks until progression of disease; at which 
point, patients can cross over to the pembrolizumab arm.  
 
Pembrolizumab 200mg every 3 weeks until progression of disease 
or up to 24 months, whichever occurs first.  
Number of Study Patients 
Approximately 98 patients will be enrolled at an anticipated 10 
sites.  
Estimated Duration of Study 
Approximately 19 to 23 months to accrue and enroll the patients, 
with an additional 6 months of follow-up to observe events for the 
primary endpoint of progression free survival after the last patient 
is started on study; we have included an additional 6 months to 
allow patients responding on study drug to remain on protocol. 
Subject Eligibility 
Patients with sensitive or refractory disease will be eligible for the 
study; where sensitive disease will be defined as those patients 
with disease progression after treatment with standard first-line 
etoposide/platinum ≥60 days from completing chemotherapy, and 
refractory disease will be defined as patients with disease 
progression < 60 days from completing chemotherapy.  Patients 
with treated brain metastases will be eligible.  Patients with 
underlying or previous paraneoplastic syndromes are not eligible.   
Study Objectives 
The primary endpoint is to determine if there is an improvement in 
progression free survival for SCLC patients treated with 
pembrolizumab compared to topotecan.  RECIST 1.1 will be used 
for this analysis. 
 
Secondary endpoints will include safety, objective response rate 
by RECIST 1.1, and overall survival.  Exploratory endpoints based 
on correlative studies will be assessed.   
Study Design 
This is a multi-institutional, randomized, open-label phase II study 
of pembrolizumab compared to topotecan, administered to patients 
with SCLC who have progressed or relapsed after first-line 
treatment with etoposide and platinum. Patients will be randomized 
in a 2:1 fashion to receive pembrolizumab or topotecan. 
Participants in the topotecan arm that progress will be allowed to 
cross-over to the pembrolizumab arm.  
  
Study Treatment Plan 
Pembrolizumab Arm: Pembrolizumab will be administered via IV 
infusion at 200 mg every 3 weeks, and treatment continued for up 
to 
24 
months, 
until 
documented 
disease 
progression, 
unacceptable side effects or intercurrent illness that prevents 
further administration of treatment, investigators’ decision to 


 
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withdraw the subject, subject withdraws consent, pregnancy of the 
patient, noncompliance of the patient, or for administrative 
reasons.  
 
Topotecan Arm: Topotecan will be administered via IV infusion at 
1.25 mg/m2 on days 1 to 5 of a 3-week cycle.  Pegfilgrastim may 
be given on day 6, 7, or 8 to offset neutropenia.  Patients who 
progress in the topotecan arm will be allowed to cross-over to the 
pembrolizumab arm.  
 
Efficacy Assessments 
Patients will be evaluated every 6 weeks (42 ± 7 days) with 
radiographic 
imaging 
to 
assess 
response 
to 
treatment.  
Investigators will make all treatment-based decisions using RECIST 
1.1.   
 
Safety Assessments 
Patients will be evaluated clinically by physical exam and with 
routine blood work every 21 days.  Adverse events will be monitored 
throughout the Study and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.   
Laboratory/Correlative Study 
Assessments 
Tumor samples will be required at study entry.  Although subjects 
will be enrolled regardless of PD-L1 status, subjects will be 
required to provide tissue of a tumor lesion (either archived tissue 
if sample was obtained no more than 42 days prior to signing 
consent or a new biopsy before initiating therapy).  Patients in the 
pembrolizumab arm will undergo a repeat biopsy while on 
treatment, if clinically feasible, during weeks four to six after 
initiating treatment.  Those patients on the topotecan arm that 
progress and cross-over to receive pembrolizumab will undergo a 
biopsy, if clinically feasible, before initiating the new treatment.   
 
Tissue-based correlative studies will be performed, including and 
not limited to, immunohistochemistry to evaluate expression of PD-
L1 and immune cell markers, whole exome sequencing for 
evaluation of mutational burden and the neoantigen landscape, 
and 
transcriptome 
analyses 
of 
the 
tumor 
and 
immune 
microenvironment. Peripheral blood cell/serum plasma samples for 
correlatives will be collected for all patients at screening, at week 4-6 
biopsy, at imaging during all cycles, and at progression/cross-overfor 
characterization of T-cell phenotypes to understand how changes 
may correlate with clinical response. 
Study Follow-Up 
After the end of treatment, each patient will be followed for a 
minimum of 30 days for adverse event monitoring. Serious 
adverse events will be collected for up to 90 days after the end of 
treatment or 30 days after the end of treatment if the subject 
initiates new anticancer therapy, whichever is earlier.  Subjects 
who discontinue treatment for reasons other than disease 
progression will have post-treatment follow-up every 6 weeks for 
disease status until progression, initiating a non-study cancer 
treatment, withdrawing consent, or becoming lost to follow-up.  All 
subjects will be followed by telephone contact every 12 weeks for 
overall survival until death or withdrawal of consent. 
 
 


 
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1.2. STUDY SCHEMA (FIGURE 1) 
 
 
 
*:With allowance of 5% ineligible, cancelling and unevaluable, the study plans to register 98 
patients, and randomize 93.  
 
Patients who progress on the topotecan arm may cross-over to receive treatment with 
pembrolizumab. 
 
Treatment is to continue for up to 24 months post-randomization or until disease progression on 
pembrolizumab or an unacceptable adverse event. 
 
Patients will be followed until death. 
 
Please refer to the full protocol text for a complete description of the eligibility criteria 
and treatment plan. 
 
 


 
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2. TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................... 3 
1.1. Study Summary ............................................................................................................ 3 
1.2. Study Schema (Figure 1) .............................................................................................. 5 
2. 
TABLE OF CONTENTS .................................................................................................. 6 
3. 
BACKGROUND ..............................................................................................................10 
3.1. Small Cell Lung Cancer................................................................................................10 
3.2. PD1 Pathway: Pharmaceutical and Therapeutic Background .......................................11 
3.3. Study Design and Intervention .....................................................................................12 
3.3.1. 
STUDY DESIGN AND INTERVENTION ....................................................................12 
3.3.2. 
INTERVENTION ........................................................................................................14 
4. 
RATIONALE ...................................................................................................................15 
4.1. Rationale for the Study and Selected Patient Population..............................................15 
4.1.1. 
THE IMMUNE SYSTEM IN SMALL CELL LUNG CANCER AND IMMUNE 
CHECKPOINT BLOCKADE .....................................................................................................15 
4.1.2. 
COMPLEX MOLECULAR LANDSCAPE OF SMALL CELL LUNG CANCER AND 
OPPORTUNITY FOR IMMUNOTHERAPY ...............................................................................15 
4.1.3. 
RATIONALE FOR USE OF PEMBROLIZUMAB IN SMALL CELL LUNG CANCER 
IN THE SECOND LINE SETTING .............................................................................................16 
4.2. Rationale for Dose Selection/Regimen/Modification .....................................................16 
4.2.1. 
PEMBROLIZUMAB AND RATIONALE FOR ITS DOSE SELECTION ......................16 
4.2.2. 
TOPOTECAN AND RATIONALE FOR ITS DOSE SELECTION ...............................17 
5. 
RATIONALE FOR ENDPOINTS .....................................................................................18 
5.1. Efficacy endpoints ........................................................................................................18 
5.1.1. 
PRIMARY ..................................................................................................................18 
5.1.2. 
SECONDARY............................................................................................................18 
5.2. Exploratory endpoints; Biomarkers of Response to immune Checkpoint Inhibitors.......19 
5.2.1. 
PD-L1 TUMOR EXPRESSION ..................................................................................19 
5.2.2. 
SMOKING STATUS, SMOKING-RELATED GENOTOXICITY, AND MUTATION 
BURDEN 19 
5.2.3. 
FUTURE BIOMEDICAL RESEARCH ...............ERROR! BOOKMARK NOT DEFINED. 
6. 
OBJECTIVES .................................................................................................................21 
6.1. Primary Objective .........................................................................................................21 
6.2. Secondary Objectives ..................................................................................................21 
6.3. Exploratory Objectives .................................................................................................22 
7. 
PATIENT SELECTION ...................................................................................................23 
7.1. Inclusion Criteria ..........................................................................................................23 
7.2. Exclusion Criteria .........................................................................................................24 
8. 
PATIENT ENROLLMENT ...............................................................................................26 
8.1. Site enrollment Requirements ......................................................................................26 
8.2. Patient enrollment Requirements .................................................................................26 
8.3. Patient screening, enrollment/Randomization Procedures ...........................................26 
8.4. stratification factors and treatment assignments ...........................................................27 


 
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9. 
SCHEDULE OF ASSESSMENTS ...................................................................................28 
9.1. Schedule of Assessments ............................................................................................28 
9.2. Tumor Imaging Schedule .............................................................................................34 
10. 
TREATMENT PLAN .......................................................................................................35 
10.1. Study Treatments .........................................................................................................35 
10.2. Dose Selection and Preparation ...................................................................................35 
10.2.1. 
TIMING OF DOSE ADMINISTRATION .....................................................................36 
10.2.2. 
PEMBROLIZUMAB ...................................................................................................36 
10.2.3. 
TOPOTECAN ............................................................................................................36 
11. 
DATA AND SPECIMEN SUBMISSION, STUDY PROCEDURES ...................................36 
11.1. Data Collection and Submission ...................................................................................36 
12. 
BIOSPECIMEN COLLECTION .......................................................................................36 
12.1. Biospecimen Collection Schema ..................................................................................37 
13. 
CORRELATIVE STUDIES ..............................................................................................38 
13.1. Immunohistochemistry Evaluation ................................................................................38 
13.2. Whole Exome Sequencing of Tumor and Matched Normal for Evaluation of Mutational 
Burden and Neoantigen Landscape ......................................................................................38 
13.3. Transcriptome Analyses ...............................................................................................39 
13.4. Peripheral Blood Based Studies ...................................................................................39 
13.5. T Cell Receptor Sequencing ........................................................................................40 
14. 
DOSE AND TREATMENT MODIFICATIONS (ESCALATION/TITRATION/OTHER), 
CONCOMITANT MEDICATIONS, SUPPORTIVE CARE ..........................................................41 
14.1. Dose Modification.........................................................................................................41 
14.1.1. 
PEMBROLIZUMAB (MK-3475) DOSE MODIFICATION ...........................................41 
14.1.2. 
TOPOTECAN DOSE MODIFICATION ......................................................................43 
14.2. Concomitant medications/vaccinations (allowed & Prohibited) .....................................44 
14.2.1. 
ACCEPTABLE CONCOMITANT MEDICATIONS .....................................................44 
14.2.2. 
PROHIBITED CONCOMITANT MEDICATIONS .......................................................45 
14.3. Rescue medications and Supportive Care ...................................................................46 
14.3.1. 
SUPPORTIVE CARE GUIDELINES FOR PEMBROLIZUMAB .................................46 
14.3.2. 
SUPPORTIVE CARE GUIDELINES FOR PNEUMONITIS ........................................48 
14.3.3. 
SUPPORTIVE CARE GUIDELINES FOR EVENTS OF CLINICAL 
INTEREST/IMMUNE RELATED ADVERSE EVENTS (IRAES) ................................................49 
14.3.4. 
SUPPORTIVE CARE GUIDELINES FOR EVENTS OF CLINICAL 
INTEREST/IMMUNE RELATED ADVERSE EVENTS (IRAES) ................................................50 
14.4. Other considerations ....................................................................................................51 
14.4.1. 
CONTRACEPTION ...................................................................................................51 
14.4.2. 
USE IN PREGNANCY ...............................................................................................52 
14.4.3. 
USE IN NURSING WOMEN ......................................................................................53 
15. 
MEASUREMENT OF EFFECT .......................................................................................53 
This randomized phase II Study will evaluate PFS as the primary endpoint based on RECIST 
1.1,29 which will be used for assessment of tumor response..................................................53 
15.1. Schedule of Evaluations ...............................................................................................53 
15.2. Response for Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors ....................................................................................................54 
15.2.1. 
RESPONSE FOR EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 
CRITERIA FOR EVALUATING RESPONSE IN SOLID TUMORS ...........................................54 
15.2.2. 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ............................54 


 
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Measurement Methods: ......................................................................................................54 
Acceptable Modalities for Measurable Disease: ...............................................................55 
Measurement at Follow-up Evaluation: .............................................................................55 
Non-Target Lesions & Non-Target Lymph Nodes .............................................................56 
15.2.3. 
RESPONSE CRITERIA .............................................................................................56 
Definitions of analysis variables ............................................................................................58 
16. 
END OF TREATMENT/INTERVENTION ........................................................................58 
16.1. Duration of Treatment ..................................................................................................58 
16.1.1. 
CR, PR OR SD ..........................................................................................................58 
16.1.2. 
DISEASE PROGRESSION .......................................................................................58 
16.1.3. 
DISCONTINUATION OF STUDY AGENT .................................................................58 
16.2. Patient Withdrawal/Discontinuation Criteria ..................................................................58 
16.2.1. 
PATIENT WITHDRAWAL .........................................................................................58 
16.3. Definitions and Follow-up Requirements ......................................................................59 
16.4. Follow up for ineligible patients ....................................................................................60 
16.5. Follow-Up for Patients Never Receiving Protocol Intervention ......................................60 
17. 
ADVERSE EVENTS .......................................................................................................60 
17.1. Routine Adverse Event Reporting ................................................................................61 
17.2. Expedited Adverse Event Reporting .............................................................................61 
17.2.1. 
SERIOUS ADVERSE EVENT (SAE) .........................................................................61 
17.2.2. 
EVENTS OF CLINICAL INTEREST AND IMMUNE RELATED ADVERSE EVENTS 63 
17.2.3. 
PROTOCOL-SPECIFIC EXCEPTIONS TO SERIOUS ADVERSE EVENT 
REPORTING ............................................................................................................................64 
17.2.4. 
DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL AND REPORTING OF 
OVERDOSE TO AFT ................................................................................................................64 
17.2.5. 
REPORTING OF PREGNANCY AND LACTATION ..................................................64 
17.3. Evaluating Adverse Events ..........................................................................................65 
18. 
DRUG INFORMATION ...................................................................................................69 
18.1. Investigational Product .................................................................................................69 
18.2. Packaging and Labeling Information ............................................................................69 
18.3. Clinical Supplies Disclosure .........................................................................................69 
18.4. Storage and Handling Requirements............................................................................69 
18.5. Returns and Reconciliation ..........................................................................................69 
19. 
STATISTICAL CONSIDERATIONS ................................................................................70 
19.1. Sample Size Justification .............................................................................................70 
19.2. Accrual and Follow-Up .................................................................................................71 
19.3. Adverse Events Monitoring ..........................................................................................71 
20. 
STATISTICAL ANALYSIS PLAN ...................................................................................71 
21. 
GENERAL REGULATORY CONSIDERATIONS ............................................................72 
21.1. Compliance with Study Enrollment and Results Posting Requirements ........................72 
21.2. Regulatory and Ethical Compliance .............................................................................72 
21.3. Ethics and Good Clinical Practice ................................................................................72 
21.4. Confidentiality ..............................................................................................................73 
21.5. Protocol Amendments ..................................................................................................73 
21.6. Informed Consent.........................................................................................................73 
21.7. Monitoring and Remote Monitoring ..............................................................................74 
21.8. Financial Disclosure .....................................................................................................74 
21.9. Protocol Deviations ......................................................................................................75 


 
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21.10. 
Retention of Records .............................................................................................75 
21.11. 
Clinical Criteria for Early Study Administration .......................................................75 
22. 
LIST OF REFERENCES .................................................................................................76 
23. 
APPENDICES.................................................................................................................79 
23.1. APPENDIX I: ECOG Performance Status ....................................................................80 
Ecog Performance Status .....................................................................................................80 
23.2. APPENDIX II: Plan to be utilized should a potentially actionable incidental finding be 
identified in the course of research conducted on samples collected under this protocol .......81 
24. 
APPROVAL SIGNATURES ............................................................................................82 
APPROVAL SIGNATURES ......................................................................................................82 
 


 
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3. BACKGROUND 
3.1. SMALL CELL LUNG CANCER 
Small cell lung cancer (SCLC) remains a worldwide public health problem.  In the 
United States, the decrease in prevalence of tobacco use has resulted in a gradual 
decrease in SCLC incidence over the past decade; nonetheless, SCLC remains a 
major cause of cancer mortality, currently accounting for 14% of all lung cancers, or 
approximately 30,000 patients annually. 1,2 Tobacco exposure is strongly associated 
with the development of SCLC, with only 2 to 3% of patients being never-smokers. 3,4 
 
Compared to non-small cell lung cancer (NSCLC), SCLC has a unique natural history 
with a shorter doubling time, higher growth fraction, earlier development of widespread 
metastases, and uniform initial response to chemotherapy and radiation. Outcomes for 
SCLC have not changed dramatically as the majority of patients, including those with 
limited-stage disease and those initially responsive to chemotherapy and radiation, 
develop chemoresistance. As a result, overall five year survival rates are a dismal 6%. 
1,2 
 
First line treatment for SCLC involves combination chemotherapy with cisplatin or 
carboplatin plus etoposide (with the addition of radiation therapy in limited stage), 
which results in a 60-80% overall response rate.  However, all patients with extensive 
stage SCLC, and the majority of patients with limited SCLC, suffer relapse within 
months of completing initial therapy.  The strongest predictor of outcome for patients 
with relapsed disease is the duration of response.  Patients who maintain an 
appropriate response to initial therapy for 3 months or more are deemed “sensitive”.  
These patients have a higher likelihood of response to second-line chemotherapy, 
though at best it is half that expected in the first-line setting, and their survival 
averages around 6 months.  Patients with “refractory” disease either had no response 
to initial therapy, or progressed within 3 months after completing treatment.  Their 
chance of response to second-line therapy is less than 10%, and survival is 3 to 4 
months.5  
 
Single agent topotecan or CAV (cyclophosphamide, doxorubicin and vincristine) are 
appropriate treatment regimens for patients with sensitive relapse.  A randomized trial 
comparing topotecan to CAV showed a response rate of 24% for topotecan and 18% 
for CAV, which was not statistically significant, with median survival of 6 months for 
both.6  In this study, sensitive disease was defined as relapse more than 60 days (or 2 
months) after the completion of first line chemotherapy.  This study led to the U.S. 
Food and Drug Administration’s approval of intravenous topotecan with an indication 
for sensitive relapsed SCLC (> 60 days from completion of first line treatment).   
 
In three single arm phase II studies, topotecan was studied in patients with recurrent or 
progressive SCLC after treatment with first line chemotherapy.  The three studies 
stratified patients for sensitive disease (response to initial therapy for   90 days) or 
refractory disease (no response to initial therapy, or progression within 90 days after 
completing treatment) and included patients with stable brain metastases.7-9  The 
European Organization for Research and Treatment of Cancer study reported a 21.7% 
overall response rate (37.8% among sensitive patients, 6.4% among refractory 
patients) and a 33-week median duration of response.7  Depierre et al. showed a 14% 
response rate (median survival, 25.7 weeks) in sensitive patients and a 2% response 


 
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rate (median survival, 16.3 weeks) in refractory patients.9  In the third study, the 
response rates were similar - 19% (median survival, 26.6 weeks) and 3% (median 
survival, 20.4 weeks) for patients with sensitive and refractory disease, respectively.8  
A pooled analysis of the sensitive patients treated with second-line topotecan in these 
three SCLC studies reported an 18% response rate.10    
 
Oral topotecan was compared to intravenous topotecan  in a randomized phase III trial 
and was found to have similar activity in patients with chemotherapy sensitive 
disease45 beneficial in both sensitive and refractory disease patients, In a phase III trial 
oral topotecan was compared to best supportive care in patients with both 
chemotherapy sensitive and refractory disease, and  with a partial response of 7% and 
prolonged overall survival at 26 weeks was observed with topotecan compared to 
overall survival of 14 weeks with best supportive care.   Currently, intravenous and oral 
topotecan remain the only drug approved for second-line treatment of SCLC. 
Although the initial studied dose of intravenous topotecan is 1.5 mg/m2, the agent has 
been evaluated at a lower dose of 1.25 mg/m2 on days 1 to 5 of an every 21-day 
cycle.12,13  
 
The prognosis for patients with recurrent SCLC is poor, especially for those with 
refractory disease.  As few options exist, there is a clear need for new therapeutic 
agents.   
 
3.2. PD1 PATHWAY: PHARMACEUTICAL AND THERAPEUTIC BACKGROUND 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.14 Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies.15-18 Additionally, the presence of CD8+ T-
cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
Notably, effector T cells are significantly higher in the peripheral blood of patients with 
limited stage SCLC compared to those with extensive stage SCLC and in long term 
disease-free survivors relative to those with recurrent disease. 19 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control. 20  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.20  PD-1 (encoded by 
the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has 
been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD-L2).21 The structure of murine PD-1 has been resolved.22 
PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail 
which is responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-
1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).21  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-
2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-
cell signaling cascade. 23-25 The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from CTLA-4 as both molecules regulate an 


 
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overlapping set of signaling proteins. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells.20 Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  
 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors.16,26 Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits 
T-cell activation triggered through the T-cell receptor.16  PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found 
in lymphoid tissue or chronic inflammatory environments.16  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen 
unwarranted T-cell function in peripheral tissues. Although healthy organs express little 
(if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of 
this T-cell inhibitor.20,26  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in patients with melanoma. This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab recently has been approved 
in the United States for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilumumab and, if BRAF V600 mutation 
positive, a BRAF inhibitor,27 as well as in previously treated patients with metastatic 
squamous and nonsquamous non-small cell lung cancer (NSCLC) whose tumors 
expressed ≥50% PD-L1.28    
 
3.3. STUDY DESIGN AND INTERVENTION 
3.3.1. 
Study Design and Intervention 
 
This is a multi-institutional, randomized, phase II study of pembrolizumab 
compared to topotecan, administered to patients with SCLC who have 
progressed or relapsed after first-line treatment with etoposide and platinum 
(cisplatin or carboplatin).  This study will be conducted to determine if there is an 
improvement in progression free survival for SCLC patients treated with 
pembrolizumab compared to the standard therapy of topotecan.  RECIST 1.1 will 
be used for this analysis.29  
 
Patients with sensitive or refractory disease will be eligible for the study; where 
sensitive disease will be defined as those patients who relapse >60 days after 
the completion of the first-line of chemotherapy.30  Patients with treated brain 
metastases will be eligible.  Those patients with underlying or previous 
paraneoplastic syndromes are not eligible.   
 
Ninety-three patients will be randomized in a 2:1 fashion to pembrolizumab or 
topotecan.  Patients will be stratified based on disease type (sensitive vs. 


 
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refractory).  Patients who progress in the topotecan arm will be allowed to cross-
over to the pembrolizumab arm. Tumor samples will be required before initiating 
new therapy (preferably a new specimen) and a repeat biopsy will be performed, 
if clinically feasible, on-treatment (during weeks 4 to 6) for those in the 
pembrolizumab arm and at the time of disease progression for those in the 
topotecan arm. Scans will be reviewed by the investigator or designee.  
 
Secondary endpoints will include safety, objective response rate by RECIST 1.1 
and overall survival.  Correlatives, including analyses of tissue and blood, will be 
assessed as well, as described below. 
 
Figure 2. Study Design 
 
 
 
*:With allowance of 5% ineligible, cancelling and unevaluable, the study plans to register 98 
patients, and randomize 93.  
 
 
 
 


 
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3.3.2. 
Intervention 
 
Patients who meet the eligibility criteria and are randomized to one of the 
treatment arms, will receive either topotecan alone intravenously at 1.25 mg/m2 
on days 1 to 5 of a 21-day cycle or pembrolizumab alone administered 
intravenously at 200mg every 21 days. 
 
During the study period, patients will be evaluated clinically by physical exam and 
with routine blood work every 21 days.  Adverse events will be monitored 
throughout the study and graded in severity according to the guidelines outlined 
in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.  
Pre-specified adverse events of clinical interest include: 1) Grade ≥ 2 diarrhea, 2) 
Grade ≥ 2 colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 2 hepatitis 5) Grade ≥ 3 
hypo- or hyperthyroidism.  
 
Patients will be evaluated every 6 weeks (42 ± 7 days) with radiographic imaging 
to assess response to treatment.  Investigators will make all treatment-based 
decisions using RECIST 1.1.  Patients will continue to receive topotecan or 
pembrolizumab every three weeks until documented disease progression, 
unacceptable side effects, intercurrent illness that prevents further administration 
of treatment, investigator’s decision to withdraw the patient, patient withdraws 
consent, pregnancy of the patient, non-compliance with study treatment or 
procedure requirements or administrative reasons.   Patients on the topotecan 
arm who progress on study will be allowed to cross-over to the pembrolizumab 
arm.   
 
After the end of treatment, each patient will be followed for a minimum of 30 days 
for adverse event monitoring. Serious adverse events will be collected for up to 
90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier.  Immune related 
serious adverse events will be followed for 90 days after end of treatment. 
Subjects who discontinue treatment for reasons other than disease progression 
will have posttreatment follow-up every 6 weeks for disease status until 
progression, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone contact 
every 3 months for overall survival until death or withdrawal of consent. 
 
Although subjects will be enrolled regardless of PD-L1 status, subjects will be 
required to provide tissue of a tumor lesion (either archived tissue or a new 
biopsy before initiating therapy).  Tumor samples will be required before initiating 
therapy (preferably a new specimen) and a repeat biopsy will be performed, if 
clinically feasible, on-treatment (during weeks 4 to 6) for those in the 
pembrolizumab arm and at the time of disease progression for those in the 
topotecan arm.  PD-L1 expression status by immunohistochemistry will be 
determined on tumors at baseline, on treatment and at the time of topotecan 
progression.  Numerous other correlative studies also will be performed, as 
outlined below.  Peripheral blood mononuclear cell samples will be collected at 
screening, at day 1 of cycles 1, 2 and 3,  and at the time of each imaging study 
(while on study), for characterization of T-cell phenotypes to understand how 
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4. RATIONALE 
4.1. RATIONALE FOR THE STUDY AND SELECTED PATIENT POPULATION  
 
4.1.1. 
The Immune System in Small Cell Lung Cancer and Immune 
Checkpoint Blockade 
 
Several lines of evidence demonstrate the immunogenic nature of SCLC and 
highlight the potential efficacy of PD-1 blockade in this disease. SCLC is 
occasionally associated with paraneoplastic auto-antibodies and these patients 
are characterized by improved survival, 31 suggesting these auto-antibodies 
may be indicative of tumor-specific immune responses. By contrast, loss of 
MHC expression is found in some SCLCs, implying that downregulation of 
tumor-specific or tumor-associated antigen presentation represents an 
important mechanism to escape immune surveillance. 32,33  Effector T cells are 
significantly higher in the peripheral blood of patients with limited stage SCLC 
compared to those with extensive stage SCLC and in long term disease-free 
survivors relative to those with recurrent disease. 19 Most recently, the PD-1 
and PD-L1 pathway has been interrogated in SCLC by immunohistochemistry 
and gene expression analysis. 34 Although PD-L1 is low on SCLC tumor cells, it 
is highly expressed on tumor infiltrating macrophages, 34 suggesting that PD-1 
blockade may be effective in this disease. 
 
Anti-CTLA-4 blockade has been combined with cytotoxic chemotherapy in 
patients with extensive stage SCLC, demonstrating early feasibility and safety 
of administering immunotherapy in this disease. 35,36 
 
The Phase IB Multicohort Study of Pembrolizumab for PD-L1 Positive 
Advanced Solid Tumors (Keynote-028, NCT02054806) included a cohort of 
SCLC patients with extensive stage disease who had progressed after 
receiving first-line chemotherapy.  To be eligible for treatment with 
pembrolizumab, an archived pre-treatment sample or newly obtained core 
evaluated for the PD-L1 expression was necessary.  One-hundred forty seven 
samples were evaluable for PD-L1, of which 42 (29%) displayed ≥1% PD-L1 
positivity in tumor, inflammatory cells or stroma.  Subsequently, 24 patients 
were treated according to protocol.  Only one patient incurred a treatment 
related death secondary to colitis.  The objective response rate was 29% (95% 
CI, 12.6-51), with a median duration of response of 29 weeks (range, 0.1 to 
29.1).  While the median progression free survival was 1.8 months (95% CI, 
1.6-8.5), the 6-month rate PFS was 33%, indicating durable responses.  
Notably, there was no relationship between the extent of PD-L1 positivity and 
the frequency of responses. 37 
 
4.1.2. 
Complex Molecular Landscape of Small Cell Lung Cancer and 
Opportunity for Immunotherapy  
 
SCLC results from chronic exposure to tobacco carcinogens, leading to a high 
burden of genomic alterations, including mutations, insertions, deletions, large 


 
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scale copy number alterations, and gross inter- and intra-chromosomal 
rearrangements.38 39-41 The only other malignancy with a higher mutational 
burden than SCLC is melanoma, caused by ultraviolet light, another potent 
carcinogen. 40-42 Most of the mutations observed in SCLC tumors are 
passengers, that is, those that do not meaningfully contribute to growth, 
progression or invasion of disease. TP53 and RB1 inactivation are almost 
universal and unlike lung adenocarcinoma, the genomic landscape of SCLC is 
not broadly characterized by targetable driver oncogenes involved in activation 
of kinase signaling. Rather, other processes such as transcriptional 
deregulation, histone modification, and dysregulation of the cytoskeleton are 
implicated. 38,40,41 Based on emerging data from the group at MSKCC, 
demonstrating 
the 
link 
between 
increased 
mutational 
burden 
and 
responsiveness to T cell checkpoint inhibitors in melanoma and NSCLCs, 43,44 
we believe the nearly universally deranged SCLC genomes intimate that these 
tumors may be particularly sensitive to immunotherapies. 
 
4.1.3. 
Rationale for Use of Pembrolizumab in Small Cell Lung Cancer in 
the Second Line Setting 
 
Therapeutic options remain limited in SCLC, and more effective therapies are 
critically needed.  
 
As SCLC is characterized by immunogenic effects and an exceptionally high 
degree of genomic alterations due to tobacco carcinogens, immune checkpoint 
blockade utilizing pembrolizumab warrants further exploration in this disease.  
Evaluating pembrolizumab in the second line setting is appropriate given the 
early data available demonstrating its activity in SCLC.  
 
4.2. RATIONALE FOR DOSE SELECTION/REGIMEN/MODIFICATION 
 
4.2.1. 
 Pembrolizumab and rationale for its Dose Selection  
 
Pembrolizumab will be provided by Merck.  Pembrolizumab 200 mg will be 
administered as a 30 minute IV infusion every 3 weeks.  
 
An open-label Phase I trial (KEYNOTE 001) is being conducted to evaluate the 
safety and clinical activity of single agent pembrolizumab (MK-3475).  The dose 
escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, 
and 10 mg/kg, administered every 2 weeks in patients with advanced solid 
tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of pembrolizumab (MK-3475) 
showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg every 2 weeks).  
No maximum tolerated dose has been identified to date.  Recent data from 
other clinical studies within the pembrolizumab (MK-3475) program has shown 
that a lower dose of the agent and a less frequent schedule may be sufficient 
for target engagement and clinical activity. 
 
Pharmacokinetic (PK) data analysis of pembrolizumab (MK-3475) administered 
every 2 weeks and every 3 weeks showed slow systemic clearance, limited 


 
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volume of distribution, and a long half-life (refer to Investigator’s Brochure, IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data 
provides scientific rationale for evaluating both an every 2 week and every 3 
week dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients.  Within the resulting population PK 
model, clearance and volume parameters of pembrolizumab (MK-3475) were 
found to be dependent on body weight.  The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized 
dosing or a fixed dose across all body weights.  Pembrolizumab (MK-3475) has 
been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen 
relative to a 2 mg/kg every 3 weeks body weight based regimen are anticipated 
to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab/MK-3475 in the melanoma indication.  The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg 
every 3 weeks vs. the proposed dose regimen of 2 mg/kg every 3 weeks (i.e. 5-
fold higher dose and exposure).  The population PK evaluation revealed that 
there was no significant impact of tumor burden on exposure.  In addition, 
exposure was similar between the NSCLC and melanoma indications.  
Therefore, there are no anticipated changes in exposure between different 
indication settings. 
 
The choice of the 200 mg every three weeks as an appropriate fixed dose is 
based on simulations performed using the population PK model of 
pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will 
provide exposures that 1) are optimally consistent with those obtained with the 
2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal 
efficacy response, and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme 
also will reduce complexity in the logistical chain at treatment facilities and 
reduce wastage. 
 
4.2.2. 
Topotecan and Rationale for its dose selection  
 
Topotecan is manufactured by GlaxoSmithKline and is commercially available.  
Topotecan will be administered intravenously at 1.25 mg/m2 on days 1 to 5 of 
each 3 week (21-day) cycle. This dose has been selected to mitigate the 
hematologic toxicities associated with topotecan at the initially studied dose of 
1.5 mg/m2, while preserving its efficacy.12,13   
 
This 1.25 mg/m2 dose was evaluated in a prospective multicenter trial to 
determine whether it could improve safety in patients with relapsed/ refractory 
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received topotecan intravenously on days 1–5, every 21 days, for up to six 
courses.  For those patients who did not incur toxicities, topotecan was 
increased to 1.5mg/m2; yet in those with severe side effects, the dose was 
reduced to 1.0 mg/m2.  Severe toxicities were considered grade 4 neutropenia 
lasting greater than 7 days; grade 4 thrombocytopenia or platelet count < 
100,000/mm3 and neutrophils < 1500/mm3; or any grade 3 or 4 non-
hematologic toxicity besides alopecia, nausea and emesis.  A total of 514 
topotecan courses were received by 164 patients; in 72.6% of those courses, 
the dose remained at 1.25 mg/m2; in 9.1% it was reduced and in 18.3% it 
increased.  Toxicities seemed to be less for the patients treated at the 1.25 
mg/m2 dose when compared to historical data, as grade 4 neutropenia and 
thrombocytopenia occurred in 7% and 5% of courses, with mild non-
hematologic toxicities.  Efficacy was maintained as the overall response rate for 
all patients (sensitive and refractory) was 14.1% and median survival was 23.4 
weeks.  Therefore, topotecan at a dose of 1.25 mg/m2 was found to be as 
effective as the dose of 1.5 mg/m2, but with reduced toxicity.  As such, we have 
chosen this dosing schedule for this study.   
 
5. RATIONALE FOR ENDPOINTS 
5.1. EFFICACY ENDPOINTS 
 
5.1.1. 
Primary 
 
This randomized phase II study will assess progression free survival (PFS) as 
the primary endpoint based on RECIST 1.1.  Given the cross-over design, PFS 
as opposed to overall survival was considered to be an acceptable scientific 
endpoint to identify the best treatment for SCLC patients in need of second-line 
therapy.  According to the findings from the phase III study studying topotecan 
vs CAV6 in the second-line treatment of SCLC patients and the phase III trial 
comparing oral and intravenous topotecan,45 we expect only a median PFS of 
12 weeks for the control arm.  Further, it is anticipated that the SCLC patients 
responding to pembrolizumab will have a longer duration of response, which 
will be assessed by RECIST 1.1.29  The PFS rate at 6 and 9 months in each 
group will be assessed and compared.   
 
5.1.2. 
Secondary 
 
The objective response rate (ORR) will be determined in each arm of the study 
by RECIST 1.1.  Notably, topotecan leads to a differential response in SCLC 
patients with sensitive vs refractory disease, which we do not anticipate in 
those receiving pembrolizumab.  With the cross-over design, we will be able to 
determine the ORR for pembrolizumab in the second- and third-line setting.  
Overall survival of patients in each arm of the study will be analyzed.  The 
treatment-related toxicity of pembrolizumab and topotecan will be summarized 
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5.2. EXPLORATORY ENDPOINTS; BIOMARKERS OF RESPONSE TO IMMUNE CHECKPOINT 
INHIBITORS 
5.2.1. 
PD-L1 Tumor Expression  
 
 
 
Tumor PD-L1 expression levels extensively have been evaluated to determine 
potential associations with response to pembrolizumab.  In Keynote-001, 449 
patients with previously treated non-small cell lung cancer patients (NSCLC) 
received pembrolizumab at 2mg/kg (N = 55) and at 10 mg/kg (N = 394).46  The 
anti-PD-L1 antibody clone 22C3 (Merck) and a prototype immunohistochemical 
assay was used to determine PD-L1 status.  PD-L1 positivity was defined as 
membranous staining in at least 1% of cells (neoplastic and intercalated 
mononuclear inflammatory cells) within tumor nests or a distinctive staining 
pattern caused by the infiltration of mononuclear inflammatory cells in the 
stroma that formed a banding pattern adjacent to tumor nests.  A tumor 
proportion score (TPS) was assigned to each sample based on the percentage 
of tumor cells with membranous PD-L1 staining.28,46 
 
Figure 3.  PD-L1 Expression 
  
TPS < 1% 
  
 
TPS ≥ 1 – 49% 
 
TPS ≥ 50% 
 
Response rates significantly were higher in patients whose samples 
demonstrated a TPS ≥ 50%.  Further, patients with higher PD-L1 expression 
seemed to have a faster time to response.   Median overall survival was 15.5 
months (95% CI, 10 – NR) in patients with TPS ≥ 50% compared to 11.3 
months (95% CI, 8.8 – 14.0) in all patients.   
 
In Keynote-028, PD-L1 expression was necessary for SCLC patients to be 
eligible, as described above.  One-hundred forty seven samples were 
evaluable for PD-L1, of which 42 (29%) displayed ≥1% PD-L1 positivity in 
tumor, inflammatory cells or stroma.  Subsequently, 24 patients were treated 
according to protocol who had received one or more prior lines of therapy for 
SCLC. Notably, there was no relationship between the extent of PD-L1 
positivity and the frequency of responses. 37 
 
5.2.2. 
Smoking Status, Smoking-Related Genotoxicity, and Mutation 
Burden  


 
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We and others have shown that smokers with lung cancers are most likely to 
benefit from PD-1 blockade. 47 In 495 patients with NSCLCs treated with 
pembrolizumab, the response rate was 22.5% in smokers compared to 10.3% 
in never smokers.28  We hypothesize this differential response is related to the 
increased mutational burden found in smoking-related cancers. To examine 
this hypothesis, we have performed whole exome sequencing of 34 NSCLC 
patients treated with pembrolizumab; higher mutational burden was associated 
with a more durable response to pembrolizumab and an improvement in 
progression-free survival (PFS) compared to those with lower mutation 
burden.44 We also applied a molecular classifier of smoking-related 
genotoxicity, which distinguishes genomes characteristic of lung cancers in 
smokers (defined by a predominance of C>T transversions, termed 
"transversion-high" or TH, smoking signature) from the genomic alterations 
characteristic of lung cancers in never smokers (transversion low, TL, non-
smoking signature). TH-tumors were highly associated with response and 
improved PFS to pembrolizumab. Moreover, TH-tumors were highly associated 
with mutation burden, suggesting that the molecular smoking signature may be 
able to identify those patients with the greatest mutation burden and most likely 
to benefit from pembrolizumab.44 The association between response to 
pembrolizumab, mutation burden, and molecular smoking history is highly 
applicable to SCLC as this disease is nearly entirely related to smoking and 
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The critical link in understanding the association between mutation burden and 
response to T cell checkpoint inhibitors may be neoantigens. Neoantigens are 
cancer-specific novel immunogenic peptides resulting from somatic, non-
synonymous mutations in tumor cells, which when presented by class I or II 
MHC molecules, can be targets for T-cell recognition and effector responses.48-
52 Whole exome sequencing and computational neoantigen prediction also  
have been performed on a series of melanomas from patients treated with 
ipilimumab.43 Responders to ipilimumab were characterized by an elevated 
mutation burden and neoantigen-specific T cell responses were identified in the 
peripheral blood of three long-term responders to ipilimumab. We also have 
begun to explore the neoantigen landscape associated with response to 
pembrolizumab in NSCLC: responders have a greater absolute burden of 
neoantigens. Additionally, in one patient with a near complete response to 
pembrolizumab, we identified a neoantigen-specific T cell response in the 
peripheral blood that corresponded with clinical response to anti-PD-1 
therapy.44 This case is suggestive that responses to anti-PD-1 therapy may be 
mediated by expansion of neoantigen-specific T cell clones and that 
neoantigen-based peripheral blood monitoring may provide an opportunity to 
examine and monitor response to PD-1 therapy. 
 
 
 
6. OBJECTIVES 
 
6.1. PRIMARY OBJECTIVE 
 
To  demonstrate an improvement in progression free survival (PFS) in patients with 
relapsed sensitive or refractory SCLC receiving pembrolizumab compared to 
topotecan, utilizing RECIST 1.1. 
 
6.2. SECONDARY OBJECTIVES 
 
i. Determine the objective response rate (ORR) in each arm of the study by 
RECIST 1.1. 
 
ii. Determine the overall survival (OS) of patients in each arm of the study. 
 
iii. Determine the ORR, and OS of pembrolizumab and topotecan, in the 
following patient groups: 
a. Sensitive disease vs. Refractory disease 
 
iv. Determine the safety and tolerability of pembrolizumab in patients with 
SCLC. 
 
 


 
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6.3. EXPLORATORY OBJECTIVES 
 
i. To 
describe 
the 
immunophenotype 
of 
SCLCs, 
assessed 
by 
immunohistochemistry and the associations with ORR, PFS and OS to each of 
the treatment arms.  
a. For those patients treated in the pembrolizumab arm, pre-treatment 
samples also will be compared to on-treatment biopsy samples to 
identify the immunophenotype of response. 
 
ii. To describe the temporal change in T cell immunophenotypes in peripheral blood 
mononuclear cell samples and correlate with clinical response.  
 
iii. To explore the relationship between mutational burden and response to 
pembrolizumab therapy. 
 
iv. To identify candidate neoantigens and explore their associations with response 
to pembrolizumab therapy.   
 
v. To examine the changes in tumors that are associated with either response or 
resistance to study therapy by performing comparative analyses on matched 
specimens.  
6.4. FUTURE BIOMEDICAL RESEARCH 
All collected biospecimens will be stored in the Alliance Foundation Biorepository (AFB), 
a CAP-accredited biorepository at Washington University in St. Louis, until biospecimen 
accrual and clinical follow-up is sufficiently complete to allow for the design and 
execution of specific correlative analyses using ‘state-of-the-art’ analytical platforms that 
will be available at that time.  
Such biomarker research will address emergent questions not described elsewhere in 
this protocol and will only be conducted on specimens from appropriately consented 
patients. The objective of collecting specimens for future biomedical research is to 
explore and identify biomarkers that inform the scientific understanding of disease and/or 
their therapeutic treatments in the context of this study. Proposals for future correlative 
research will undergo rigorous scientific, programmatic, and statistical review by AFT, 
and biospecimens will only be released to those investigators who have obtained 
appropriate regulatory approval and demonstrate adequate funding to successful 
complete proposed research aims. AFT will ensure that all collected specimens are used 
only for approved research protocols.  
Anonymized (de-identified) data generated from biospecimens used for future correlative 
research, including somatic and constitutional (germline) genomic data, may be shared 
with other researchers or deposited in a publicly accessible or controlled-access data 
repositories. Correlative study results and data will never be returned to individual 
patients.  
 
 


 
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7. PATIENT SELECTION 
7.1. INCLUSION CRITERIA  
 
In order to be eligible for participation in this study, the patient must: 
 
1. Have histologically or cytologically confirmed small cell lung cancer.  Confirmation 
will be done at each participating site. 
 
2. Have relapsed or progressed after only one prior chemotherapy regimen, which 
must have been an etoposide-platinum doublet.  Eligible patients will be defined as 
follows: 
 
“Sensitive” Disease: 
Patients who had one previous line of chemotherapy 
and relapsed after ≥ 60 days of completion of treatment.  
 
“Refractory” Disease: Patients with no response to first-line chemotherapy or 
progression <60 days after completing treatment.   
 
3. Be  18 years of age on day of signing informed consent. 
 
4. Have a life expectancy of at least 3 months. 
 
5. Have a performance status of ≤ 1 on the ECOG Performance Scale.  
 
6. Have measurable disease based on RECIST 1.1.   
7. Have a tumor tissue specimen available from either a core or excisional biopsy.   
The tumor specimen should be of adequate size and tumor cellularity to perform 
whole exome sequencing and immunohistochemistry. In subjects for whom newly 
obtained samples cannot be obtained (e.g. tumor inaccessible or safety concern), 
archived tissue may be submitted, if it otherwise satisfies all specimen criteria. 
Archival samples must have been obtained within 42 days prior to signing consent 
(please refer to section 12.1 of protocol).  
 
8. Demonstrate adequate organ function as defined in Table 1. 
 
Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥8 g/dL (without transfusion)  
Renal 
Serum creatinine 
 
OR 
 
Glomerular Filtration Rate (GFR)  
≤1.5 X upper limit of normal (ULN)  
 
OR 
 
GFR ≥60 mL/min* for patient with 
creatinine levels > 1.5 X institutional ULN 


 
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Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN  
 
OR 
 
Direct bilirubin ≤ ULN for patients with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN   
 
OR 
 
≤ 5 X ULN for patients with liver 
metastases 
Albumin 
≥ 2.5 mg/dL 
*GFR should be calculated per institutional standards. 
 
9. Female patients of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours of starting treatment.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.  
  
10. Female patients of childbearing potential must be willing to an adequate method of 
contraception as outlined in Section 14.4.1 – Contraception for the course of the 
study through 120 days after the last dose of study medication (see Section 
13.4.1).  Patients of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.  
 
11. Male patients must agree to use an adequate method of contraception as outlined 
in Section 14.4.1 – Contraception - starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. Note: Abstinence is 
acceptable if this is the usual lifestyle and preferred contraception for the subject.  
 
7.2. EXCLUSION CRITERIA 
 
The patient must be excluded from participating in the study if the patient: 
 
1. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 14 days of the first dose of treatment. 
 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of study treatment. 
 
 
3. Has had a prior monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 14 days earlier.  
 


 
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4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
Note:  Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an 
exception to this criterion and may qualify for the study. 
 
5. Has undergone major surgery, he/she must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.  
  
6. Has a known additional malignancy that is progressing or requires active 
treatment.  
 
7. Has known active central nervous system (CNS) metastases. Patients with 
previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first 
dose of study treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using steroids 
for at least 7 days prior to study treatment.  
 
8. Has known carcinomatous meningitis.  
 
9. Has an active autoimmune disease requiring systemic treatment in the past 2 
years or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Patients 
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Patients that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Patients with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
 
10. Has evidence of interstitial lung disease, or history of (non-infectious) pneumonitis 
that required steroids, or current pneumonitis.  
 
11. Has an active infection requiring systemic therapy. 
 
12. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the patient’s 
participation for the full duration of the study, or is not in the best interest of the 
patient to participate, in the opinion of the treating investigator.  
 
13.  Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study. 
 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the pre-screening or screening visit 
through 120 days after the last dose of study treatment. 
 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways). 
 


 
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16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
18. Has received a live vaccine within 30 days prior to the planned first dose of study 
therapy.  
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 
19. Has a known history of active TB   (Bacillus Tuberculosis). 
 
20. Hypersensitivity to pembrolizumab or any of its excipients. 
 
21. Patients with underlying or previous paraneoplastic syndromes 
 
 
8. PATIENT ENROLLMENT 
 
8.1. SITE ENROLLMENT REQUIREMENTS 
 
Requirements for Site Enrollment 
• 
IRB Certification  
 
• 
IRB/Regulatory Approval  
 
Submit completed forms along with a copy of your IRB Approval, Model Informed 
Consent and any other required documentation to the AFT eTMF system.  
 
8.2. PATIENT ENROLLMENT REQUIREMENTS 
 
Informed consent: The patient must be aware of the neoplastic nature of his/her 
disease and willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, 
and discomforts. Current human protection committee approval of this protocol and a 
consent form is required prior to patient consent and enrollment. 
 
8.3. PATIENT SCREENING, ENROLLMENT/RANDOMIZATION PROCEDURES 
Patient enrollment will be facilitated using the AFT web-based IRT (interactive 
response technology) system.   
 
Patients must be screened and sign informed consent prior to any study related 
testing, including submission of biospecimens.  After written informed consent has 
been obtained, the study site will obtain a unique patient number or unique patient 


 
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identifier, which will stay the same throughout the entire study.  Patients screened but 
not randomized for any reason have to be registered as a Screening Failure in IRT. 
 
Prior to accessing AFT IRT, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated time frames.  
 
• 
All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
 
• 
Adequate tumor tissue will be available and can be sent to the AFT biorepository 
for central laboratory analysis within 14 days of randomization. 
 
The AFT IRT system will provide the site with a printable confirmation of enrollment 
and treatment randomization information.  Please print this confirmation for your 
records. The site will receive instructions for drug ordering via IRT, upon 
randomization. 
 
 
8.4. STRATIFICATION FACTORS AND TREATMENT ASSIGNMENTS 
 
Randomization will be stratified according to:  
 
1) Sensitive Disease vs Refractory Disease: sensitive disease will be defined as 
those patients with disease progression who relapse after treatment with 
standard first-line etoposide/platinum ≥60 days from completing chemotherapy, 
and refractory disease will be defined as patients with disease progression < 60 
days from completing chemotherapy.  
 
This is an open-label study; therefore, AFT, the investigator and patient will know the 
treatment administered. 


 
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9. SCHEDULE OF ASSESSMENTS 
9.1. SCHEDULE OF ASSESSMENTS 
Table 2.  Schedule of Assessments 
Study Period: 
Treatment Cycles1 
End of 
Treatment§ 
Post-Treatment 
Evaluations 
Treatment Cycle/Title: 
 
Screening 
(Visit 0) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
At time of 
treatment 
discontinuation 
Safety 
Follow-
up19 
Follow 
Up 
Visits20 
Survival 
Follow-
Up21 
5 
6 
7 
8  
Scheduling Window (Days)2: 
-14 to -1 
 
± 3 ± 3 
± 3 ± 3 
± 3 
± 3 
± 3 
At time of 
treatment 
discontinuation 
30 
days 
Every 6 
weeks  
Every 
12 
weeks  
Informed Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medication 
Review5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
SCLC Disease Details6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Review Adverse Events7, 8, 22 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital Signs and Weight9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test – Urine or Serum 
β-HCG10, 12 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT11, 12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential12, 13 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry 
Panel12, 13 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis12, 14 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 


 
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Study Period: 
Treatment Cycles1 
End of 
Treatment§ 
Post-Treatment 
Evaluations 
Treatment Cycle/Title: 
 
Screening 
(Visit 0) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
At time of 
treatment 
discontinuation 
Safety 
Follow-
up19 
Follow 
Up 
Visits20 
Survival 
Follow-
Up21 
5 
6 
7 
8  
Scheduling Window (Days)2: 
-14 to -1 
 
± 3 ± 3 
± 3 ± 3 
± 3 
± 3 
± 3 
At time of 
treatment 
discontinuation 
30 
days 
Every 6 
weeks  
Every 
12 
weeks  
T3, FT4 and TSH12, 13, 15 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging (CT Scan/MRI)16, 17 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
Archival or Newly Obtained Tissue 
Collection18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Newly Obtained Tissue Collection 
X23 
 
X24 
 
 
 
 
 
 
X25 
 
 
 
Correlative Studies Blood 
Collection26 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 


 
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1  In general, assessments/procedures are to be performed on day 1 and prior to the first dose of study treatment for each cycle unless otherwise 
specified. Treatment cycles are 3 weeks (21-days); however the treatment cycle interval may be increased due to toxicity according to the 
dose modification guidelines provided in Section 13. If treatment cycles are increased all procedures except imaging will be completed 
according to cycle number and not weeks on treatment, imaging will be performed every 6 weeks (±7 days) from the first dose of study 
treatment regardless of any treatment delays during the first 8 cycles.  
2  In general, the window for each visit is ± 3 days unless otherwise specified.  
3  Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the patient signing 
consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame. Informed 
consent and assessment of eligibility criteria can be obtained 21 days prior to the start of treatment.   
4  Medical history should be completed by study staff and include all comorbidities, as well as a detailed assessment of smoking history:  number 
of years of tobacco smoke, packs of cigarettes smoked, ongoing tobacco smoke or time since quitting smoking. This will also include 
documentation of SCLC disease status.  
5  Prior medications – record all medications taken within 14 days of visit 1 and all treatments for a prior cancer other than SCLC. After the Safety 
Follow-up Visit record all medications taken for SAEs and ECIs as defined in Section 17.  
6  Disease details are to be collected, including: sites of disease; first-line chemotherapy (cisplatin vs carboplatin); number of cycles of first-line 
chemotherapy; administration of prophylactic cranial irradiation, consolidative mediastinal radiation or palliative radiation to an osseous site; 
best response to prior therapy (stable disease, partial response, complete response, progression of disease); time to relapse (sensitive 
disease vs resistant disease). 
7  AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, whether gradable by CTCAE or not will also be 
evaluated for seriousness.  
8  All AEs of unknown etiology associated with study treatment exposure should be evaluated to determine if it is possibly an ECI.  
9  Vital signs to include: temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 1 only.  
10 For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first dose of study treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. 
Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.  
11 Coagulation factors (PT/INR and aPTT) should be performed if clinically indicated and monitored closely throughout the study for any patient 
receiving anticoagulant therapy.  
12 Laboratory tests for screening are to be performed within 14 days prior to the first dose of study treatment. See Table 3 for details regarding 
laboratory tests.  
13 After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Laboratory results must be known and acceptable 
prior to dosing.  
14 Perform urinalysis every 4 cycles.  
15 Required at baseline. Perform thyroid testing every other cycle while patients are receiving pembrolizumab. 


 
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16 Baseline tumor imaging will include the following:  CT chest and abdomen with contrast OR CT chest without contrast and MRI abdomen 
with/without gadolinium and imaging of other known sites of disease; and brain imaging with MRI with/without contrast (or CT with contrast if 
the patient cannot tolerate an MRI).  Imaging of the pelvis should be performed as clinically indicated or if there is known metastases in the 
pelvis. The initial tumor imaging will be performed within 14 days prior to the first dose of study treatment. Scans performed as part of routine 
clinical management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 14 days prior to the 
first dose of study treatment. On-study imaging will be performed every 6 weeks (42 ± 7 days) after the first dose of study treatment or more 
frequently if clinically indicated.  The timing for imaging studies should follow calendar days and should not be adjusted for delays in 
cycle starts or extension of topotecan or pembrolizumab cycle frequencies. The same imaging technique should be used in a patient 
throughout the study. Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for patient 
management.  
17 After first documentation of progression (if the patient is clinically stable) or response per RECIST 1.1 repeat imaging for confirmation is 
required. Confirmatory imaging may be performed as early as 28 days later; alternatively, the scan performed at the next scheduled time point 
may be used as confirmation.  
18 Tumor tissue for biomarker analysis from an archival tissue sample (not more than 42 days prior to signing consent) or newly obtained tumor 
tissue from a recent biopsy of a tumor lesion not previously radiated. Please see AFT 17 Correlative Science Manual for specimen collection 
instructions. If a NEW biopsy is performed, the investigator should ensure that adequate tissue is collected.  


 
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19 Patients who discontinue study treatment for a disease progression, will undergo a mandatory Safety Follow-up Visit approximately 30 days 
after the last dose of study treatment or before the initiation of a new antineoplastic treatment, whichever comes first. Patients with an AE of 
grade > 1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever 
occurs first.  
20 Patients who discontinue study treatment for a reason other than disease progression will move into the Follow-up Phase and should be 
assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status, development of drug related SAEs and ECIs/irAEs, 
and initiation of a new antineoplastic therapy. Follow-up visit 1 should be scheduled 6 weeks after the last dose of study treatment. Unless 
otherwise noted in the flow chart, every effort should be made to collect patient information until the start of new antineoplastic therapy, 
disease progression, or death, whichever comes first.  
21 Once a patient experiences disease progression or starts a new antineoplastic therapy, the patient moves into the Survival Follow-up Phase and 
should be contacted by telephone every 3 months to assess for survival status, development of drug related SAEs and ECIs/irAEs and the 
start of new antineoplastic therapy if applicable.  
22 Record all AEs occurring within 30 days after the last dose of study treatment or until initiation of a new antineoplastic therapy, whichever comes 
first. Report all SAEs (related and unrelated to study treatment) occurring within 90 days of the last dose of study treatment or the start of new 
anti-cancer treatment, whichever comes first. All ECIs/irAEs occurring within 90 days of the last dose of study treatment should be reported 
regardless of initiating new anticancer therapy. After this time, report only SAEs and ECIs/irAEs that are considered related to study treatment.  
23 If archival sample is not available, fresh tissue samples will be collected for correlative studies. 
24Those patients receiving pembrolizumab will undergo a biopsy obtained during week 4 to 6 of treatment for biomarker analysis, if clinically 
feasible and safe.  A tumor lesion not previously radiated (required for PD-L1 determination) should be biopsied.  The tumor sample must be 
sent to the AFT-Biorepository. See AFT 1 Correlative Science Manual for additional details.  
25 Patients on the topotecan arm who progress and are to cross-over to the pembrolizumab arm, will undergo a biopsy just before initiating 
experimental treatment, if clinically feasible and safe.  A tumor lesion not previously radiated (required for PD-L1 determination) should be 
biopsied.  The tumor sample must be sent to the AFT-Biorepository. 
26 Whole blood samples for genomic analyses, and peripheral blood cell/serum plasma samples for correlatives will be collected for all patients at 
screening, at week 4-6 biopsy, at imaging during all cycles, and at progression/cross-over.  Samples will be collected per Section 12. Note that 
each time point requires differing types of blood collection. Please refer to the lab manual for detailed instructions on sample collection. §  For 
patients who cross-over from the topotecan arm to the pembrolizumab arm, they will undergo the same assessments and procedures from 
study start, except that a repeat tumor biopsy will not be performed during weeks 4 to 6.


 
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Table 3. Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum pregnancy test (β-human 
chorionic gonadotropin, β-hCG )† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR)  
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
aPTT 
WBC (total and differential, 
including absolute neutrophil 
count) 
Aspartate aminotransferase (AST) Specific gravity  
Total thriiodothyronine (T3) 
Red Blood Cell Count 
 
Microscopic exam (If abnormal)  
Free tyroxine (T4) 
 
Carbon Dioxide ‡ 
results are noted 
Thyroid stimulating hormone (TSH) 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.   
‡ If considered standard of care in your institution. 
 
Laboratory tests for screening should be performed within 14 days prior to the first dose of treatment.  After Cycle 1, pre-dose 
laboratory procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to each dose of study treatment.  At cross-over, laboratory tests can be performed up to 
72 hours prior to dosing of pembrolizumab. 
 
 


 
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9.2. TUMOR IMAGING SCHEDULE 
 
The initial tumor imaging will be performed within 14 days prior to the first dose of study treatment.  Scans performed as part of 
routine clinical management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 14 
days prior to the first dose of study treatment.   
 
On-study imaging will be performed every 6 weeks (42 ± 7 days) after the first dose of study treatment, or more frequently if clinically 
indicated.  The timing for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or 
extension of pembrolizumab (MK-3475) or topotecan cycle frequencies.  The same imaging technique should be used in a patient 
throughout the study.  Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for 
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10. TREATMENT PLAN 
 
10.1. STUDY TREATMENTS 
 
The treatment to be used in this study is outlined below in Table 4.  
 
Table 4. Study Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Every 3 
weeks 
IV Infusion 
Day 1 of each 3 
week cycle 
Experimental 
Topotecan 
1.25 mg/m2 
Days 1 to 5 
Every 3 
weeks 
IV Infusion 
Days  1-5 of 
each 3 week 
cycle 
Standard/ 
Control 
The pembrolizumab (MK-3475) dosing interval may be increased due to toxicity.  
 
Study treatment should begin on the day of randomization and no later than 48 hours 
from the date on which treatment is allocated/assigned (or 72 hours if randomization 
occurs on a Friday). 
 
Experimental Arm 
 
Pembrolizumab:  200 mg IV every 21-days until progression of disease or 
unacceptable toxicities. 
 
Control Arm 
 
Topotecan at 1.25mg/m2 on days 1 to 5 every 21-days until progression of disease or 
unacceptable toxicities.  Pegfilgrastim can be administered on day 6, 7 or 8 of every 
cycle as determined by the investigator. 
 
Patients with progression of disease by RECIST 1.1 will be allowed cross over to 
receive pembrolizumab 200 mg IV every 21-days for up to 1 year until progression of 
disease or unacceptable toxicities. 
 
10.2. DOSE SELECTION AND PREPARATION 
 
The rationale for selection of doses to be used in this study is provided in Sections 
4.2.1 and 4.2.2. 
 
The specific instructions for pembrolizumab (MK-3475) preparation and administration 
are included in the Pharmacy Manual. 
 
Topotecan will be prepared and administered as per the approved product label or 
institutional standard practice. 
 


 
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10.2.1. 
Timing of Dose Administration 
 
Study treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Schedule of 
Assessments (Section 9).  Study treatment may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
 
All study treatments will be administered on an outpatient basis. 
 
10.2.2. 
Pembrolizumab 
 
The specific instructions for pembrolizumab (MK-3475) dose calculation, 
reconstitution, preparation of the infusion fluid, and administration are included 
in the Pharmacy Manual. 
 
10.2.3. 
Topotecan 
 
Topotecan will be administered as a 30 minute IV infusion daily for 5 days.  
Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible.  However, given the variability of infusion pumps from site 
to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time 
is 30 minutes: -5 min/+10 min). 
 
Antiemetics will be administered prior to each dose of topotecan as per 
institutional standards. 
 
Pegfilgrastim can be given on day 6, 7 or 8 of every cycle, as determined 
necessary by the investigator. 
 
11. DATA AND SPECIMEN SUBMISSION, STUDY PROCEDURES 
 
11.1. DATA COLLECTION AND SUBMISSION 
 
Data collection for this study will be done through the Medidata Rave clinical data 
management system. Access to the study in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in AFT CTMS System.   
 
12. BIOSPECIMEN COLLECTION  
 
In order to be eligible for the study, all subjects with progressive or recurrent SCLC 
must provide a tumor tissue specimen.  A newly acquired specimen will be preferred, 
although a recently-obtained (≤ 42 days prior to consent) archived sample can be used 
if available.  Patients in the pembrolizumab (MK-3475) arm will undergo a repeat 
biopsy while on treatment (during weeks 4 to 6 (days 29 to 42), if clinically feasible. 
Patients in the topotecan arm will undergo a repeat biopsy at the time of disease 
progression just before the cross-over to pembrolizumab, if clinically feasible.  


 
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 The AFT Biorepository at Washington University is the central laboratory to 
receive these samples.  
 
Fine needle aspirates or cytologic specimens will not be accepted.  Core needle or 
excisional biopsies, or resected tissue is required at each time point. Importantly, the 
specimen should not be from a previously irradiated lesion.   
 
In addition, whole blood and peripheral blood mononuclear cell (PBMC) samples will 
be collected at baseline and at specified times throughout the study. Please see the 
biospecimen collection schema in Section 11.1 below for specific time points. Detailed 
information regarding the collection, processing and shipping of samples collected for 
screening and during the study are included in the AFT 17 Correlative Science 
Manual. 
 
12.1. BIOSPECIMEN COLLECTION SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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13. CORRELATIVE STUDIES 
 
13.1. IMMUNOHISTOCHEMISTRY EVALUATION 
Expression of phenotypic and functional immune cell markers on tumor infiltrating 
cells, as well as immune signaling markers on the surface of tumor cells will be 
evaluated by multispectral immunohistochemistry.  FFPE tumor tissue collected 
from 
pre-treatment 
and 
on-treatment 
biopsy 
will 
be 
utilized.  
Immunohistochemical markers may include, but not be limited to PDL-1, PD-L2, 
PD-1, CD3, CD4, CD8, FoxP3, CD68, MHC I and II, GITR, OX40, LAG-3 and 
TIM-3.   
 
We will correlate expression of these markers to response, PFS and OS.  For 
those patients treated in the pembrolizumab arm, pre-treatment samples also will 
be compared to on-treatment biopsy samples to identify the immunophenotype of 
response. 
 
13.2. WHOLE EXOME SEQUENCING OF TUMOR AND MATCHED NORMAL FOR EVALUATION 
OF MUTATIONAL BURDEN AND NEOANTIGEN LANDSCAPE 
 
Tumor DNA and matched normal DNA will be extracted for whole exome 
analyses.  Once DNA has been obtained and extracted, we will perform 
massively parallel sequencing of the tumor tissue and the available matched 
normal tissue.  Genomic DNA will be captured via solution based hybrid 
selection and sequenced on the Illumina HiSeq platform.  Matched normal DNA 
also will be collected from whole blood and sequenced in conjunction with 
somatic tumor DNA.  This is necessary to make the variant calls in next-
generation sequencing assays.  It is not the intent of this analysis to utilize 
these samples to identify germline susceptibility mutations.  However, in the 
course of investigating somatic sequence variations, germline susceptibility 
variants may be suggested by comparative germline sequencing.  In addition, 
some somatic mutations are themselves directly suggestive of a germline 
predisposition (e.g. BRCA1).  See Appendix II for plan should a potentially 
actionable incidental finding is identified during the course of this research. 
 
Assessment of total somatic mutational burden: 
The somatic sequencing data will be analyzed for base mutations, insertions, 
fusions, deletions, copy number alterations and in all target genes.  Total 
nonsynonymous mutation burden per tumor sample will be determined and 
correlated to radiographic response. Other analysis may include differential 
impact of individual genomic alterations and response to study therapy. 
 
Assessment of the neoantigen landscape: 
Utilizing whole exome sequencing, we will identify candidate neoantigenics in 
SCLCs and explore their associations with response to pembrolizumab 
therapy.  
 
Neoantigens are modeled in silico by examining the components of antigen 
presentation on MHC (antigenicity).53  Expressed somatic missence mutations 


 
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are translated into pairs of short peptide strings:  one including the mutation 
and one corresponding to the wild type sequence.  In silico analysis is 
performed 
(for 
example 
using 
NetMHC 
(http://www.cbs.dtu.dk/services/NetMHC-3.2/ 54,55 or similar algorithm to predict 
the binding affinity of a given peptide for patient specific MHC I and II. 
Candidate neoantigens of particular interest will be identified by having a 
predicted class I or II MHC binding affinity to patient-specific HLA alleles of at 
least 500nM. 
 
HLA typing may be inferred using ATHLATES or determined directly using 
normal DNA. 
 
13.3. TRANSCRIPTOME ANALYSES 
 
Gene expression profiling of the immunologic composition of the tumor 
microenvinroment is assessed by RNAseq. This may be performed on pre-
treatment tumor, on-treatment tumor samples, as well as serially collected 
peripheral blood lymphocytes. RNA is extracted, quality controlled and mRNA 
is isolated, fragmented, purified, and undergoes whole transcriptome library 
preparation per protocol.  
 
We will utilize gene expression data to evaluate changes in the tumor and 
tumor microenvironment between pre- and matched on-treatment (for the 
pembrolizumab arm) or post-treatment (for the topotecan arm) specimens that 
are associated with either response or resistance to study therapy.   
 
13.4. PERIPHERAL BLOOD BASED STUDIES 
 
Multiparametric flow cytometry will be performed at baseline and during 
treatment to assess baseline and changes in composition/activation status of 
lymphocyte subsets present in peripheral blood mononuclear cell preparations 
(PBMCs). Lymphocyte subsets to be assayed may include, but are not limited 
to CD3+, CD8+ and CD4+ T-cell subsets (activated; effector/memory; 
regulatory) and populations of those cells as defined by the expression of 
activation, exhaustion, or signaling markers such as, but not limited to, FoxP3, 
Ki67, ICOS, CTLA-4, PD-1, LAG-3, and Tim-3.   
 
Serially collected PBMCs may also be used to screen for autologous 
neoantigen-specific T cell responses in the peripheral blood.  Methods for 
doing so include combinatorial coding with peptide-MHC multimers,51,56 which 
permits high-throughput detection of antigen-specific T-cells to multiple 
potential antigens in parallel. Briefly, using synthesized peptides from 
candidate neoantigens as described above, large quantities of fluorochome-
labeled peptide-MHC complexes are generated such that each neoantigen is 
coded by a unique fluorochrome combination. Then, using conditional MHC 
ligands that are cleaved upon exposure to UV-light, empty, peptide-reactive 
MHC molecules are then exposed to autologous T-cells and reactivity of TILs 
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Neoantigen-specific T-cells will be isolated and may be expanded and used for 
future experiments. 
 
As improvements in technology and scalability permit, alternative strategies for 
identifying neoantigen-specific T cells in treated patients may be explored. 
 
13.5. T CELL RECEPTOR SEQUENCING 
 
Using serial RNA samples extracted from PBMC and tumor samples, we will 
comprehensively characterize their T cell receptor repertoire.  We will compare 
their diversity and dynamics in responders versus non-responder and also 
assess their correlation with changes in mutational/neoantigen burden during 
treatment.  
 
In order to examine all possible variable (V), diversity (D), and joining (J) 
segments of the T cell receptor combinations, we will first apply the 5’RACE (5’ 
rapid amplification of cDNA end) method using a SMART (Switching Mechanism 
At 5’ end of RNA Transcript) library construction kit (Clontech). We will perform 
PCR amplification of T cell receptor α (TCRA) and T cell receptor β (TCRB) 
gene products with adapter-conjugated primer sets in order to prepare amplicon 
libraries compatible with Illumina NGS platform. The template library will then be 
amplified by Nextera XT index kit (Illumina) that allows barcode tagging and 
pooling of up to 16 samples. Subsequently, the prepared library will be analyzed 
using MiSeq Reagent 600-cycle kit v3 and MiSeq system (Illumina) that will 
generate 3-6 million T cell receptor reads per sample. The final data will be 
analyzed using Tcrip software or MiTCR.  
 
In addition, we will perform similar comprehensive T cell receptor analyses for 
clones of neoantigen-specific T cells isolated from PBMCs and/or TILs in section 
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14. DOSE AND TREATMENT MODIFICATIONS (ESCALATION/TITRATION/OTHER), CONCOMITANT 
MEDICATIONS, SUPPORTIVE CARE 
 
14.1. DOSE MODIFICATION 
14.1.1. 
Pembrolizumab (MK-3475) Dose Modification  
 
Adverse 
events 
(both 
non-serious 
and 
serious) 
associated 
with 
pembrolizumab (MK-3475) exposure may represent an immunologic 
etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab dosing may 
continue in the event of an unrelated or grade 1 adverse event.  
Pembrolizumab (MK-3475) must be withheld for drug-related toxicities and 
severe or life-threatening adverse events, as per Table 5 below.  Drug-
related toxicities are managed by dose delay or interruption rather than 
dose reduction. See Section 14.3.1 for supportive care guidelines, including 
use of corticosteroids. 
 
Table 5. Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse 
Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 6 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM  
or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 
3-4 hyperglycemia associated with 
evidence of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable, yet discontinue treatment if patients are 
not improved within 6 weeks of last dose 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite adequate 
premedication 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 6 weeks of last dose or 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
prednisone or equivalent per day within 6 weeks.  
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity, 
excluding 
hematologic 
toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 6 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 6 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hematologic Toxicity 
Thrombocytopenia 
associated with 
bleeding 
3 
Toxicity resolves to Grade 0-1 or 
baseline 
May increase the dosing interval by 
1 week 
Toxicity does not resolve within 6 weeks of last dose  
Permanently discontinue if associated with severe or life 
threatening bleeding event 
Neutropenia, 
anemia, or 
thrombocytopenia  
4 
Toxicity resolves to Grade 0-1 or 
baseline 
May increase the dosing interval by 
1 week 
Toxicity does not resolve within 6 weeks of last dose 
Permanently discontinue if associated with any severe or life 
threatening event 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then patients should be discontinued. 
2bIf symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose: 
Refer to Table 8 Infusion Treatment Guidelines for further management details.  
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 6 weeks 
of the last dose. 
 
If toxicity does not resolve to Grade 0-1 within 6 weeks after last infusion, 
study treatment should be discontinued after consultation with the Study PI. 
With Study Chair and AFT agreement, patients with a laboratory adverse 
event still at Grade 2 after 6 weeks may continue treatment in the study 
only if asymptomatic and controlled.  
 
Patients who experience a recurrence of the same severe or life-
threatening event at the same grade or greater with re-challenge of 
pembrolizumab (MK-3475) should be discontinued from study treatment. 
 
Dosing interruptions are permitted in the case of medical / surgical events 
or logistical reasons not related to study therapy (e.g., elective surgery, 
unrelated medical events, patient vacation, and/or holidays).  Patients 
should be placed back on study therapy within 1 week of the scheduled 
interruption, unless otherwise discussed with the Study Chair and AFT. The 
reason for interruption should be documented in the patient's study record. 
 
 
 
 
 
 


 
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14.1.2. 
Topotecan Dose Modification 
Should toxicity develop, treatment should be modified rather than 
discontinued.  Patients will be allowed to have no more than two separate 
dose reductions. All dose reductions are permanent. 
 
Patients will be evaluated on Day 1 of each 21-day cycle.  In the setting of 
grade 1 or greater toxicity, treatment will be adjusted according to the 
tables below.  If there is an indication for treatment to be held, re-evaluation 
will occur 7 days later.  If treatment can be resumed on day 8, there will be 
at least one decrease in dose level as noted below for topotecan.  If 
treatment must be held again at day 8, there will be a decrease by two dose 
levels whenever treatment resumes.  If treatment must be held for 22 days 
or more (≥ 6 weeks since initiation of last cycle), the patient will be 
withdrawn from study.  
 
Table 6.  Dose Reduction Guidelines for Topotecan 
Dose level 
Topotecan Dose 
Schedule 
-1 
Decrease by 0.25 mg/m2 
(To 1.0 mg/m2) 
Days 1-5 
-2 
Decrease by 0.5 mg/m2 
from baseline (To 0.75 
mg/m2) 
Days 1-5  
 
Table 7.  Dose Modification Guidelines for Topotecan Drug-Related Adverse Events 
Adverse Event 
Parameters 
on day of treatment 
CTCAE v4.0 
Grade 
Topotecan 
Hematologic 
ANC 
1000 – 1499 /mm3 
 
 
< 1000 /mm3 
Grade 2 
 
 
Grade 3 – 4 
Hold, then decrease by one 
dose level 
 
Hold, then decrease by one 
dose level 
Hemoglobin 
8.0 – 9.9 g/dL 
 
< 8.0 g/dL 
Grade 2 
 
Grade 3 – 4 
No change 
 
Hold, then decrease by one 
dose level 
Platelets 
 
75,000 – 99,000 /mm3 
 
50,000 – 74,000 /mm3 
 
 
< 50,000 /mm3 
        --- 
 
Grade 2 
 
 
Grade 3 – 4 
Hold 
 
Hold, then decrease by one 
dose level 
 
Hold, then decrease by one 
dose level 
Neutropenic Fever 
--- 
Grade 3 – 4 
Off study 
Infection 
(Documented clinically) 
with Grade 3 / 4 ANC 
Local intervention 
 
 
IV antibiotics indicated 
Grade 2 
 
 
Grade 3 – 4 
Hold, then decrease by one 
dose level 
 
Off study 
Non-Hematologic, Non-Neurologic 
Creatinine Clearance 
Cockcroft-Gault 
 60 ml/min 
 
--- 
 
No change 
 


 
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(non CTCAE) 
40-59 ml/min 
 
 
20-39 ml/min 
 
 
 < 20 ml/min 
--- 
 
 
--- 
 
 
--- 
Hold, then decrease by one 
dose level 
 
Hold, then decrease by two 
dose levels 
 
Off study 
AST or ALT1 
 
2.6 – 5.0 x ULN 
 
> 5.0 x ULN 
Grade 2 
 
Grade 3 – 4 
Hold 
 
Hold, then decrease by one 
dose level 
Total Bilirubin 
 
1.6 – 3.0 x ULN 
 
> 3.0 x ULN 
Grade 2 
 
Grade 3 - 4 
Hold 
 
Hold, then decrease by one 
dose level 
Alkaline phosphatase 2.6 – 5.0 x ULN 
 
> 5.0 x ULN 
Grade 2 
 
Grade 3 – 4 
Hold 
 
Hold, then decrease by one 
dose level 
Other Non-Hematologic2 
--- 
 
--- 
 
 
--- 
Grade 2 
 
Grade 3 
 
 
Grade 4 
No Change 
 
Hold, then decrease by one 
dose level 
 
Hold, then decrease by one 
dose level 
1  For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then 
patients should be discontinued. 
2  Excludes: alopecia, cough, dehydration, dry mouth, dry skin, dysphagia, edema, flatulence, 
flushing, heartburn, hemorrhoids, hiccoughs, hyper- or hypopigmentation, insomnia, nail changes, 
patient odor, or sweating. 
 
14.2. CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & PROHIBITED) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study.  If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the study, 
discontinuation from study therapy may be required.  The investigator should 
discuss any questions regarding this with the Study Chair. The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the 
patient’s primary physician. However, the decision to continue the patient on study 
therapy or vaccination schedule requires the mutual agreement of the Study Chair, 
AFT, and the patient.  
 
14.2.1. 
Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a patient’s welfare may 
be administered at the discretion of the investigator in keeping with the community 
standards of medical care.  All concomitant medication will be recorded on the 
case report form (CRF) including all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids.  If changes occur during the study 


 
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period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
All concomitant medications received within 28 days before the first dose of study 
treatment and 30 days after the last dose of study treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of study 
treatment should be recorded if administered due to a severe adverse event (SAE) 
or SAEs and/or event of clinical interest, as defined in Section 17.2.2.  
14.2.2. 
Prohibited Concomitant Medications 
  
Patients are prohibited from receiving the following therapies during the 
screening and treatment Phase of this study: 
 
 
Anti-cancer systemic chemotherapy or biological therapy 
 
 
Immunotherapy not specified in this protocol 
 
 
Chemotherapy not specified in this protocol 
 
 
Investigational agents other than pembrolizumab (MK-3475) 
 
 
Radiation therapy  
o Note:  Radiation therapy to a symptomatic, non-target solitary 
lesion or to the brain may be allowed after consultation with the 
Study PI and Sponsor 
 
 
Live vaccines within 30 days prior to the first dose of study treatment 
and while participating in the study.  Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. 
Flu-Mist®) are live attenuated vaccines, and are not allowed.  
 
 
Immunosuppressive medications including, but not limited to systemic 
corticosteroids (>10 mg/day prednisone or equivalent), methotrexate, 
azathioprine, and tumor necrosis factor alpha (TNF-α) blockers. Use 
of 
immunosuppressive 
medications 
for 
the 
management 
of 
investigational product-related AEs and in subjects with contrast 
allergies.  The use of physiologic steroid replacement may be 
approved after consultation with the investigator and Study PI. In 
addition, use of inhaled and intranasal corticosteroids is permitted. 
The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.   
 
 
Systemic glucocorticosteroids for any other purpose other than to 
modulate symptoms from an event of clinical interest or for use as a 
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for use for COPD exacerbation requiring steroid for recovery. 
Replacement doses of steroids (for example, prednisone 5-7.5 mg 
daily) are permitted while on study. Inhaled corticosteroids are 
allowed.  
 
Patients who, in the assessment by the investigator, require the use of any 
of the aforementioned treatments for clinical management should be 
removed from the study.   
 
The Exclusion Criteria describes other medications which are prohibited in 
this study. 
 
There are no prohibited therapies during the Post-Treatment Follow-up 
Phase. 
 
14.3. RESCUE MEDICATIONS AND SUPPORTIVE CARE 
 
14.3.1. 
Supportive Care Guidelines for Pembrolizumab 
 
 
Patients should receive appropriate supportive care measures as deemed 
necessary by the treating investigator, including but not limited to the items 
outlined below:  
 
Diarrhea:  Patients should be carefully monitored for signs and symptoms 
of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, 
with or without fever) and of bowel perforation (such as peritoneal signs 
and ileus).  In symptomatic patients, infectious etiologies should be ruled 
out, and if symptoms are persistent and/or severe, endoscopic evaluation 
should be considered. 
 
o All patients who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.   
 
o In patients with moderate enterocolitis (Grade 2), pembrolizumab (MK-
3475) should be withheld and anti-diarrheal treatment should be 
started.  If symptoms are persistent for more than one week, systemic 
corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or 
equivalent). When symptoms improve to Grade 1 or less, corticosteroid 
taper should be started and continued over at least one month.  
  
o In patients with severe enterocolitis (Grade 3), pembrolizumab (MK-
3475) will be permanently discontinued and treatment with systemic 
corticosteroids should be initiated (1 to 2 mg/kg/day of prednisone or 
equivalent). Prophylactic antibiotics should be initiated for opportunistic 
infections.  When symptoms improve to Grade 1 or less, corticosteroid 
taper should be started and continue over at least 1 month.  
 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, 
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administration of prophylactic antiemetic therapy according to standard 
institutional practice.  Patients should be strongly encouraged to maintain 
liberal oral fluid intake. 
 
Anti-infectives: Patients with a documented infectious complication should 
receive oral or IV antibiotics or other anti-infective agents as considered 
appropriate by the treating investigator for a given infectious condition, 
according to standard institutional practice. 
 
Immune-related adverse events: Please see Section 13.3.1.3. below 
regarding diagnosis and management of adverse experiences of a potential 
immunologic etiology. 
 
Management of Infusion Reactions:  Acute infusion reactions (which can 
include cytokine release syndrome, angioedema, or anaphylaxis) are 
different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs.  Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Signs/symptoms may 
include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia 
(joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of 
breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; 
Myalgia 
(muscle 
pain); 
Nausea; 
Pruritis/itching; 
Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; 
Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting. 
Table 8 below shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).  
 
Table 8: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
 
Stop the infusion and monitor 
symptoms. 
 
Additional appropriate medical 
therapy may include but is not 
limited to: 
 IV fluids 
 Antihistamines 
 NSAIDS 
 Acetaminophen 
 Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
Patient may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab  
with: 
 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject 
should be premedicated for the 
next scheduled dose. 
 
Patients who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study treatment 
administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
 IV fluids 
 Antihistamines 
 NSAIDS 
 Acetaminophen 
 Narcotics 
 Oxygen 
 Pressors 
 Corticosteroids 
 Epinephrine 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
Hospitalization may be indicated. 
 
Patient is permanently 
discontinued from further study 
treatment administration. 
 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov 
 
14.3.2. 
Supportive Care Guidelines for Pneumonitis 
 
Patients with symptomatic pneumonitis should immediately stop receiving pembrolizumab 
and have an evaluation.  The evaluation may include bronchoscopy and pulmonary function 
tests to rule out other causes such as infection.  If the patient is determined to have study 
drug associated pneumonitis, the suggested treatment plan is detailed in Table 9. 
 
 


 
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Table 9. Recommended Approach to Handling Pneumonitis 
Study Drug 
Associated 
Pneumonitis 
Withhold/Discontinue 
Pembrolizumab (MK-
3475)? 
Supportive Care 
Grade 1 
(asymptomatic) 
No action 
Intervention not 
indicated 
Grade 2 
Withhold pembrolizumab 
(MK-3475), may return to 
treatment if improves to 
Grade 1 or resolves within 
6 weeks 
Systemic 
corticosteroids are 
indicated.   
Taper if necessary. 
 
Grade 3 and Grade 4 
Discontinue 
pembrolizumab (MK-
3475) 
Systemic 
corticosteroids are 
indicated.  
The use of infliximab 
may be indicated as 
appropriate.   
Refer to the Events 
of Clinical Interest 
and Immune-related 
Adverse Event 
Guidelines in 
Section 13.3.3 below 
for additional 
recommendations.   
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 6 weeks, the following 
rules should apply: 
 
 
For the first episode of pneumonitis  
o May increase dosing interval by one week in subsequent cycles 
 
 
For the second episode of pneumonitis 
o Permanently discontinue pembrolizumab if upon rechallenge, the 
patient develops pneumonitis  Grade 2 
 
14.3.3. 
Supportive Care Guidelines for Events of Clinical 
Interest/Immune Related Adverse Events (IRAEs) 
 
Events of clinical interest of a potential immunologic etiology 
(IRECIs) may be defined as an adverse event of unknown etiology, 
associated with drug exposure and is consistent with an immune 
phenomenon.  IRAEs may be predicted based on the nature of the 
pembrolizumab (MK-3475) compound, its mechanism of action, 
and reported experience with immunotherapies that have a similar 
mechanism of action.  Special attention should be paid to AEs that 
may be suggestive of potential IRAEs.  An IRAE can occur shortly 
after the first dose or several months after the last dose of 
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If an IRAE is suspected, efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes 
prior to labeling an adverse event as an IRAE. Patients who 
develop a Grade 2 or higher IRAE should be discussed 
immediately with the Study PI.  
  
Recommendations to managing IRAEs not detailed elsewhere in 
the protocol are detailed in Table 10. 
 
Table 10.  General Approach to Treating IRAEs 
IRAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab 
(MK-3475) 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment 
Grade 3 and Grade 4 
Withhold pembrolizumab (MK-
3475) 
Discontinue if unable to reduce 
corticosteroid dose to < 10 mg per 
day prednisone equivalent within 
6 weeks of toxicity 
Systemic corticosteroids are indicated 
in addition to appropriate symptomatic 
treatment, utilizing 1 to 2 mg/kg 
prednisone or equivalent per day. 
 
Steroid taper should be considered 
once symptoms improve to Grade 1 
or less and tapered over at least 4 
weeks. 
 
 
14.3.4. 
Supportive Care Guidelines for Events of Clinical 
Interest/Immune Related Adverse Events (IRAEs) 
 
Patient should receive appropriate supportive care measures as deemed 
necessary by the treating investigator, including but not limited to the items 
outlined below:  
 
Diarrhea:  Patients should be carefully monitored.  Patients can receive 
aggressive anti-diarrheal agents, including and not limited to: loperamide 
and atropine/diphenoxylate.    
 
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.   
 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, 
and consideration should be given in subsequent cycles to the 
administration of prophylactic antiemetic therapy according to standard 
institutional practice.  Patients should be strongly encouraged to maintain 
liberal oral fluid intake. 
 
Anti-infectives: Patients with a documented infectious complication should 
receive oral or IV antibiotics or other anti-infective agents as considered 
appropriate by the treating investigator for a given infectious condition, 
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Bone Marrow Support:   Pegfilgrastim can be administered on day 6, 7 or 
8 of every cycle at the discretion of the investigator.  Pegfilgrastim can be 
initiated at cycle 1 or after neutropenia is observed.  There are no 
contraindications to blood transfusions. 
14.4. OTHER CONSIDERATIONS 
 
14.4.1. 
Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if pembrolizumab (MK-3475) has transient adverse effects 
on the composition of sperm.   
For this study, male subjects will be considered to be of non-reproductive 
potential if they have azoospermia (whether due to having had a vasectomy 
or due to an underlying medical condition).  
 
Female subjects will be considered of non-reproductive potential if they are 
either:  
 
(1) Postmenopausal (defined as at least 12 months with no menses without 
an alternative medical cause; in women <45 years of age a high follicle 
stimulating stimulating hormone (FSH) level in postmenopausal range 
may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.): 
 
OR 
 
(2)  Have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior 
to screening;  
 
OR 
(3) Has a congenital or acquired condition that prevents childbearing.  
 
Female and male subjects of reproductive potential must agree to avoid 
becoming pregnant or impregnating a partner, respectively, while receiving 
study drug and for 120 days after the last dose of study drug by complying 
with one of the following:  
 
(1) Practice abstinence* from heterosexual activity; 
 
OR 
 
(2) Use (have their partner use) acceptable contraception during 
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The following are considered acceptable barrier methods of contraception:  
 
Single method (one of the following is acceptable): 
 
• Intrauterine device (IUD) 
• Vasectomy of a female subject’s male partner 
• Contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
 
• 
Diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
• 
Cervical cap with spermicide (nulliparous women only) 
• 
Contraceptive sponge (multiparous women only)  
• 
Male condom or female condom (cannot be used together) 
• 
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin – 
only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection) 
 
*Abstinence (relative heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the subject’s 
preferred and usual lifestyle and if considered acceptable by local 
regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g. calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception. 
 
*If a contraceptive method listed above is restricted by local 
regulations/guidelines then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region.  
 
Patients should be informed that taking the study medication may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during 
the study.  In order to participate in the study patients of childbearing 
potential must adhere to the contraception requirement (described above) 
from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up 
to 120 days after the last dose of study therapy.  If there is any question 
that a patient of childbearing potential will not reliably comply with the 
requirements for contraception, that patient should not be entered into the 
study. 
 
14.4.2. 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with 
pembrolizumab (MK-3475), the subject will immediately be removed from 
the study.  The site will contact the patient at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated.  
The outcome of the pregnancy will be reported to AFT without delay and 
within 24 if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening 
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The study investigator will make every effort to obtain permission to follow 
the outcome of the pregnancy and report the condition of the fetus or 
newborn to AFT.   If a male patient impregnates his female partner the 
study personnel at the site must be informed immediately and the 
pregnancy reported to AFT and followed as described above. AFT will 
report pregnancy outcomes to Merck.  
 
14.4.3. 
Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for 
serious adverse reactions in the nursing infant, patients who are breast-
feeding are not eligible for enrollment. 
 
15. MEASUREMENT OF EFFECT 
 
This randomized phase II study will evaluate PFS as the primary endpoint based on 
RECIST 1.1,29 which will be used for assessment of tumor response.   
 
15.1. SCHEDULE OF EVALUATIONS 
The initial tumor imaging will be performed within 14 days prior to the first dose of study 
treatment. Scans performed as part of routine clinical management are acceptable for use 
as the screening scan if they are of diagnostic quality and performed within 14 days prior to 
the first dose of study treatment. On-study imaging will be performed every 6 weeks (42 ± 7 
days) after the first dose of study treatment or more frequently if clinically indicated.  The 
timing for imaging studies should follow calendar days and should not be adjusted for 
delays in cycle starts or extension of topotecan or pembrolizumab (MK-3475) cycle 
frequencies. The same imaging technique should be used in a patient throughout the study.  
 
After the first documentation of progression while receiving pembrolizumab (MK-3475) alone 
it is at the discretion of the investigator to keep a clinically stable patient on study treatment 
or to stop study treatment until repeat imaging performed 4-6 weeks later confirms 
progression.  
 
Clinical stability in a patient whose disease displays radiographic progression is defined as:  
 
Absence of symptoms and signs indicating clinically significant progression of disease 
(including worsening laboratory values).  
 
NO decline in ECOG performance status.  
 
Absence of rapid progression of disease or progressive tumor at critical anatomical sites 
(e.g. cord compression) requiring urgent alternative medical intervention.  
 
Patients that are deemed clinically unstable are not required to have repeat imaging for 
confirmation. Upon repeat imaging, if progression is confirmed, then the patient will be 
discontinued from study treatment. As the primary endpoint is PFS, the date of the first scan 
that documented progression should be used. If progression is not confirmed, then the 
patient should resume/continue study treatment and have the next scan according to the 
every 6-week (42 ± 7 days) schedule from the first dose of study treatment. When feasible, 
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For patients who discontinue study treatment for reasons other than disease progression,  
imaging should continue according to the same schedule (every 6 weeks/ 42  ±  7 days) until 
the patient experiences confirmed disease progression or starts a new antineoplastic 
therapy. 
 
Study eligibility will be according to RECIST 1.1 criteria. 
15.1.1. 
Response for Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors  
RECIST Version 1.1* will be used in this study for assessment for tumor response.  
 
*As published in the European Journal of Cancer 
15.1.2. 
Response for Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors  
 
Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan,   
 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as assessed using calipers (e.g. skin nodules) or imaging.  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).   
Lesions that are previously irradiated must show clear evidence of progression to be 
considered as measurable disease.  
Non-Measurable Disease 
All other lesions (or sites of disease) are considered non-measurable disease, including 
pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm).  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT), are considered as non-
measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.  In addition, lymph nodes that have a short axis < 1.0 cm are considered non-
pathological (i.e., normal) and should not be recorded or followed. 
 
15.1.3. 
Guidelines for Evaluation of Measurable Disease 
 
Measurement Methods:   
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
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patients having only lesions measuring at least 1 cm to less than 2 cm must use CT 
imaging for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect 
of a treatment.  
Acceptable Modalities for Measurable Disease: 
 
Conventional CT: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness be at least 2.5 mm but no greater 
than 5 mm. 
 
 Measurement at Follow-up Evaluation:   
 
A subsequent scan must be obtained not less than 4 weeks following initial 
documentation of an objective status of either complete response (CR) or partial 
response (PR). 
 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of not less than 6 weeks. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response 
or stable disease is mandatory to differentiate between response or stable disease 
(an effusion may be a side effect of the treatment) and progressive disease.  
 
Cytologic and histologic techniques can be used to differentiate between PR and CR 
in rare cases (e.g. residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain.) 
 
Measurement of Treatment/Intervention Effect 
Target Lesions & Target Lymph Nodes 
 
Measurable lesions up to a maximum of 5 lesions representative of all involved 
organs, should be identified as “Target Lesions” and recorded and measured at 
baseline.  These lesions can be non-nodal or nodal where no more than 2 lesions 
are from the same organ and no more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there 
often will be), there is no reason to perform additional studies beyond those specified 
in the protocol to discover new lesions.   
 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the 
case that, on occasion, the largest lesion (or malignant lymph node) does not lend 
itself to reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected.   
 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD).  The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
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 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD).  If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm.  If the target lesion (or 
target lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned.  If it is the opinion of the 
radiologist that the target lesion or target lymph node has likely disappeared, the 
measurement should be recorded as 0 cm. 
 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
 
Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease are classified as non- target lesions or non-target 
lymph nodes and should also be recorded at baseline.  These lesions and lymph 
nodes should be followed. 
 
15.1.4. 
Response Criteria 
 
All target lesions and target lymph nodes followed by CT must be measured on re 
evaluation at evaluation times specified in Section 15.2.1 & 15.2.3.  Specifically, a change in 
objective status to either a PR or CR cannot be done without re-measuring target lesions 
and target lymph nodes.  
 
Note: Non –target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In selected 
circumstances, certain non-target organs may be evaluated less frequently. For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected.  
 
Evaluation of Target Lesions 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to < 1.0 cm. 
• 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the BSD. 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node 
that was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 
cm short axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes 
at current evaluation) taking as reference the MSD. In addition, the PBSD 
must also demonstrate an absolute increase of at least 0.5 cm from the 
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patient no longer wishes to continue protocol therapy, protocol therapy shall 
be discontinued. 
 
A patient must be discontinued from the study for any of the following 
reasons: 
 
 
The patient or legal representative (such as a parent or legal 
guardian) withdraws consent. 
 
Confirmed 
radiographic 
disease 
progression 
while 
receiving 
pembrolizumab as per RECIST 1.1. 
Note: A patient may be granted an exception to continue on 
treatment with confirmed radiographic progression if clinically 
stable or clinically improved, per the investigator’s discretion, 
given the potential of tumor flare.  
 
Unacceptable adverse experiences  
 
Intercurrent illness that prevents further administration of treatment 
 
Investigator’s decision to withdraw the patient 
 
The patient has a confirmed positive serum pregnancy test 
 
Noncompliance with study treatment or procedure requirements 
 
The patient is lost to follow-up 
 
Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 9. 
After the end of treatment, each patient will be followed for a minimum of 30 
days for adverse event monitoring. Serious adverse events will be collected for 
up to 90 days after the end of treatment or 30 days after the end of treatment if 
the subject initiates new anticancer therapy, whichever is earlier.  Patients who 
discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status every 6 weeks until disease progression, initiating a 
non-study cancer treatment, withdrawing consent or becoming lost to follow-up.  
After documented disease progression each patient will be followed by 
telephone every 12 weeks for overall survival until death, withdrawal of consent, 
or the end of the study, whichever occurs first. 
 
16.3.  DEFINITIONS AND FOLLOW-UP REQUIREMENTS 
 
Definition of ineligible patients: A study participant who is registered to the study 
but does not meet all of the eligibility criteria is deemed to be ineligible. 
  
Definition of clinical follow-up: The follow-up period where the study participant is 
no longer receiving treatment, but is still following the study calendar for tests, 
exams, and correlative endpoints (e.g., specimen collection, quality of life, disease 
assessments as required by the study). 
 
Definition of survival only follow-up: The follow-up period where the study 
participant is monitored for long-term endpoints, is no longer receiving study 
treatment, and is not required to follow the study calendar for tests, exams, and 
correlative endpoints (e.g. specimen collection, quality of life, disease assessments 
as required by the study). In this follow-up period, there is a schedule in which case 


 
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report forms should be submitted, but the physician visits are based on the 
standard of care.  
16.4. FOLLOW UP FOR INELIGIBLE PATIENTS 
Study participants who are registered to the study and receive any protocol 
treatment but deemed ineligible must follow the schedule of assessments detailed 
in Section 9. 
16.5. FOLLOW-UP FOR PATIENTS NEVER RECEIVING PROTOCOL INTERVENTION 
Study participants who are enrolled into the study but who never go on to receive 
study intervention must still complete follow-up requirements as specified below. 
Screening, on-study, endpoint (e.g., relapse or progression), and survival data 
submission required. 
 
17. ADVERSE EVENTS 
 
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 to have a causal relationship with this treatment.  An adverse event 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to 
the medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of pembrolizumab is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to onset of menses or menopause 
occurring at a physiologically appropriate time. 
 
Adverse events may occur during the course of the use of pembrolizumab (or topotecan) 
during this study, or as prescribed in clinical practice, from overdose (whether accidental 
or intentional), from abuse and from withdrawal. 
 
Progression of small cell lung cancer is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
 
The prompt reporting of adverse events is the responsibility of each investigator 
engaged in clinical research, as required by Federal Regulations.  Adverse events must 
be described and graded using the terminology and grading categories defined in the 
NCI’s Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The 
CTCAE 
is 
available 
at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Attribution 
to 
protocol treatment for each adverse event must be determined by the investigator and 
reported on the required forms, using the codes provided. 
 


 
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17.1. ROUTINE ADVERSE EVENT REPORTING 
 
Adverse event data collection and reporting, which are required as part of every 
clinical study are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. AEs will be 
recorded as part of medical history during Screening. All adverse events that occur 
after the consent form is signed but before treatment allocation/randomization must 
be reported by the investigator if they cause the subject to be excluded from the 
study, or are the result of a protocol specified intervention, including but not limited 
to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   Any new AEs or increase of a documented AE from screening/history 
will be recorded from the time of the first treatment allocation/randomization 
through 30 days following cessation of treatment. Adverse events are reported in a 
routine manner at scheduled times according to the study calendar in Section 9. All 
adverse events are entered into the eCRF in Rave. The investigator will make 
every attempt to follow all subjects with non-serious adverse events for outcome.  
 
Adverse events will not be collected for patients during the pre-screening period as 
long as that patient has not undergone any protocol-specified procedure or 
intervention.  If the patient requires a blood draw, fresh tumor biopsy etc., the 
patient is first required to provide consent to the main study and AEs will be 
captured according to guidelines for standard AE reporting. 
 
17.2. EXPEDITED ADVERSE EVENT REPORTING 
 
Investigators are required by Federal Regulations to report serious adverse events 
as defined in the table below.  Investigators are required to notify the AFT and their 
Institutional Review Board if a patient has a reportable serious adverse event. The 
descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE 
reporting.  The CTCAE is identified and located on the CTEP website at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
SAEs/Infusion Associated Reactions (IARs) must be entered into the eCRF via 
Rave EDC within 24 hours of learning of the event. This will allow the safety 
monitor and monitor to review the information and assess the safety of the patient. 
 
Note:  All deaths on study require reporting via Rave EDC, regardless of 
causality.  Attribution to treatment or other cause should be provided. 
 
17.2.1. 
Serious Adverse Event (SAE) 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event due to any cause other than progression of the cancer under study 
that occurs to any subject must be reported within the timelines listed in Table 12 
below if it causes the patient to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  
 
 


 
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Table 12. Serious Adverse Event Reporting Requirements 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS  
NOTE:  Investigators MUST immediately report to the sponsor (AFT) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
 
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect 
 
Note:  Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, they 
may jeopardize the patient or patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. In addition to the above criteria, 
although not serious per ICF definition, are reportable to AFT in the same timeframe as 
SAEs to meet certain local requirements. Therefore these events are considered serious 
by AFT for collection purposes:  
• 
The development of a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
the AFT via the Rave Electronic Data Capture (EDC) system within the timeframes detailed in 
the table below.  AFT will send SAE reports to Merck Global Safety within 2 working days. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization > 24 hrs 
Enter into Rave EDC within 24 hours of the sites awareness of the 
event 
 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required to enter into Rave 
EDC as an SAE.  
Enter into Rave EDC as an SAE 
within 24 hours of the sites 
awareness of the event 
Expedited AE reporting timelines are defined as: 
 
“All Grade 3, 4 and 5 AEs: 24-Hour; 4 Calendar Days” - The AE must initially be reported via 
Rave EDC ≤ 24 hours of learning of the AE, followed by a complete expedited report 
≤ 4 calendar days of the initial 24-hour report. 
 
“All Grade 1 and 2 AEs resulting in hospitalization or prolonged hospitalization: 24-Hour; 10 
Calendar Days” - The AE must initially be reported via Rave EDC ≤ 24 hours of learning of 
the AE, followed by a complete expedited report ≤ 10 calendar days of the initial 24-hour 
report. 
 


 
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Serious adverse events will be recorded from the time of treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following cessation of treatment if 
the patient initiates a new antineoplastic therapy, whichever comes first. Any serious adverse 
event, or follow up to a serious adverse event, including death due to any cause other than 
progression of the cancer under study whether or not related to pembrolizumab (MK-3475) 
must be reported into Rave EDC within 24 hours of awareness of the event.  
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to pembrolizumab (MK-3475) that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph must also be reported immediately to AFT.  
 
All patients with serious adverse events must be followed up for outcome.  
 
NOTE: Deaths occurring outside of the serious adverse event reporting period that are 
clearly due to progressive disease should be reported via routine reporting methods 
in the  Rave data capture system.  Deaths occurring within the reporting window, 
even if considered to be related to disease progression as the cause of death should 
be reported within Rave EDC with death noted as the outcome of the event. 
 
 
17.2.2. 
Events of Clinical Interest and Immune Related Adverse Events 
Selected non-serious and serious adverse events are also known as (ECI) and/or 
Immune Related Adverse Events (irAEs) and must be reported within 24 hours within 
Rave EDC system.  
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject if 
it causes the subject to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure must be reported as an SAE within 
Rave EDC within System 24 hours and AFT will report to Merck Global Safety within 2 
days 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to 
an ECI, whether or not related to pembrolizumab (MK-3475), must be reported within 
via Rave EDC within 24 hours and AFT will report to Merck Global Safety within 2 days 
 
ECIs/ir AEs for this study include: 
 
1.   
An overdose of pembrolizumab, as defined in Section 16.3 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to AFT, that is not associated 
with clinical symptoms or abnormal laboratory results.  
 
2. 
An elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater than or 


 
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equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase 
lab value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.   
 
 
17.2.3. 
Protocol-Specific Exceptions to Serious Adverse Event 
Reporting  
 
Efficacy endpoints as outlined in this section will not be reported to AFT as described 
in Section 16.2.1 – Table 12, unless there is evidence suggesting a causal relationship 
between pembrolizumab and the event. Any such event will be submitted to AFT via 
Rave EDC within 24 hours and AFT will report to Merck Global safety within 2 working 
days.  
 
Specifically, the suspected/actual events covered in this exception include any event 
that is disease progression of the cancer under study. 
 
AFT will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the study. Any suspected endpoint which upon 
review is not progression of the cancer under study will be forwarded by AFT to Merck 
Global Safety within 2 working days of determination that the event is not progression 
of the cancer under study.  
 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be 
considered a SAE.  
 
 
17.2.4. 
Definition of an overdose for this protocol and reporting of 
overdose to AFT 
 
For purposes of this study, an overdose will be defined as any dose exceeding the 
prescribed dose for pembrolizumab by 20% over the prescribed dose.  No specific 
information is available on the treatment of overdose of pembrolizumab.  In the event 
of overdose, pembrolizumab should be discontinued and the patient should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a 
pembrolizumab, the adverse event(s) is reported as a serious adverse event, even if 
no other seriousness criteria are met. 
 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.” 
 
17.2.5. 
Reporting of Pregnancy and Lactation 


 
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Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in 
a patient (spontaneously reported to them) that occurs during the study. Sites may use 
the pregnancy form in Rave EDC to report pregnancies.  
 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.  
 
Pregnancies 
and 
lactations 
that 
occur 
from 
the 
time 
of 
treatment 
allocation/randomization through 120 days following cessation of pembrolizumab, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator. All pregnancies must be 
followed to the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
 
17.3. EVALUATING ADVERSE EVENTS 
 
An investigator who is a qualified physician will evaluate all adverse events according 
to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any 
adverse event which changes CTCAE grade over the course of a given episode will 
have each change of grade recorded on the adverse event case report 
forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. See Table 13 below for additional guidance. 


 
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Table 13. Evaluating Adverse Events 
 
An investigator who is a qualified physician, will evaluate all adverse events.  
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Pembrolizumab that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused 
death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization to treat a preexisting condition that has not worsened is not a serious adverse event. A pre-existing condition is 
a clinical condition that is diagnosed prior to the use of pembrolizumab and is documented in the patient’s medical history); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) (although serious per ICH definition, is reportable to  AFT within 24 hours 
and AFT will report to Merck Global Safety within 2 working days). 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  Did the adverse event cause Pembrolizumab to be discontinued? 


 
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Relationship 
to study 
drug  
Did Pembrolizumab cause the adverse event? The determination of the likelihood that Pembrolizumab caused the adverse 
event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug 
and the adverse event based upon the available information.  
 
The following components are to be used to assess the relationship between Pembrolizumab and the AE; the greater 
the correlation with the components and their respective elements (in number and/or intensity), the more likely Pembrolizumab 
caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Pembrolizumab such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Pembrolizumab?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Relationship to 
Pembrolizumab 
(continued) 
The following components are to be used to assess the relationship between the test drug and the AE:  
(continued) 
 
 
Dechallenge 
Was Pembrolizumab discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of Pembrolizumab; or (3) Pembrolizumab(s) is/are only 
used one time.) 
 
Rechallenge 
Was the subject re-exposed to Pembrolizumab in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) Pembrolizumab(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY PEMBROLIZUMAB, OR IF REEXPOSURE TO 
PEMBROLIZUMAB POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency with 
Study Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding 
Pembrolizumab or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to 
his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a 
Pembrolizumab relationship). 
Yes, there is a reasonable 
possibility of Pembrolizumab 
relationship. 
There is evidence of exposure to Pembrolizumab.  The temporal sequence of the AE onset relative to the 
administration of Pembrolizumab is reasonable.  The AE is more likely explained by Pembrolizumab than by 
another cause. 
No, there is not a reasonable 
possibility Pembrolizumab 
relationship 
Patient did not receive Pembrolizumab OR temporal sequence of the AE onset relative to administration of 
Pembrolizumab is not reasonable OR the AE is more likely explained by another cause than pembrolizumab..  
(Also entered for a subject with overdose without an associated AE.) 
 


 
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18. DRUG INFORMATION 
18.1. INVESTIGATIONAL PRODUCT 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution 
and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 14. 
 
Table 14.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
18.2.  PACKAGING AND LABELING INFORMATION 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
18.3.  CLINICAL SUPPLIES DISCLOSURE 
This study is open-label; therefore, the patient, the study site personnel, the 
Sponsor and/or designee are not blinded to treatment. Drug identity (name, 
strength) is included in the label text; random code/disclosure envelopes or lists 
are not provided. 
 
18.4.  STORAGE AND HANDLING REQUIREMENTS 
Clinical supplies must be stored in a secure, limited-access location under the 
storage conditions specified on the label.   
 
Receipt and dispensing of study medication must be recorded by an authorized 
person at the study site. 
 
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 
18.5.  RETURNS AND RECONCILIATION 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the 
patients and the amount remaining at the conclusion of the study. 
  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
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applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
19. STATISTICAL CONSIDERATIONS 
This phase II study will determine if there is a benefit in progression free survival 
(PFS) for SCLC patients receiving pembrolizumab (Experimental arm, E) as 
compared to topotecan (Control arm, C) in the second-line setting. The primary 
endpoint will be PFS, defined as the time between randomization and disease 
progression or death of all  causes, whichever comes first.  
 
A total of 98 patients will be registered to this study. Taking into account 5% rate of 
ineligibility and cancellation, a total of 93 eligible patients will be randomized 2:1 
allocation to arm E and arm C. Randomization will be implemented with dynamic 
allocation algorithm with the stratification factor for disease type (sensitive vs. 
refractory). All patients will be followed for a minimum of 6 months after the last 
enrollment of the study. 
 
19.1. SAMPLE SIZE JUSTIFICATION 
According to the findings from the phase III study studying topotecan vs CAV6 in 
the second-line treatment of SCLC patients and the phase III study comparing oral 
and intravenous topotecan,45 we expect a median PFS of 12 weeks for the control 
arm (C) and 20 weeks (a 67% increase) for the experimental therapy (E) in the 
pooled patient population with relapsed sensitive or refractory SCLC.  Under the 
assumption of exponential survival time, it corresponds to a hazard ratio λE/λC = 
0.60. Assuming an accrual rate of 4 randomized patients per month, it will take 
approximately 23 months to enroll 93 randomized patients (62 arm E and 31 arm 
C).  With additional follow-up of 26 weeks (approximately 6 months) after the 
enrollment of the last patient, or approximately 86 events (59 arm E, 27 arm C), the 
study has approximately 82% power to reject the null hypothesis λE/λC = 1 and 
accept the alternative hypothesis λE/λC < 1 when the true λE/λC = 0.60 using a 
stratified log rank test at a 1-sided significance level of 0.10.  
 
Per above, eligible patients will be randomized with 2:1 allocation to two arms (E 
and C). The patients on arm C are allowed to receive pembrolizumab after 
progression. The final analysis is expected to take place 6 months after the last 
enrolled patient has been treated.  
 
In the primary analysis, a stratified log rank test with equal weights over time will be 
used to test the PFS difference between two arms. As late treatment effect is often 
observed for immunotherapy, a weighted log rank test with Fleming-Harrington 
weights58 also will be used as a supplementary analysis to maximize the test 
efficiency for late treatment effect. More details can be found in the Analytic 
Method section. 
 
Objective response rate (ORR) is a secondary endpoint. The sample size of the 
study is not determined by having adequate power to test ORR. With 62/31 
patients on arm E/C, the study has approximately 82% power to differentiate 
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19.2. ACCRUAL AND FOLLOW-UP 
With allowance of 5% ineligible, cancelling and unevaluable, the study plans to 
register 98 patients.  We estimate to enroll and randomize 4 patients per month 
and anticipate approximately 23 months to achieve the target accrual. A minimum 
of 6 months of follow-up is needed to evaluate the primary objective if the accrual 
rate is at the expected range. 
 
19.3. ADVERSE EVENTS MONITORING 
 
If 5 or more of the first 20 patients in any of the two arms experience grade 4/5 
non-hematologic adverse events that are probably, possibly, or definitely related 
to study treatment, OR if the rate of treatment-related deaths within the first 60 
days exceeds 4 or more in an arm among the first 20 patients at any time, accrual 
to the study will be suspended to allow for investigation. After consideration by the 
study team, a decision will be made as to whether accrual can be resumed, 
potentially with modifications to entry criteria and/or study conduct.   
20. STATISTICAL ANALYSIS PLAN 
 
The primary analysis will include all randomized patients but exclude ineligible patients 
or patients who cancel this study before receiving any protocol treatment.  
 
The primary efficacy endpoint is PFS, which is defined as the time from the date of 
randomization to the date of earliest radiographic disease progression or death. If the 
subject does not experience radiographic disease progression or death, then the data 
will be censored at the date of the last disease assessment. PFS will be analyzed by 
Kaplan Meier methodology and compared between arm E and arm C, using a log-rank 
test stratified by disease type (sensitive vs refractory). A two-sided, stratified log-rank 
test P value will be provided. Median PFS time will be calculated and 95% confidence 
interval for median PFS will be presented. Overall survival (OS) will be analyzed in a 
similar manner as PFS.  
 
Late treatment effect is often expected for immunotherapy. For this reason, a weighted 
log rank test with Harrington-Fleming weights that optimize the expected late treatment 
effect will be conducted as a supplementary analysis for both PFS and OS. In particular, 
the following three parameter settings will be used: (1) ρ = 0 and γ = 0.5; (2) ρ = 0 and γ 
= 1; and (3) ρ = 0 and γ = 2 (39). 
 
The proportion of subjects with objective response as assessed by the investigator using 
RECIST version 1.1 will be evaluated for randomized subjects. The objective response 
rate will be estimated and compared between arm E and arm C, using a Cochran-
Mantel-Haenszel (CMH) test stratified by tumor volume. A two-sided, stratified CMH test 
P value will be provided. In addition, a 95% confidence interval will be constructed for 
the estimated proportions. Similar analysis will be conducted for disease control rate 
(DCR), which is defined as the proportion of patients achieving complete, partial and 
stable disease after the protocol treatment. 
 
All subjects who receive at least one dose of the study drug will be included in safety 
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class. Comparisons of the percentages of subjects experiencing an adverse event 
between arm E and arm C will be performed using Fisher's exact test. 
 
The association between candidate biomarkers in tumor samples, including, but not 
limited to, CD3, CD4, CD8, FoxP3, PD-1, CD68, MHC class I and II, and PD-L1, with 
response will be evaluated using Wilcoxon rank sum test. The association of these 
biomarkers with PFS and OS will be evaluated using single-predictor Cox models. 
 
The correlation between T-cell immunophenotypes in peripheral blood mononuclear cell 
samples and clinical response will be evaluated with Chi-square test.  
 
The correlation between mutational burden in tumor specimens and objective response 
will be evaluated using Wilcoxon rank sum test separately for patients treated by 
pembrolizumab and topotecan.  
 
The difference in neoantigen signature between SCLC tumors responding to PD-1 
inhibition and those not responding to therapy will be evaluated. 
 
21. GENERAL REGULATORY CONSIDERATIONS 
21.1. COMPLIANCE WITH STUDY ENROLLMENT AND RESULTS POSTING REQUIREMENTS 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) 
and the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of 
the study is solely responsible for determining whether the study and its results are 
subject to the requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov.  Information posted will allow patients to identify 
potentially appropriate studies for their disease conditions and pursue participation 
by calling a central contact number for further information on appropriate study 
locations and study site contact information. 
 
21.2. REGULATORY AND ETHICAL COMPLIANCE 
By signing the Protocol the investigator agrees to treat all of the information that is 
provided with the strictest confidentiality and to require the same of his personnel 
as well as the IRB. Study documents (protocols, investigator`s brochures, eCRFs, 
etc.) provided by the AFT will be stored in an appropriate manner in order to 
ensure confidentiality. The information provided to the investigator by AFT must not 
be made available to other parties without a direct written authorization by the 
aforesaid parties, with the exception of the extent to which disclosure is necessary 
in order to obtain informed consent from the patients who wish to participate in the 
study. 
 
21.3. ETHICS AND GOOD CLINICAL PRACTICE 
This study will be conducted in compliance with the study protocol, subsequent 
amendment(s) and with the study-specific manuals/guidelines, if applicable. These 
documents ensure that the ICH E6 guideline for Good Clinical Practice is 
maintained as well as compliance with the principles of the Declaration of Helsinki 
(World Medical Association), or the laws and regulations of the country in which the 
research is conducted, whichever afford the greater protection to the individual. 


 
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The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting). 
 
Studies conducted in the United States or under a U.S. Investigational New Drug 
(IND) application will comply with U.S. FDA regulation and applicable local, state 
and federal laws. 
 
By signing the study protocol the investigator agrees to comply with the instructions 
and procedures described therein and thus to adhere to the principles of good 
clinical practice, which these instructions and procedures reflect. 
 
21.4. CONFIDENTIALITY 
Patient medical information both, associated with biologic specimens or not, is 
confidential and may only be disclosed to third parties as permitted by the ICF (or 
separate authorization for use and disclosure of personal health information) which 
has been signed by the patient, unless permitted or required by law. Data derived 
from biologic specimen analysis on individual patients will in generally not be 
provided to study investigators unless a request for research use is granted. The 
overall results of any research conducted using biologic specimens will be 
available in accordance with the effective AFT policy on study data publication. 
 
21.5. PROTOCOL AMENDMENTS 
Any modifications to the protocol or the Informed Consent Form which may impact 
on the conduct of the study, potential benefit of the study, or may affect patient 
safety, including changes of study objectives, study design, patient population, 
sample sizes, study procedures, or significant administrative aspects will require a 
formal amendment to the protocol. Such amendment will be released by AFT, 
agreed by the investigator(s) and approved by relevant IRBs prior to 
implementation. A signed and dated statement that the protocol, any subsequent 
relevant amended documents and the Informed Consent Form have been 
approved by relevant IRBs must be provided to AFT before the study is initiated.  
 
Administrative changes of the protocol are minor corrections and/or clarifications 
that have no effect on the way the study is to be conducted. These administrative 
changes will be released by the AFT, agreed by the investigator(s) and notified to 
the IRB.  
 
21.6. INFORMED CONSENT 
It is the responsibility of the Investigator, or a person designated by the Investigator 
(if acceptable by local regulations), to obtain written Informed Consent from each 
patient participating in this study, after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study. This information must be 
provided to the patient prior to undertaking any study-related procedure which is 
not part of the routine clinical management of the patient (i.e. would not be 
indicated outside the study).  
 


 
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For patients not qualified or incapable of giving legal consent, written consent must 
be obtained from the legally acceptable representative. In the case where both the 
patients and his/her legally acceptable representative are unable to read, an 
impartial witness should be present during the entire informed consent discussion. 
After the patient and representative have orally consented to participation in the 
study, the witness’ signature on the form will attest that the information in the 
consent form was accurately explained and understood. The Investigator or 
designee must also explain that the patients are completely free to refuse to enter 
the study or to withdraw from it at any time, for any reason.  
 
Furthermore, it is the investigator’s responsibility to obtain the signed Informed 
Consent Form, and a signature from the person conducting the informed consent 
discussion, prior to undertaking any study-related procedure. The proposed 
Informed Consent Form must accomplish with the ICH GCP guideline and 
regulatory requirements.  
 
If new pembrolizumab safety information results in significant changes in the 
risk/benefit assessment, the Informed Consent Form should be reviewed and 
updated if necessary. All patients who may be directly affected (including those 
already being treated) should be informed of the new information, given a revised 
form and give their consent to continue in the study. 
 
21.7. MONITORING AND REMOTE MONITORING 
The Investigator is responsible for being available during sponsor monitoring visits.  
Study staff should be available to answer questions and address any issues or 
data clarifications.  Prior to these visits, the monitor will send a confirmation letter 
to the Investigator outlining the data that they would need access to.   The site 
should have this readily available prior to the visit.  This includes ICFs, source 
records as needed, medical/electronic medical records, safety, drug accountability 
and the ISF.  The first site monitoring visit will occur approximately four weeks after 
the first AFT-17 patient is enrolled. 
 
It is expected that the data is entered into the eCRF in a timely manner after the 
first information is collected, preferably within 3-5 days after the study procedure 
has been performed.   The monitor will also be able to review this data remotely.  
In this case, the monitor will request de identified source data to be sent to them for 
cross references. 
 
21.8. FINANCIAL DISCLOSURE 
Investigators will provide AFT with adequate and accurate financial information in 
accordance with local regulations and laws in order to allow AFT to submit 
complete and accurate financial certification or disclosure statements to the 
appropriate health authorities. Investigators are responsible for providing updated 
information on financial interests during the course of the study as well as for 1 
year after completion of the study. 
 


 
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21.9. PROTOCOL DEVIATIONS 
The investigator is responsible to document and explain any deviations from the 
approved protocol. The investigator should promptly report any deviations that 
might impact patient safety and data integrity to AFT and if locally applicable, to the 
respective IRB in accordance with local IRB policies and procedures.  
 
A deviation is a departure from the protocol.   If deviations are discovered by the 
monitor or data manager, other member of study staff or otherwise, they will be 
discussed with the Investigator and study staff. AFT does not grant protocol 
deviation waivers.    
 
21.10. RETENTION OF RECORDS 
Any records and documents relating to the conduct of this study and the 
distribution of investigational drug, including ICFs, eCRFs, PRO data, laboratory 
test results, and medication inventory records, must be retained by the study chair 
until notification by AFT, or for the length of time required by relevant national or 
local health authorities, whichever is longer. After that period of time, the 
documents may be destroyed, subject to local regulations. No records may be 
disposed of without the written approval of AFT. Written notification should be 
provided to AFT prior to transferring any records to another party or moving them 
to another location. 
 
21.11. CLINICAL CRITERIA FOR EARLY STUDY ADMINISTRATION 
Early study termination will be the result of the criteria specified below: 
1. 
Quality or quantity of data recording is inaccurate or incomplete 
2. 
Poor adherence to protocol and regulatory requirements 
3. 
Incidence or severity of adverse drug reaction in this or other studies 
indicates a potential health hazard to subjects 
4. 
Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made.


 
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22. LIST OF REFERENCES 
1. 
American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer 
Society; 2014. 
2. 
Gaspar LE, McNamara EJ, Gay EG, et al. Small-cell lung cancer: prognostic factors and 
changing treatment over 15 years. Clin Lung Cancer 2012;13:115-22. 
3. 
Varghese AM, Zakowski MF, Yu HA, et al. Small-cell lung cancers in patients who never 
smoked cigarettes. J Thorac Oncol 2014;9:892-6. 
4. 
Ou SH, Ziogas A, Zell JA. Prognostic factors for survival in extensive stage small cell 
lung cancer (ED-SCLC): the importance of smoking history, socioeconomic and marital 
statuses, and ethnicity. J Thorac Oncol 2009;4:37-43. 
5. 
Krug LM, Kris MG, Rosenzweig K, Travis W. Small cell and other  neuroendocrine 
tumors of the lung. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice 
of Oncolology. 8th ed: Lippincott, Williams, and Wilkins; 2008. 
6. 
von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, 
doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 
1999;17:658-67. 
7. 
Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the 
second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and 
sensitive disease. The European Organization for Research and Treatment of Cancer Early 
Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative 
Group. J Clin Oncol 1997;15:2090-6. 
8. 
Eckardt J, Gralla R, Palmer MC, et al. Topotecan as second-line therapy in patients with 
small cell lung cancer: a phase II study. Ann Oncol 1996;7:107 (abstr 513). 
9. 
Depierre A,  von Pawel J, Hans L, et al. Evaluation of Topotecan (Hycamtin) in relapsed 
small-cell lung cancer (SCLC): A multicenter phase II study. Lung Cancer 1997;18:35 (abstract 
126). 
10. 
Eckardt J, Depierre A, Ardizzoni A, von Pawel J, Fields SZ. Pooled analysis of topotecan 
in the second-line treatment of patients with sensitive small cell lung cancer. Proc Am Soc Clin 
Oncol 1997;16:452a (abstr 1624). 
11. 
O'Brien M, Eckardt J, Ramlau R. Recent advances with topotecan in the treatment of 
lung cancer. Oncologist 2007;12:1194-204. 
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23. APPENDICES 
Appendix I: ECOG Performance Status 
Appendix II: Plan to be Utilized Should a Potentially Actionable Incidental Finding be 
Identified in Course of Research Conducted on Samples Collected Under this Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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23.1. APPENDIX I: ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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23.2. APPENDIX II: PLAN TO BE UTILIZED SHOULD A POTENTIALLY ACTIONABLE 
INCIDENTAL FINDING BE IDENTIFIED IN THE COURSE OF RESEARCH CONDUCTED ON 
SAMPLES COLLECTED UNDER THIS PROTOCOL  
In the event an investigator’s research identifies a finding that he or she believes should be 
communicated to the subject (and/or family designee), the investigator shall communicate this 
to the institutional IRB, should it be a requirement.  The finding will be reviewed by a group 
convened by the institutional IRB to determine whether the incidental finding should be 
discussed with the subject.  In the event that group convened by the institutional IRB determines 
that the finding should be discussed with the subject, and the subject has consented to be re-
contacted, then the treating/consenting physician shall be contacted by the institutional IRB 
representative and asked to refer the subject to the Clinical Genetics Service of the institution 
for further discussion of the research finding.  After appropriate counseling and consent, the 
Clinical Genetics Service of the institution will request permission to confirm the result in a New 
York Department of Health-approved laboratory prior to communication of the specific result.  If 
the patient is not available (e.g. deceased), then the surrogate designated on the consent will be 
contacted and the above will occur. 
 
Germline BAM files will not be separately analyzed in the future without additional informed 
consent, anonymization, and/or human subjects review by the institutional IRB.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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24. APPROVAL SIGNATURES 
APPROVAL SIGNATURES 
Printed 
Signature 
Title 
Date 
Suzanne 
George, 
M.D. 
 
 
 
Xiaofei 
Wang, 
Ph.D. 
 
 
 
Thomas 
Stinchcombe, MD