Clinical trial NCT02551432
Conditions: Small Cell Lung Cancer
Keywords: pembrolizumab paclitaxel
Sponsor: Seoul National University Hospital
Start date: 2015-09-01; Completion date: 2018-02-01
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with refractory SCLC. Patients will be treated with paclitaxel and pembrolizumab.

Detailed description:
Open, uncontrolled, multi-center, phase II study.

Arms: arm 1: * PD-L1 Induction phase : Paclitaxel 175 mg/m2, Day 1 q 3weeks, intravenous,
* Post Induction treatment phase: Paclitaxel 175 mg/m2, Day 1 q 3weeks (maximum up to total 6 cycles) + pembrolizumab 200 mg D1 q 3 weeks, intravenous,
* Maintenance phase: pembrolizumab 200 mg D1 q 3 weeks, intravenous till PD or unacceptable toxicity
Interventions: intervention 1: pembrolizumab, paclitaxel
Intervention descriptions: intervention 1: pembrolizumab, paclitaxel

Protocol documents:
Prot_SAP_000.pdf: 
SCLC MK3475 v1.4 (version dated 20160408) 
 
1 
 
 
A phase II study of pembrolizumab and 
paclitaxel in refractory small cell lung cancer 
 
 
Version No.: v1.4 
Effective Date: 08Apr2016 
 
 
Protocol History 
Original : 20Aug2015(version1.0) 
Revised : 13Oct2015(version 1.1) 
Revised : 27Nov2015(version 1.2) 
Revised : 08Dec2015(version 1.3) 
Revised : 08Apr2016(version 1.4) 
 
 
 
Seoul National University Hospital  
Internal Medicine 
 
Pf. Bhumsuk Keam  
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
2 
 
TRIAL SUMMARY 
 
Study title 
Phase II study of pembrolizumab and paclitaxel in refractory small cell lung 
cancer  
Principle 
Investigator (PI) 
Bhumsuk Keam, Seoul National University Hospital  
Supporter 
MSD Korea 
Study centers 
Seoul National University Hospital  
Seoul National University Bundang Hospital 
Seoul National University Boramae Medical Center 
Study objectives 
1) Primary endpoint: Response rate (RR) 
2) Secondary endpoint: Progression-Free Survival (PFS), Overall Survival (OS), 
Toxicity. 
Study design 
Open, multicenter, single arm, phase II 
Planned number 
of patients 
26 Patients  
Vulnerable 
subject 
N/A 
Inclusion criteria 
1) Have histologically or cytologically-confirmed diagnosis of small cell lung 
cancer 
2) Extensive disease (distant metastasis, contralateral hilar lymph node 
involvement, or cytologically confirmed malignant pleural effusion) 
3) Have had progression of SCLC following receipt of etoposide plus platinum 
combination chemotherapy.  
4) If patients have brain metastasis with neurological symptom, they should 
be stabilized neurologically with prior radiotherapy or surgery for the brain 
metastasis (no neurologic symptom in progress and without further steroid 
treatment) 
5) Have measurable disease based on RECIST 1.1 
6) Be ≥20 years of age on day of signing informed consent. 
7) Have a performance status of 0 or 1 on the ECOG Performance Scale 
8) Have provided tissue for biomarker analysis from an archival tissue sample 
or newly obtained core or excisional biopsy of a tumor lesion after previous 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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chemotherapy 
9) Demonstrate adequate organ function as 
- Absolute neutrophil count 1,500 cells/mm3, platelets 100,000 cells/mm3, 
Hemoglobin ≥9 g/dL 
- Serum creatinine ≥ institutional upper normal limit (UNL) x 1.5 or GFR ≥ 
60 mL/min (creatinine levels > 1.5 X ULN for subject with Cockcroft-Gault 
Equation estimated GFR ≥60 mL/min is allowed.) 
- Serum transaminase ≤ UNL x 2.5 (for subjects with liver metastases  
UNL x 5.0), Serum bilirubin ≤ UNL x 1.5 
10) Informed consent from patient which conforms to Institutional Review 
Board 
11) Expected survival ≥ 3 months 
Exclusion criteria 
1) Is currently participating in or has participated in a study of an 
investigational agent or using an investigational device within 4 weeks prior 
to the first dose of trial 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 trial treatment. 
3) Has had a prior anti-cancer 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 4 weeks earlier. 
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: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an 
exception to this criterion and may qualify for the study. 
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy. 
5) Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in 
situ cervical cancer. 
6) Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated brain metastases 
may participate provided they are stable (without evidence of progression by 


SCLC MK3475 v1.4 (version dated 20160408) 
 
4 
 
imaging for at least four weeks prior to the first dose of trial 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 trial treatment. This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability. 
7) Has an active autoimmune disease requiring systemic treatment within the 
past 2 years or a documented history of clinically severe autoimmune disease, 
or a syndrome that requires systemic or immunosuppressive agents. (Subjects 
that require intermittent use of bronchodilators, inhaled steroids, or local 
steroid injections would not be excluded from the study. Subjects with 
hypothyroidism stable on hormone replacement, diabetes Type I, or resolved 
childhood asthma/atopy will not be excluded from the study.) 
8) Has evidence of interstitial lung disease or active non-infectious 
pneumonitis. 
9) Has an active infection requiring systemic therapy. 
10) Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best 
interest of the subject to participate, in the opinion of the treating 
investigator. 
11) Has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
12) Is pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the screening visit 
through 120 days after the last dose of trial treatment. (Female and male 
subject of childbearing potential must use an effective barrier method of 
contraception during study)  
13) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or 
anti CTLA-4 agent. 
14) Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 
antibodies). 
15) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected). (Inactive healthy carriers of HBV with 
appropriate prophylactic antiviral agents are allowed.) 
16) Has received a live virus vaccine within 30 days of planned start of trial 
treatment. 
17) Has a known history of active TB (Bacillus Tuberculosis) 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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18) Has a history of severe hypersensitivity reaction to pembrolizumab or 
paclitaxel, or has a known contraindication to paclitaxel. 
Planned 
treatment 
1) PD-L1 induction phase:  
- Paclitaxel 175mg/m2, Day 1 q 3weeks, intravenous 
2) Post induction treatment phase  
- Paclitaxel 175mg/m2, Day 1 q 3weeks (maximum up to total 6 cycles) 
+ Pembrolizumab 200mg D1 q 3 weeks, intravenous 
3) Maintenance phase  
- Pembrolizumab 200mg D1 q 3 weeks, intravenous 
 till PD or unacceptable toxicity  
Statistical 
methods 
Progression free survival, Overall survival (Survival curve: Kaplan-Meier)  
H0 : Response rate (RR) 25% H1: RR 50%  
Efficacy 
evaluation  
RR (modified RECIST1.1), PFS, OS 
 Safety evaluation 
NCI CTCAE version 4.0 
Study period 
IRB approval ~ 31 Aug 2018 
Follow up : 12 months for each patient 
  
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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1. 
STUDY TITLE AND PHASE ..................................................................................... 9 
2. 
STUDY CENTERS ..................................................................................................... 9 
3. 
PRINCIPLE INVESTIGATOR AND SUB-INVESTIGATOR .................................... 9 
4. 
FUNDING AGENCY ............................................................................................... 10 
5. 
PLANNED STUDY PERIOD .................................................................................. 10 
6. 
CLINICAL INDICATION ......................................................................................... 10 
7. 
BACKGROUND AND RATIONALE ...................................................................... 11 
7.1. 
Background .................................................................................................................................... 11 
7.2. 
Rationale ......................................................................................................................................... 12 
8. 
STUDY OBJECTIVES AND HYPOTHESIS ........................................................... 15 
8.1. 
Primary objective .......................................................................................................................... 16 
8.2. 
Secondary objectives .................................................................................................................... 16 
8.3. 
Exploratory objective ................................................................................................................... 16 
9. 
INCLUSION AND EXCLUSION CRITERIA, PLANNED SAMPLE SIZE AND 
RATIONALE ...................................................................................................................... 16 
9.1. 
Inclusion criteria ............................................................................................................................ 16 
9.2. 
Exclusion criteria ........................................................................................................................... 17 
9.3. 
Planned sample size and Rationale ........................................................................................... 19 
9.4. 
Informed consent and Entry in to the trial ............................................................................. 20 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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10. TREATMENT PLAN ................................................................................................ 20 
10.1 Discontinuation ................................................................................................................................ 22 
10.2 Trial treatment .................................................................................................................................. 23 
10.3 Concomitant medications .............................................................................................................. 24 
10.4. Supportive care ............................................................................................................................... 25 
10.5. Adverse events and Dose modification ..................................................................................... 26 
10.6. Diet/Activity/Other Considerations ............................................................................................. 31 
11. ASSESSMENT AND FOLLOW-UP ....................................................................... 31 
11.1. 
Pretreatment evaluation .......................................................................................................... 31 
11.2. 
Assessment during treatment ................................................................................................. 33 
11.3. 
Follow up .................................................................................................................................... 34 
12. ASSESSMENT ......................................................................................................... 34 
12.1. 
Safety Assessment..................................................................................................................... 34 
12.2. 
Efficacy Assessment .................................................................................................................. 34 
13. SUBJECT REGISTRATION ..................................................................................... 36 
14. ADVERSE EVENT ................................................................................................... 36 
14.1. 
Definition .................................................................................................................................... 36 
14.2. 
Evaluating and Recording Adverse Events ........................................................................... 38 
14.3. 
Causality assessment ................................................................................................................ 38 
14.4. 
Adverse events reporting ........................................................................................................ 39 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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14.5. 
Monitoring of Subject with Adverse events ........................................................................ 40 
15. STATISTICAL CONSIDERATION .......................................................................... 41 
15.1. 
Definition of analysis population ........................................................................................... 41 
15.2. 
Statistical analysis...................................................................................................................... 41 
16. BIOMARKER ASSESSMENT ................................................................................. 42 
17. POLICY AND PROCEDURES FOR THE PROTECTION OF HUMAN SUBJECTS
 
42 
17.1. 
Ethical Aspects ........................................................................................................................... 42 
17.2. 
Subject Consent ......................................................................................................................... 43 
17.3. 
Subject Protection/Safety ........................................................................................................ 43 
17.4. 
Confidentiality of Subject information ................................................................................. 44 
17.5. 
Records retention ...................................................................................................................... 44 
17.6. 
Clinical Trials Monitoring ......................................................................................................... 44 
18. STORAGE AND DISPOSAL OF HUMAN BIOSPECIMENS .............................. 45 
19. REFERENCES ........................................................................................................... 46 
 
 
 
 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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1. Study title and phase 
1.1. Title 
  
1) English : Phase II study of pembrolizumab and paclitaxel in refractory small cell lung 
cancer  
2) Korean : 불응성 소세포폐암에서 Pembrolizumab 과 paclitaxel 병용 치료요법에 
대한 제2 상 임상연구 
 
2. Study centers 
Center 
Address 
Seoul National University Hospital  
28-21, Yeongeon-dong, Jongno-gu, Seoul 
Seoul 
National 
University 
Bundang Hospital 
300, Gumi-dong, Bundang-gu, Seongnam-si, 
Gyeonggi-do 
Seoul 
National 
University 
Boramae Medical Center 
425, Sindaebang 2-dong, Dongjak-gu, Seoul 
 
 
3. Principle investigator and Sub-investigator  
3.1. Principle investigator (PI) 
Seoul National University Hospital, Internal medicine 
Professor, Bhumsuk Keam  
Tel 02-2072-7215, FAX 02-764-7379, e-mail bhumsuk@snu.ac.kr 
 
3.2. Sub-investigator  
(Seoul National University Hospital) 
Hemato-oncology Professor 
 
Dae Seog Heo 
Hemato-oncology Professor 
 
Dong Wan Kim 
Hemato-oncology Professor 
 
Tae Min Kim 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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Hemato-oncology Professor 
 
Mi So Kim 
 
(Seoul National University Bundang Hospital) 
Hemato-oncology Professor 
 
Jong Seok Lee 
Hemato-oncology Professor 
 
Yu Jung Kim 
Hemato-oncology Professor 
 
Se Hyun Kim 
 
(Seoul National University Boramae Medical Center) 
Hemato-oncology Professor 
 
Jin Soo Kim 
 
3.3. Clinical trial pharmacists 
Seoul National University Hospital, Department of Pharmacy, Hong Won Jang, 
daisy0625@snuh.org, 02-2072-7439 
MSD, Medical Project Associate, Mi Sung Choi, mi.sung.choi@merck.com, 02-331-2248 
 
 
4. Funding agency 
MSD Korea 
163, Mapo-daero, Mapo-gu, Seoul 
 
 
5. Planned study period 
IRB approval ~ 31 Aug 2018 
 
 
6. Clinical indication 
Refractory SCLC, ED (Etoposide failure)  
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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7. Background and Rationale 
 
7.1. Background 
7.1.1. Small cell lung cancer 
Small cell lung cancer (SCLC) accounts for approximately 20% of lung cancer.1 First-
line threatment for patients with extensive disease, which means that the cancer had 
spread outside of the chest, is platinum-based combination chemotherapy. Despite 
60-70 % of response rate to platinum-based combination chemotherapy, SCLC 
shows very poor prognosis with a median survival of less than 12 months.2 While 
monotherapy or combination chemotherapies have been investigated in the 
treatment of relapsed SCLC, no standard second-line chemotherapy established.  In 
addition, response rate for the second-line chemotherapy currently used is only 10-
30 %.3. For this reason, there remain considerable unmet needs for active 
chemotherapeutic agent in the treatment of relapsed/refractory SCLC.  
 
7.1.2. Pembrolizumab 
The PD-1 receptor-ligand interaction is a major immune check point pathway 
hijacked by tumors to suppress immune control. Therapeutic studies in mouse 
models have shown that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately 
to tumor rejection, either as a mono-therapy or in combination with other treatment 
modalities. 
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. Ongoing clinical trials are being conducted 
in advanced melanoma, non-small cell lung cancer, a number of advanced solid 
tumor indications including bladder cancer. The US FDA approved pembrolizumab 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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for the following treatment with ipilimumab, or after treatment with ipilimumab and 
a BRAF inhibitor in advanced melanoma patients who carry a BRAF V600E mutation. 
 
7.1.3. Rationale for Pembrolizumab and Paclitaxel Combination  
There has been studies to investigate PD-L1 expression as a potential predictive 
marker of response. In KEYNOTE 001, a phase 1 study of pembrolizumab in 
advanced NSCLC patients, ORR was 45.4% in patients with PD-L1 expression in at 
least 50% of tumor cells, while ORR was 16.5% and 10.7%, respectively in patients 
with PD-L1 expression in 1~49% and < 1% of tumor cells. 
Cytotoxic chemotherapy modulate the expression of PD-L1 on cancer cell. While 
doxorubicin has been reported to down-regulate PD-L1 expression on cancer cell 
surface, whereas paclitaxel and etoposide increase PD-L1 expression.5,6 Paclitaxel 
monotherapy showed ORR 29%, median survival time 100 days in refractory SLCL.7 
To combine pembrolizumab with paclitaxel in etoposide failure SCLC, we expect 1) 
upregulation of PD-L1 expression on tumor cell, 2) tumor shrinkage by paclitaxel and 
3) long duration of response by pembrolizumab. 
 
7.2. Rationale 
7.2.1. Rational for Dose selection 
An open-label Phase I trial (KEYNOTE 001) is being conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab. Two cohort evaluations of 
melanoma and non-small cell lung cancer (NSCLC) subjects receiving pembrolizumab 
at a dose of 2 mg/kg Q3W or 10 mg/kg Q2W or Q3W have been completed. The 
clinical efficacy and safety data demonstrate a lack of clinically important differences 
in efficacy response or safety profile at these doses. The rationale for a 200 mg fixed 
dose Q3W regimen of Pembrolizumab in this study is based on: 1) similar efficacy 
and safety of Pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in 
melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for 
both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, and 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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200 mg fixed dose Q3W, and current phase II or III clinical trials are being conducted 
with200 mg fixed dose Q3W. 3) the lack of effect of tumor burden or indication on 
distribution behavior of Pembrolizumab (as assessed by the population PK model) 
and 4) the assumption that the dynamics of Pembrolizumab target engagement will 
not vary meaningfully with tumor type. 
Keynote-012 Cohorts A and C in NSCLC received paclitaxel+ carboplatin + 
pembrolizumab (4 cycles of pembrolizumab 2 or 10 mg/kg plus carboplatin area 
under the time-concentration curve (AUC) 6 and paclitaxel 200 mg/m2 Q3W, 
followed by pembrolizumab monotherapy). Except anemia and febrile neutropenia, 
one in the 2mg/kg group and one in the 10mg/kg group experienced treatment-
related grade 3-4, and twelve in 25 patients experienced ≥ grade1 adverse event. 
Relationship between toxicities and pembrolizumab was not certain and most 
toxicities were considered due to paclitaxel plus carboplatin. Therefore, it was 
difficult to consider that pembrolizumab combined with chemotherapy significantly 
increased toxicity.9 Because there were no significant toxicities in this study using 
pembrolizumab plus paclitaxel and carboplatin, treatment-related toxicities of 
pembrolizumab plus paclitaxel in our study would not be considerable.  
 
7.2.2. Rational for Efficacy Endpoints 
The primary efficacy objective of this study is to evaluate the overall response rate 
(ORR) of MK-3475 and paclitaxel. If radiologic imaging by local/site assessment 
shows PD based on RECIST v1.1, tumor assessment may be repeated 4 weeks later in 
order to confirm PD with the option of continuing treatment per below while 
awaiting radiologic confirmation of progression according to modified RECIST 1.1. If 
repeat imaging still meets the threshold for PD (≥ 20% increase in tumor burden 
compared to nadir) but shows a reduction in tumor burden compared to the 
previous time point, treatment may be continued. If repeat imaging confirms 
progressive disease without reduction in tumor burden compared to the previous 
time point, subjects will be discontinued from study therapy. In determining whether 


SCLC MK3475 v1.4 (version dated 20160408) 
 
14 
 
or not the tumor burden has increased or decreased, investigators should consider 
all target lesions as well as non-target lesions. 
Subjects who have initial evidence of radiological PD, it is at the discretion of the 
treating physician whether to continue a subject on study treatment until repeat 
imaging is obtained a minimum of 4 weeks later. This decision should be based on 
the clinical judgment of the subject’s overall clinical condition, including performance 
status, clinical symptoms, and laboratory data. Subjects may receive study treatment 
while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria: 
 
• 
Absence of signs and symptoms indicating disease progression 
• 
No decline in ECOG performance status 
• 
Absence of rapid progression of disease 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
If possible, the subject should not stop the treatment until disease progression is 
confirmed. This study will allow continuing treatment in subjects have initial evidence 
of radiological PD, because some subjects experienced transient tumor flare 
(pseudoprogression) 
within 
the 
first 
few 
months 
after 
the 
initiation 
of 
immunotherapy and delayed tumor response.  
 
 
7.2.3. Rational for Safety Endpoints 
All adverse events will be assessed by the investigator. The primary safety analysis 
will be based on subjects who experienced toxicities as defined by CTCAE criteria 
v4.0. The attribution to drug, time-of-onset, duration of the event, its resolution, and 
any concomitant medications administered will be recorded. AEs will be analyzed 
including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. 
 


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7.2.4. Rational for exploratory biomarker research 
 
Biomarker research to identify predictive factors for pembrolizumab therapy will be 
performed. Pre- & post- tumor, tumor at progression time and blood samples from this 
study will be performed. Biomarker research may undergo proteomic, genomic and 
transcriptional analyses. Pre- biopsy will be done before paclitaxel and post- biopsy will 
be done after one cycle of induction paclitaxel. After that, patients will be administered 
pembrolizumab 
and 
paclitaxel 
combination 
chemotherapy 
till 
progression 
or 
unacceptable toxicity. After one cycle of paclitaxel and after progression biopsy will be 
done in case of patient agreement. If there was clinically significant risk for biopsy (i.e. 
emphysema and pneumothorax), pre- and post biopsy can be waivered by investigator's 
judgement. Blood samples will be collected at the time of baseline and after 2cycle of 
paclitaxel to carry out translational research, and tumor tissues were collected in case of 
patient agreement 
 
 
Tumor IHC: tumor (PD-L1, PD-L2, MHC class I), TIL (CD8, PD1, CD3, CD4), Treg 
(FoxP3), Macrophage (PD-L1, CD68, CD163, CD206), Spatial association of PD-1+ 
tumor infiltrating lymphocytes (TILs) and PD-L1+ / PD-L2+ cell.  
 
tumor: target gene sequencing using cancer panel 
 
blood sampling at baseline, after 2nd cycle, at progression(optinal): IFN gamma 
quantitation, FACS - CD3+/ CD16+56+/ CD45+,  CD4+, CD8+ 
 
 
8. Study objectives and hypothesis 
This is a phase II multi-center, open-label study to evaluate efficacy and safety of 
paclitaxel and pembrolizumab combination treatment in patients with refractory 
SCLC.  
 
 


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8.1. Primary objective 
1) Objective: Response rate based on RECIST 1.1  
2) Hypothesis: Intravenous administration of pembrolizumab and paclitaxel has 
clinically meaningful benefit in RR 
 
8.2. Secondary objectives 
1) Overall Survival (OS), defined as time from first dose to death or last date of 
follow-up.   
2) Progression-free Survival (PFS) base on modified RECIST 1.1 
3) Toxicity  
 
8.3. Exploratory objective  
Biomarker analysis will be done by paired biopsy before and after induction phase 
and blood sampling for immune monitoring in order to find out potential predictive 
biomarker for pembrolizumab. Tumor tissue will be used for target gene sequencing 
and immunohistochemistry (IHC). Tumor IHC parameters will be include following 
parameters: tumor (PD-L1, PD-L2, MHC class I), TIL (CD8, PD1, CD3, CD4), Treg 
(FoxP3), Macrophage (PD-L1, CD68, CD163, CD206)  etc. 
 
 
9. Inclusion and Exclusion criteria, Planned sample size and 
Rationale 
9.1. Inclusion criteria 
1) Have histologically or cytologically-confirmed diagnosis of small cell lung cancer 
2) Extensive disease (distant metastasis, contralateral hilar lymph node involvement, 
or cytologically confirmed malignant pleural effusion) 
3) Have had progression of SCLC following receipt of etoposide plus platinum 
combination chemotherapy.  


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4)  If patients have brain metastasis with neurological symptom, they should be 
stabilized neurologically with prior radiotherapy or surgery for the brain metastasis 
(no neurologic symptom in progress and without further steroid treatment) 
5) Have measurable disease based on RECIST 1.1 
6) Be ≥20 years of age on day of signing informed consent. 
7) Have a performance status of 0 or 1 on the ECOG Performance Scale 
8) Have provided tissue for biomarker analysis from an archival tissue sample or 
newly obtained core or excisional biopsy of a tumor lesion after previous 
chemotherapy 
9) Demonstrate adequate organ function as 
- Absolute neutrophil count  1,500 cells/mm3, platelets  100,000 cells/mm3, 
Hemoglobin ≥9 g/dL 
- Serum creatinine  Institutional upper normal limit (UNL) x 1.5 or GFR ≥60 mL/min 
(creatinine levels > 1.5 X ULN for subject with Cockcroft-Gault Equation estimated 
GFR ≥60 mL/min is allowed.) 
- Serum transaminase  UNL x 2.5 (for subjects with liver metastases  UNL x 5.0), 
Serum bilirubin  UNL x 1.5 
10) Informed consent from patient which conforms to Institutional Review Board (IRB) 
11) Expected survival ≥ 3 months 
 
9.2. Exclusion criteria 
1) Is currently participating in or has participated in a study of an investigational 
agent or using an investigational device within 4 weeks prior to the first dose of trial 
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 
trial treatment. 


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3) Has had a prior anti-cancer 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 4 weeks earlier. 
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: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study. 
Note: If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
5) Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
6) Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects 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 trial 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 trial treatment. This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
7) Has an active autoimmune disease requiring systemic treatment within the past 2 
years or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic or immunosuppressive agents. (Subjects that require 
intermittent use of bronchodilators, inhaled steroids, or local steroid injections would 
not be excluded from the study. Subjects with hypothyroidism stable on hormone 
replacement, diabetes Type I, or resolved childhood asthma/atopy will not be 
excluded from the study.) 


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19 
 
8) Has evidence of interstitial lung disease or active non-infectious pneumonitis. 
9) Has an active infection requiring systemic therapy. 
10) Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
11) Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12) Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 120 days 
after the last dose of trial treatment. (Female and male subject of childbearing 
potential must use an effective barrier method of contraception during study)  
13) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti 
CTLA-4 agent. 
14) Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 
antibodies). 
15) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). (Inactive healthy carriers of HBV with appropriate 
prophylactic antiviral agents are allowed.) 
16) Has received a live virus vaccine within 30 days of planned start of trial treatment. 
17) Has a known history of active TB (Bacillus Tuberculosis) 
18) Has a history of severe hypersensitivity reaction to pembrolizumab or paclitaxel, 
or has a known contraindication to paclitaxel.  
 
 
9.3. Planned sample size and Rationale 
9.3.1. Planned sample size 
Twenty-six patients will be enrolled 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
20 
 
9.3.2. Rationale for sample size 
The primary efficacy objective of this study is to evaluate RR of pembrolizumab and 
paclitaxel. Response evaluation will be done according to RECIST 1.1. There has been 
no known data of pebrolizumab and paclitaxel combination in SCLC.  
 
 
alpha = 0.05, beta =0.20, one side  
 
H0: RR= 25%7 
 
H1: RR= 50% 
 
sample size =23  
 
considering 10% drop out rate --> final sample size = 26 
 
We assume that the null hypothesis is the RR of 25% (based on known response to 
paclitaxel monotherapy in refractory SCLC) versus the alternative hypothesis (H1) is 
the RR of least 50%. At a type 1 error (α) of 5% and power (1-β) of 80%, the study 
has to enroll 23 assessable patients. Considering a drop-out rate of 10%, total 
accrual patients will be 26. 
 
9.4. Informed consent and Entry in to the trial 
After pre-screening for subject based on the inclusion and exclusion criteria, the 
written informed consent from eligible subject will be obtained and subject will 
participate in this study.  
 
 
10.  Treatment plan 
This study is designed to open, multi-center, single arm, phase II clinical trial. The 
study scheme is as follows (Figure 1).  
 
 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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Figure 1.  
 
 
 
 
10.1 Discontinuation 
10.1.1 Discontinuation of Study Therapy  
A subject must be discontinued from the trial for any of the following reasons before 
completion of planned 6 cycles.  
 
Radiographic disease progression (A subject may be granted an exception to 
continue on treatment with confirmed radiographic progression (Based on 
modified RECIST 1.1) if clinically stable or clinically improved 


SCLC MK3475 v1.4 (version dated 20160408) 
 
22 
 
 
Unacceptable adverse events 
 
Pregnancy 
 
Patient decides to withdraw from the study  
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator  
 
The subject is lost to follow-up 
 
Noncompliance with trial treatment or procedure requirements 
 
10.1.2 Early Trial Termination 
If the observed results during the study indicate that continuation of the trial is 
unjustifiable, investigator should request for early termination of the trial to IRB, and 
terminate the trial by IRB approval.  
 
 
Safety of the clinical trial is greatly threatened. 
- 
Repeated noncompliance that causes substantial harm to subjects.  
- 
Increasing frequency and severity of serious adverse events 
specified in the protocol. 
- 
Missing major clinical test items than those described study 
protocol, informed consent form (ICF) and investigator's brochure.  
 
Poor enrollment of subjects making completion of the trial within an 
acceptable time frame unlikely.  
 
Although the need arises to replace the PI due to personal problems, there 
are no substitute investigators. 
 
There are serious problems with the reliability of the study site. 
 
10.1.3 Treatment completion 
 
After completion of planned 6 cycles, pembrolizumab treatment may continue 
until confirmed PD or unacceptable adverse events if duration of response and 
clinical benefit from pembrolizumab is expected.  


SCLC MK3475 v1.4 (version dated 20160408) 
 
23 
 
10.2 Trial treatment 
Table1. Trial treatment  
Drug 
Dose 
Dose frequency 
Rout of 
administration 
Regimen/Treatment 
perioid 
Paclitaxel 
175mg/m2 
Q3W 
IV infusion 
Day 1 of each cycle 
Paclitaxel + 
Pembrolizumab 
175mg/m2 
+ 200mg 
Q3W 
IV infusion 
Day 1 of each cycle 
Pembrolizumab 
200mg 
Q3W 
IV infusion 
Day 1 of each cycle 
 
 
10.2.1 Pembrolizumab 
Trial treatment of pembrolizumab (MK-3475) should be administered on Day 1 of 
each 3 week cycle after all procedures/assessments have been completed as detailed 
on the Trial Flow Chart Pembrolizumab. Pembrolizumab (MK-3475) 200 mg will be 
administered as a 30 minute IV infusion every 3 weeks. 
 
 
10.2.2 Paclitaxel 
Trial treatment of paclitaxel should be administered on Day 1 of each 3 week cycle 
after all procedures/assessments have been completed as detailed on the Trial Flow 
Chart. Paclitaxel 175 mg/m2 will be administered as an IV infusion administered over 
3 hours. If the patient's body surface area (BSA) changes by more than 10% of 
baseline BSA (increase or decrease), it is necessary to re- calculate dose of paclitaxel.  
Premedications 
before 
paclitaxel 
include 
chlorpheniramine, 
ranitidine 
and 
dexamethasone as institutional guideline. Pembolizumab will be given followed by 
paclitaxel. 
 
 
 
 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
24 
 
10.3 Concomitant medications 
10.3.1 Acceptable concomitant medications 
All treatments that the investigator considers necessary for a subject’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. 
 
10.3.2 Prohibited concomitant medications 
Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) of 
this trial. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required. 
 
 
Anti-cancer systemic chemotherapy or biological therapy 
 
Immunotherapy not specified in this protocol 
 
Chemotherapy not specified in this protocol 
 
Investigational agents other than paclitaxel and pembrolizumab 
 
Radiation therapy  
 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. (measles, mumps, rubella, varicella/zoster,  and yellow 
fever) 
 
Glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids or corticosteroids before paclitaxel to prevent severe 
hypersensitivity reaction may be approved based on the investigator’s judgment.   
 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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10.4. Supportive care 
10.4.1 Supportive care guidelines for Pembrolizumab  
1) Anti-infectives: Subjects 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. 
 
2) 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; Pruritus/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 2. Treatment guidelines for infusion reaction to pembrolizumab  
Grade 
Treatment 
1 
Increase monitoring of vital signs as medically indicated until the subject is deemed 
medically stable in the opinion of the investigator. 
Interruption not indicated; 
2 
Stop Infusion and monitor symptoms. Additional appropriate medical therapy may include 
but is not limited to: IV fluids, Antihistamines, NSAIDS, Acetaminophen, Narcotics 
If symptoms resolve within one hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate.  
Subjects who develop Grade 2 toxicity despite adequate premedication should be 
permanently discontinued from further trial treatment administration. 
3/4 
Stop infusion, Additional appropriate medical therapy. 


SCLC MK3475 v1.4 (version dated 20160408) 
 
26 
 
Subject is permanently discontinued from further trial treatment administration.  
 
 
10.4.2 Supportive Care Guidelines for Paclitaxel 
Pre-medications for paclitaxel paclitaxel will be given as per standard of care. In order 
to avoid the occurrence of severe hypersensitivity reactions, all patients treated with 
paclitaxel should be premedicated.  Subjects who experience severe hypersensitivity 
reactions (e.g., generalized rash/erythema, hypotension and/ bronchospasm, 
angioedema or anaphylaxis) should be discontinued from trial treatment.  
Other supportive care includes antidiarrhea, opioid and nonopioid analgesics, appetite 
stimulant, granulocyte-colony stimulating factor (G-CSF), and erythropoietin. 
Nonpharmacologic supportive care such as intervention or transfusion also can be 
provided. Primary use of G-CSF for preventing neutropenia is not permitted. If grade 
4 neutropenia or ≥ grade 3 febrile neutropenia occurs, use of G-CSF is permitted for 
secondary prophylaxis according to investigator's discretion. However, G-CSF for 
secondary prophylaxis can be administered 24 hours after the end of paclitaxel.  
 
 
 
10.5. Adverse events and Dose modification  
10.5.1. Dose modification for Pembrolizumab  
Both non-serious and serious adverse events related to exposure to pembrolizumab 
may have an immunologic etiology. IrAEs may be predicted based on the nature of 
the pembrolizumab, its mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action. An irAE can occur shortly 
after the first dose or several months after the last dose of treatment. 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. Permanent 
discontinuation should be considered for any severe or life-threatening AEs per Table 
3 below. 


SCLC MK3475 v1.4 (version dated 20160408) 
 
27 
 
 
Table 3. Dose Modification Guidelines for Pembrolizumab 
Toxicity 
Grade 
Timing for restarting 
treatment 
Discontinue Subject 
Diarrhea/Colitis 
Grade 2,3 
Toxicity 
resolves 
to 
Grade 0-1 or baseline 
Toxicity does not resolve within 12 
weeks of last infusion, or corticosteroid 
dosing cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 
12 weeks 
Grade 4 
N/A  
Yes 
AST, 
ALT 
or 
Total 
bilirubin 
increase 
Grade 2 
Toxicity 
resolves 
to 
Grade 0-1 or baseline 
Toxicity does not resolve within 12 
weeks of last infusion 
Grade 3,4 
N/A 
Yes 
Type 
1 
DM 
(newly 
developed), 
or 
hyperglycemia 
T1DM or 
Grade 3,4 
Withhold any scheduled 
dose of pembrolizumab 
until metabolic control is 
achieved 
Once 
clinically 
and 
metabolically 
stabilized, 
the 
delayed 
dose 
of 
pembrolizumab may be given  
Hypophysitis 
Grade 2-4 
Toxicity 
resolves 
to 
Grade 0-1 or baseline.  
 
Toxicity does not resolve within 12 
weeks of last infusion, or corticosteroid 
dosing cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 
12 weeks 
Hyperthyroidism 
Grade 3 
Toxicity 
resolves 
to 
Grade 0-1 or baseline 
Toxicity does not resolve within 12 
weeks of last infusion, or corticosteroid 
dosing cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 
12 weeks 
Grade 4 
N/A  
Yes 
Hypothyroidism   
Hypothyroidism may be 
managed 
with 
replacement 
therapy 
without 
treatment 
interruption. 
Hypothyroidism may be managed with 
replacement therapy without treatment 
interruption. 
Infusion-related 
reactions 
Grade 3,4 
N/A  
Yes 


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Pneumonitis 
Grade 2 
Toxicity 
resolves 
to 
Grade 0-1 or baseline 
Toxicity does not resolve within 12 
weeks of last infusion, or corticosteroid 
dosing cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 
12 weeks 
Grade 3-4 
N/A  
Yes 
Nephritis 
Grade 2 
Toxicity 
resolves 
to 
Grade 0-1 or baseline 
Toxicity does not resolve within 12 
weeks of last infusion, or corticosteroid 
dosing cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 
12 weeks 
Grade 3-4 
N/A  
Yes 
Others  
Grade 3-4  Toxicity 
resolves 
to 
Grade 0-1 or baseline 
Toxicity does not resolve within 12 
weeks of last infusion, or corticosteroid 
dosing cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 
12 weeks 
Grade 4 
N/A  
Yes 
Note: Subjects who experience a recurrence of the same severe or life-threatening event at the 
same grade or greater with rechallenge of pembrolizumab should be discontinued from trial 
treatment 
 
 
10.5.2. Dose modification for Paclitaxel   
Subjects must have adequate organ function (Table 4) before each dose of study 
drug and recovered from previous treatment-related toxicities to baseline or < grade 
If not, treatment have to hold until recovery. The laboratory tests must be measured 
within 48 hours before each dose of study drug. 
 
Table 4. Adequate Organ Function Laboratory Values 
System 
 
Laboratory value 
Hematological 
Absolute neutrophil count 
> 1,500 cells/mm3 
 
Platelets 
> 100,000 cells/mm3 


SCLC MK3475 v1.4 (version dated 20160408) 
 
29 
 
 
Hemoglobin 
≥9 g/dL 
Renal 
Creatinine 
Serum creatinine  institutional (UNL) x 1.5 or 
Cockcroft-Gault Equation estimated GFR ≥60 
mL/min  
Liver 
Transaminase (AST, ALT) 
≤ UNL x 2.5 (≤ UNL x 5.0 for subjects with liver 
metastases) 
 
Total bilirubin 
≤ UNL x 1.5 
 
Dose modification guidelines for paclitaxel-related adverse events are listed in Table 5.  
 
Table 5. Paclitaxel Dose Modification for Drug-Related Adverse Events 
Toxicity 
Grade 
Occurrence 
Dose 
modification 
Hold treatment 
Discontinuation 
Hematologic toxicities 
Neutropenia 
Grade 1, 
2, 3 or 
Grade 4 
lasting 
≤7 days 
All 
Restart treatment 
at Paclitaxel 135 
mg/m2 
N/A 
N/A 
Grade 4 
lasting 
>7 days 
1st & 2nd 
occurrence 
Restart treatment 
at Paclitaxel 135 
mg/m2 
Hold 
treatment 
until neutrophils 
recover to >1500 
cells/mm3 
Treatment 
discontinuation 
should be 
considered 
3rd 
occurrence 
N/A 
Yes 
Yes 
Febrile 
neutropenia 
 
1st 
occurrence 
Restart treatment 
at Paclitaxel 135 
mg/m2 
Hold 
treatment 
until neutrophils 
recover to >1500 
cells/mm3 
 
2rd 
occurrence 
Restart treatment 
at Paclitaxel 100 
mg/m2 
Hold 
treatment 
until neutrophils 
recover to >1500 
cells/mm3 
 
3차 
N/A 
Yes 
Yes 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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Anemia 
Grade 
1,2,3 
All 
N/A 
Until 
anemia 
resolves to Grade 
1 or baseline 
N/A 
Grade 4 
1st & 2nd 
occurrence 
Restart treatment 
at Paclitaxel 135 
mg/m2 
Until 
anemia 
resolves to Grade 
1 or baseline 
Treatment 
discontinuation 
should be 
considered 
3rd 
occurrence 
N/A 
Yes 
Yes 
Thrombocytopenia 
Grade 
1,2,3 
All 
N/A 
Hold 
treatment 
until 
platelets 
recover 
to 
>100,000 
cells/mm3 
N/A 
Grade 4 
1st & 2nd 
occurrence 
Restart treatment 
at Paclitaxel 135 
mg/m2 
Hold 
treatment 
until 
platelets 
recover 
to 
>100,000 
cells/mm3 
Treatment 
discontinuation 
should be 
considered 
3rd 
occurrence 
N/A 
Yes 
Yes 
Non-hematological toxicity 
Peripheral 
neuropathy 
Grade 
1,2 
 
Restart treatment 
at 
Paclitaxel 
135 mg/m2 
No 
N/A 
Grade 
3,4 
 
N/A 
Yes 
Yes 
Other toxicity 
Grade 
1,2 
All 
None 
No 
N/A 
Grade 
3,4 
1st & 2nd 
occurrence 
Restart treatment 
at Paclitaxel 135 
mg/m2 
Yes, until toxicity 
resolves to Grade 
0-1 or baseline 
Treatment 
discontinuation 
should be 
considered 
3rd 
occurrence 
N/A 
Yes 
Yes 


SCLC MK3475 v1.4 (version dated 20160408) 
 
31 
 
10.6. Diet/Activity/Other Considerations 
10.6.1. Diet 
Subjects should maintain a normal diet unless modifications are required to manage 
an AE such as diarrhea, nausea or vomiting. 
 
10.6.2. Pregnancy and Contraception 
Study drug may have adverse effects on a fetus in utero. Non-pregnant, non-
breastfeeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive. 
If a subject inadvertently becomes pregnant while on treatment with study drug, the 
subject will immediately be removed from the study. The study investigator will 
contact the subject and document the subject’s status until the pregnancy has been 
completed or terminated. If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to 
the investigator. 
 
10.6.3. Using in Nursing women 
It is unknown whether MK 3475 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, subjects who are breast-feeding are not eligible for enrollment. 
 
 
11. Assessment and Follow-up 
11.1. Pretreatment evaluation 
Screening procedures are to be completed within 28 days prior to the first dose of 
trial treatment.  
 
Table 6. Pretreatment evaluation  


SCLC MK3475 v1.4 (version dated 20160408) 
 
32 
 
 
Period 
Informed consent 
 
Prior 
to 
participating in a 
clinical trial 
Diagnosis 
of 
cancer 
Date of diagnosis, Diganosis, stage, Prior 
treatment for SCLC 
Within 28 days 
Past 
medical 
history 
and 
physical exam  
Past medical history  
Physical exam – Vital sign, Height, Weight, 
Body temperature, Neurologic exam, ECOG 
performance status,  Electrocardiogram, Chest 
X-ray 
Within 28 days 
Hematology 
WBC, Absolute neutrophil count, Platelet 
count, Hemoglobin 
Within 28 days 
Chemistry 
Albumin, 
Glucose, 
Alkaline 
phosphatase,  
Transaminase 
(AST, 
ALT), 
Total 
bilirubin, 
Creatinine, Electrolyte (Na, K, Mg), Calcium, 
phosphorus 
Within 28 days 
Serology 
HBsAg, HCV Ab, HIV Ab 
Within 28 days 
Coagulation 
PT, aPTT, INR 
Within 28 days 
Thyroid 
function 
test 
free T4, TSH 
Within 28 days 
Urinalysis 
pH, blood, glucose, albumin, Microscopic 
exam, if abnormal results are noted 
Within 28 days 
Blood sampling 
IFN 
gamma 
quantitation, 
FACS-
CD+/CD16+56+/ CD45+, CD4+, CD8+ 
Within 28 days 
Tumor biopsy  
IHC: Spatial association of PD-1+ tumor 
infiltrating lymphocytes (TILs), PD-L1+ cells, 
PD-L2+ (tumor and myeloid cells 등 
Archival tissue  
Tumor imaging 
Chest CT  
Abdomen-Pelvis CT (If necessary,) 
Within 28 days 
Pregnancy test 
Perform on women of childbearing potential 
only. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy 
test (HCG) will be required. (age ≥ 60 years 
or amenorrhea lasting 12 or more months is 
considered postmenopausal.) 
Within 72 hours 


SCLC MK3475 v1.4 (version dated 20160408) 
 
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Other 
If clinically required 
Within 28 days 
Concomitant 
Medications 
record prior medication taken by the subject 
within 30 days before starting the trial 
Within 28 days 
 *For serology, the previous test results may be used.  
 
11.2. Assessment during treatment   
All subjects will be evaluated according to the following schedule  
 
Table 7. Assessment during treatment 
 
Period 
Physical exam 
Vital sign, Height, Weight, Body 
temperature, ECOG performance 
status, Chest X-ray 
Within 3 days prior to Day 1 
of each cycle 
Hematology 
WBC, Absolute neutrophil count, 
Platelet count, Hemoglobin 
Within 3 days prior to Day 1 
of each cycle 
Chemistry 
Albumin, 
Glucose, 
Alkaline 
phosphatase,  Transaminase (AST, 
ALT), Total bilirubin, Creatinine, 
Electrolyte (Na, K, Mg), Calcium, 
phosphorus 
Within 3 days prior to Day 1 
of each cycle 
Urinalysis 
pH, 
blood, 
glucose, 
albumin, 
Microscopic 
exam, 
if 
abnormal 
results are noted 
Within 3 days prior to Day 1 
of each cycle 
Thyroid 
function 
test 
free T4, TSH 
Within 3 days prior to Day 1 
of each cycle 
Tumor 
assessment 
Physical exam  
Every visits 
Chest CT 
 
Day 14-21 of each 2-cycle 
(each 3-cycles, after 
completion of 6 cycles) 
Abdomen-pelvis CT (if necessary) 
 
Day 14-21 of each 2-cycle 
(each 3-cycles, after 
completion of 6 cycles) 
Others 
If clinically required 
 
Concomitant 
Medications 
record newly or added medication 
taken by the subject 
Every visits 


SCLC MK3475 v1.4 (version dated 20160408) 
 
34 
 
AEs 
Record most severe NCI CTCAE 
v.4.0 grade on CRF 
Within 3 days prior to Day 1 
of each cycle 
     * A blood sample: after 2 cycle, disease progression (optional) 
     * Tumor tissue : 1cycle After ( optional ) , disease progression( optional ) 
 
 
11.3. Follow up  
Patients will be followed for 3 weeks after removal from study or until death, 
whichever occurs first. Patients removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event. 
 
 
12.  Assessment 
12.1. Safety Assessment 
Safety will be assessed for all subjects and documented according to the CTCAE v4.0 
Common Terminology Criteria for Adverse Events (CTCAE). Results that meet the 
criteria for serious adverse events or are considered clinically meaningful should be 
reported and recorded terms and severity of adverse events on CRF according to 
CTCAE v4.0.   
 
 
 
12.2. Efficacy Assessment 
Tumor response will be assessed based on modified RECIST 1.1, according to planned 
schedule. All lesions (measurable, evaluable, non-evaluable) must be recorded.  
Assessment of tumor response must be carried out in the same way during study 
period. The planned schedule of assessment is as follows; 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
35 
 
 
Day 14-21 of every 2 cycle during 6 cycles of pembrolizumab plus paclitaxel. (If 
treatment is delayed, assessment should be done before the start of next cycle.) 
Then, day 14-21 of every 3 cycles after 7 cycles of pembrolizumab monotherapy.  
 
At the time of suspected disease progression 
 
12.2.1. Response Rate (RR) 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest as a clinical response after an 
initial increase in tumor burden or even the appearance of new lesions. Response 
rate will be evaluated based on RECIST 1.1 in order to account for the unique tumor 
response profile. PFS and ORR per modified RECIST 1.1 are defined as specified for 
the respective endpoints using RECIST 1.1, with the exception that a confirmation 
assessment of PD (at least 4 weeks after the initial PD assessment) is required for 
subjects who remain on treatment following a documented PD per RECIST 1.1.  
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
12.2.2.  Progression Free Survival (PFS) 
PFS is the secondary objective of this study. PFS is defined as the time from first 
dose to disease progression or death due to any cause. Disease progression is 
assessed by modified RECIST 1.1. Subjects with no documented progression of death 
will be censored at the last date at which they are known to have no progression. 
Patients lacking an evaluation of disease after first study treatment will have their 
PFS time censored on the date of first dose with duration of 1 day. Date of the first 
assessment at which PD is objectively documented will be used for PFS analysis, 


SCLC MK3475 v1.4 (version dated 20160408) 
 
36 
 
although PD is confirmed in subsequent tumor assessments The Kaplan-Meier 
method will be used to estimate the survival curves and median time and confidence 
interval will also be reported.  
 
12.2.3.  Overall Survival (OS) 
Overall Survival is defined as the time from first dose to death due to any cause.   
Through the follow-up within 30 days after study completion or termination of the 
last subject, death and date of death will be checked for subject alive during 
treatment period. Patients without documented death at the time of the final 
analysis will be censored at the date of the last follow-up. The Kaplan-Meier method 
will be used to estimate the survival curves and median time and confidence interval 
will also be reported. 
 
 
13.  Subject registration 
Eligible subjects have to be registered before start of treatment. Subjects will be 
competitively enrolled at multiple centers sites. Seoul National University Bundang 
Hospital and Seoul National University Boramae Medical Center are participating 
centers.  Registration will be done to enter subject information on eCRF.  Subjects 
will be given a three-digit institution number and a three-digit subject number.   
 
 
14.  Adverse event 
14.1. Definition  
1) Adverse Event (AE) : Any untoward or unfavorable medical occurrence in a 
human study participant, including any abnormal sign (e.g. abnormal physical 
exam or laboratory finding), symptom, or disease, whether or not considered 
related to participation in the research. 


SCLC MK3475 v1.4 (version dated 20160408) 
 
37 
 
2) Adverse Drug reaction (ADR):  
“Adverse Drug Reaction (ADR)” : Any response to study drug which is noxious and 
unintended, and which occurs at doses normally used in human. The causal 
relationship between study drug and the adverse event cannot be excluded.  
3) A serious adverse event (SAE/ADR) is any adverse event occurring at any dose or 
during any use of study drug that: 
- 
Results in death; Is life threatening; 
- 
Results in or prolongs an existing inpatient hospitalization;  
- 
Results in persistent or significant disability/incapacity  
- 
Is a congenital anomaly/birth defect;  
- 
Is another important medical event  
 
However, following events should not be considered as SAEs 
- 
A hospitalization/prolonged hospitalization for treatment related to a pre-
existing condition  
- 
A hospitalization/prolonged hospitalization due to evaluate the tumor 
assessment 
- 
A hospitalization/prolonged hospitalization for pre-planned treatment  
- 
The admission results in a hospital (or an emergency room) stay of less than 
24 hours 
- 
Admission due to disease progression  
- 
 
4) Unexpected Adverse Drug Reaction : an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g., Clinical 
trials instruction manual or product labeling). 
 
 
 
 


SCLC MK3475 v1.4 (version dated 20160408) 
 
38 
 
14.2. Evaluating and Recording Adverse Events  
An investigator will evaluate all adverse events according to the NCI Common 
Terminology for Adverse Events (CTCAE), version 4.0. For any AEs not listed in CTCAE 
v4.0, medical terms describing symptoms or signs observed by investigator or reported 
by subject will be recorded, according to the appropriated grading of the general 
definition (Table 8) . 
 
Table 8. Evaluating Adverse Events 
 
Grade 1 
Mild 
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 
Life threatening consequences; urgent intervention 
indicated. 
Grade 4 
Life-threatening or 
Disabling Adverse Event 
Life threatening consequences; urgent intervention 
indicated. 
Grade 5 
Death  
Death related to AE 
 
14.3. Causality assessment 
The causality relationship of study drug to the adverse event will be assessed by 
the investigator as either: Related or Not related 
 
The following criteria should be considered in order to assess the relationship as 
“related”: 
Reasonable temporal association with drug administration 


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Known response pattern to suspected drug 
Disappearance or decrease on cessation or reduction in dose 
Reappearance on re-challenge 
 
The following criteria should be considered in order to assess the relationship as “not 
related”: 
It does not follow a reasonable temporal sequence from administration of the drug. 
It may readily have been produced by the patient’s clinical state, environmental, or 
toxic factors, or other modes of therapy administered to the patient. 
It does not reappear or worsen when the drug is re-administered. 
 
If investigator’s final decision on a causal relationship is not clear, or if investigator 
does not exactly know the cause of the adverse event, the adverse event considered 
likely related to study drug. If the investigator's causality assessment is "unknown but 
not related to study drug," this should be recorded in the CRF as “not related.” 
 
14.4. Adverse events reporting 
14.4.1. Reporting non-serious adverse event 
Information about all AEs is collected and recorded on the Adverse Event report 
form. Any AEs experienced after 30 days after the patient has stopped study 
treatment should only be reported if the investigator suspects a causal relationship 
to the study drug. 
  
14.4.2. Reporting serious adverse event  
Any clinical AE or abnormal laboratory test value that is serious (as defined in 
section 14.1 above) and which occurs during or after the course of the study, 
regardless of the treatment arm must be reported to IRB. In the event of any new 
SAE occurring, the investigator should immediately inform IRB and SAE report form 


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will be submitted to IRB. Immediate and follow-up reporting specify the subject 
using an assigned code.  
 
Seoul National University Hospital 
Kimseunghee:  kshsh8@naver.com 
 
Merck Global Safety 
Fax: 215-993-1220 
 
 
14.4.3. Reporting death 
Deaths occurred within study period and within 30 days of last administration of 
study drug should be reported within 24 hours, regardless of the relevance of the 
study. Deaths that occur within the follow-up period and may be relevant to the 
study should be documented in the SAE form. All deaths, regardless of causes, 
should be recorded in the death CRF.  
 
14.5. Monitoring of Subject with Adverse events 
All adverse events (and their treatments) should be recorded during the treatment 
phase of the study and for 30 days after the administration of the final dose, and 
the patient should be followed up until the adverse event is resolved or until the 
pertinent explanation is available even after the subject completes the 
administration of study drug. Unrelated, mild or moderated adverse events will be 
followed up for 30 days after the administration of the final dose. Subjects with 
severe, life-threatening or related adverse events should be followed up until the 
adverse event is resolved, death occurs, new chemotherapy is started or the causal 
relationship is re-evaluated.  
 
 


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15. Statistical Consideration 
15.1. Definition of analysis population 
 
Intention-To-Treatment (ITT) population will comprise all subjects who receive at 
least one dose of study treatment (one dose of paclitaxel in cycle 1) and who 
have measurable lesion at baseline. The ITT population will serve as the efficacy 
analysis population in this study.  
 
Per-protocol(PP) population will include all ITT subjects who completed the full 
course of assigned treatment and who do not have major protocol violations. 
 
Efficacy will be assessed mainly in ITT population and PP population will be employed 
for supplementary analyses.   
 
The Safety analysis will be conducted for all subjects who receive at least one 
dose of study treatment. 
 
15.2. Statistical analysis 
A one-sided test at the 5% significance level for primary efficacy analysis and a two-
sided test at the 5% significance level for other statistical analysis will be used. In 
addition, number of observations, mean, standard deviation, median, minimum and 
maximum values for continuous variables will be presented. Frequency and ratio for 
categorical variables will be presented.   
- Primary end point: Calculate response rate and estimate the one-sided 95% 
confidence interval   
- Secondary end point: Survival Curves using Kaplan-Meier method, Multivariate 
analysis using Cox proportional hazard regression model.  
- Safety endpoint: Estimated frequency of treatment-related toxicities, especially a 
frequency of 5 percent or grade 3-4. 
 
 


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16.  Biomarker assessment  
Informed consent for specimens be obtained during screening for protocol enrollment 
from all subjects or legally acceptable representative, at a trial visit by the investigator 
or designate. Pretreatment blood sampling and tumor biopsies will be done. After one 
cycle of paclitaxel, blood sampling and tumor biopsies will be performed for 
translational research by investigator's discretion. Archival tissue obtained from the 
patients before the administration of study drug may also be used. Biomarker 
assessment before the administration of study drug will be performed at Seoul 
National University (SNU) Cancer Research Institute and QualTek, and later assessment 
will be performed at SNU Cancer Research Institute. Results of genetic test will be used 
for research purpose only, personal information will be protected. All specimens will be 
destroyed after storage for 5 years. Subjects may withdraw their consent and have 
their specimens and all derivatives destroyed. 
 
17.  Policy and procedures for the protection of human subjects 
17.1.  Ethical Aspects 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, 
October 2013) and in compliance with the relevant law in Korea (the pharmaceutical 
affairs law, Medical Appliances Act, Bioethics and Safety Act, and relevant Korea FDA 
Notification) 
and 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use-Good Clinical 
Practice (ICH GCP). Prior to commencement of this study, this trial protocol will be 
approved by Ministry of Food and Drug Safety (MFDS) and IRB, and amendment to 
the study will also be approved by MFDS and IRB.  
 


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17.2.  Subject Consent 
The initial assessment is conducted within 28 days before the start of treatment, 
and subject should read and sign the ICF approved by IRB before study procedures. 
It is the responsibility of the investigator to obtain written informed consent from 
each individual participating in this study after adequate explanation of the aims, 
methods, objectives and potential hazards of the study. It must also be explained 
to the subjects that they are completely free to refuse to enter the study or to 
withdraw from it at any time for any reason. Subjects should be given a period of 
time to understand the study and contemplate their decision before signing a 
consent document. The subject’s written informed consent to participate in the trial 
must be given before any trial-related activities are carried out. Investigator and 
subject or legally acceptable representative. Investigator or designee and subject 
should sign and date the consent form. The original signed and dated ICF will be 
kept at the study site and copy will be provided to subjects. A copy of the signed 
and dated ICF should be given to the subject before participation in the trial. If 
the subject or legally acceptable representative is unable to read, a reliable and 
independent witness should be present during the entire informed consent 
discussion. The choice of the witness must not breach the subject’s right to 
confidentiality. A reliable independent witness is defined as one not affiliated with 
the institution or engaged in the investigation. A family member or acquaintance is 
an appropriate independent witness. After the subject or legally acceptable 
representative orally consents and has signed, if capable, the witness should sign 
and personally date the consent form attesting that the information is accurate and 
that the subject or legally acceptable representative has fully understood the 
content of the informed consent agreement and is giving true informed consent. 
 
17.3. Subject Protection/Safety  
Each study sites should provide specialized personnel and adequate facilities to 


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conduct the clinical trial in accordance with the protocol and to protect subjects. 
Clinical trial personnel should understand adverse events and precautions described 
in the protocol, stop the study in case of SAE, take appropriate management 
measures and inform IRB and all investigators. Every effort should be made to treat 
adverse event and recover from side effects. In case of hospitalization due to the 
study drug, effort should be made to minimize the burden on the subject. For these 
reasons, insurance coverage will be provided for each sites participating to the trial. 
Investigator will inform the review of safety information every 6 months  
 
17.4.  Confidentiality of Subject information 
All information generated in this study will be considered confidential, and 
confidentiality of subjects will be maintained in case of publishing results of this 
study. All study-related documents will be kept as classified documents in a facility 
with regulation, and the subject will be identified by unique code only. By signing 
this protocol, the investigator agrees that IRB/ERC, or regulatory authority 
representatives may consult and/or copy trial documents in order to verify 
worksheet/case report form data. By signing the consent form, the subject agrees to 
this process. 
 
17.5. Records retention 
The Investigator should keep all study-related documents (CRF, ICF, clinical result 
report, study drug administration form and the relevant information form etc.) for 3 
years from the IRB approval date of study completion report.  
 
17.6.  Clinical Trials Monitoring 
During the clinical trials, monitors designated by PI will carry out monitoring ethically 
and scientifically according to GCP guidelines. Monitoring includes reviewing study-


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related documents (ICF, CRF data etc.) and verifying compliance to study protocol  
 
 
18.  Storage and Disposal of human biospecimens  
Human biospecimens collected for exploratory biomarker research will be stored at 
SNU Cancer Research Institute and QualTek until 5 years after the completion of this 
study. Collected human biospecimens will be kept under strict control in accordance 
with SOP for SNU cancer research institute storage facility and storage/disposal 
procedures which Merck request to QualTek. When human biospecimens are stored, 
encrypted serial numbers will be assigned to subjects to conceal personal 
identification information (personal details, medical record number, name, and 
resident registration number) and guarantee anonymity. In case of QualTek, 
information will be encrypted and stored in compliance with U.S. privacy laws. 
Examination report and results, and the agreement is preserved for three years, and 
human biospecimens will be disposed immediately after the end of the storage period.  
 
 
 
 
 
 
 
 
 
 


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