A Phase 2 Study of Docetaxel, Ramucirumab, and Pembrolizumab for Patients With Metastatic or Recurrent Non-Small Cell Lung Cancer Who Progressed on Platinum-Doublet and PD-1/PD-L1 Blockade
Phase: PHASE2
Conditions: Metastatic Non-Small Lung Cell Cancer, Recurrent Non-Small Lung Cell Cancer, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: Emory University

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 1 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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PROTOCOL TITLE: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and 
PD-1/PD-L1 blockade
WINSHIP PROTOCOL #: WINSHIP4950-20
COORDINATING CENTER: Winship Cancer Institute, Emory University 
PRINCIPAL INVESTIGATOR:
Badi El Osta, MD, FACP
Associate Professor of Hematology and Medical Oncology
Winship Cancer Institute
1365 Clifton Rd NE
Atlanta, GA 30322
404-778-1900
belosta@emory.edu 
CO-INVESTIGATORS:
Suresh Ramalingam, MD, FACP, FASCO
Professor of Hematology and Medical Oncology
Winship Cancer Institute
1365 Clifton Rd NE
Atlanta, GA 30322
404-778-1900
ssramal@emory.edu
 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 2 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Jennifer Carlisle, MD
Assistant Professor of Hematology and Medical Oncology
Winship Cancer Institute
1365 Clifton Road NE
Atlanta, GA 30322
404-778-2304
Jennifer.w.carlisle@emory.edu 
Ticiana Leal, MD
Associate Professor of Hematology and Medical Oncology
Winship Cancer Institute
1365 Clifton Road NE
Atlanta, GA 30322
404-251-5544
Ticiana.a.leal@emory.edu
Madhav V. Dhodapkar, MBBS
Professor of Hematology and Medical Oncology
Winship Cancer Institute
1365 Clifton Rd NE
Atlanta, GA 30322
404-778-1900
madhav.v.dhodapkar@emory.edu
STATISTICIAN:
Yuan Liu, PhD, MS
Winship Cancer Institute 
1518 Clifton Road
Atlanta, GA 30322
404-778-1989
yliu31@emory.edu
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 3 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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VERSION: (Version 4.0; 3/7/2025)
FUNDING SOURCE: Merck
INVESTIGATIONAL PRODUCT (IP): pembrolizumab (supplied by Merck)
OTHER AGENT(S):  docetaxel and ramucirumab (commercially available)
IND #:
X Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 4 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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REVISION HISTORY
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 5 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Section 
Number
Section Title
Description of Change(s)
Rationale
Header
Header
Correction: version and date updated throughout the 
document
New Version
Cover page
Cover page
Correction: statistician name, address, and telephone
Previous statistician left institution
Deletion:  12. Human immunodeficiency virus (HIV) 
infected patients on effective anti-retroviral therapy with 
undetectable viral load within 6 months are eligible for 
this trial
To be consistent program wide 
requirement (including Company 
Sponsored and MISP studies) and 
align with exclusion criteria #18
4.1.1
Participant 
Inclusion Criteria
Deletion:  13.  For patients with evidence of chronic 
hepatitis B virus (HBV) infection, the HBV viral load must 
be undetectable on suppressive therapy, if indicated. 
Patients with a history of hepatitis C virus (HCV) infection 
must have been treated, cured and have an undetectable 
HCV viral load.
To be consistent with program wide 
requirement (including Company 
Sponsored and MISP studies) and 
align with exclusion criteria #19
Insertion:  18. … Note: no HIV testing is required unless 
mandated by local health authority.
4.1.2
Participant 
Exclusion Criteria
Insertion:  19. … Note: no testing for Hepatitis B and 
Hepatitis C is required unless mandated by local health 
authority.
To align with pembrolizumab 
program standard version 11 protocol 
template
4.2.3
Dose 
modification and 
toxicity 
management
Correction: Table 4. Aligned left instead of justified some 
of the contents
Alignment correction
Deletion: “:” after Trial Period, Treatment Cycle/Title, 
Scheduling window (Days)
Typo correction
5.1
Study Flow Chart 
(Table)
Correction: Follow-Up (use dash and capital U throughout 
table); Discon (capital D throughout table)
Typo correction
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 6 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Correction: blood tests that will be ordered if clinically 
indicated were moved and placed after mandatory tests
Better organized
Correction: mandatory imaging (CT) moved and placed 
ahead of the imaging that will only be ordered if clinically 
indicated
Better organized
Deletion: PET/CT and MRI chest/Abdomen
List only the strongly preferred 
imaging in calendar
Correction: interval of imaging
Align with primary endpoint 6-month 
PFS
Insertion: Every 12 weeks and at end of treatment
Clarify timing of MRI Brain and Bone 
Scan if clinically indicated
Insertion: e and f next to X
Clarify correlative studies blood 
collection
Correction: Font in the mid of the legend
Font correction
Deletion: “End of Treatment” from a:
Typo correction
Insertion: Subsequent tumor imaging will be performed 
every 6 weeks (42 days ±7 days) from Cycle 1 Day 1 
during first 6 months, then every 9 weeks (63 days ±7 
days) between 6 months and 1year, then every 12 weeks 
(84 days ±7 days) after 1 year. Imaging timing should 
follow calendar days and should not be adjusted for 
delays in cycle starts. Every effort should be made to 
continue tumor imaging using same interval for 
participants who discontinue study treatment without 
documented disease progression.
Provided specifics for interval of 
imaging to align with primary 
endpoint 6-month PFS and 
clarification for spacing interval of 
imaging
5.1 
Study Flow Chart 
(Legend and 
footnotes)
Deletion: footnote g
Not needed
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 7 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Deletion: footnote h
Not needed; clarification added to 
footnote c
Insertion:  End of Treatment
Clarify acronym
Change:  Subsequent tumor imaging should be performed 
every 6 weeks (42 days ±7 days) or more frequently if 
clinically indicated.  
Provided specifics for interval of 
imaging to align with primary 
endpoint 6-month PFS
6.1.2.6.1
Initial Tumor 
Imaging
Change and insertion: After 6 months, participants who 
remain on treatment will have imaging performed every 9 
weeks (63 days ±7 days) until 1 year, and every 12 weeks 
(84 days ±7 days) thereafter.  
Clarified spacing interval of imaging; 
since 6 months is a fixed period, it is 
not necessary to place equivalent in 
days
Correction: (Section 9.2.1.6) will be replaced by (Table 7, 
Figure 3)
Correction: Section 9.2.1.6 will be replaced by Appendix 4
6.1.2.6.2
Tumor imaging 
during the study
Insertion and correction:  Exceptions are possible upon 
consultation with Merck; (Section 9.2.1.6) will be replaced 
by (Table 7, Figure 3, and Appendix 4)
Section 9.2.1.6 does not exist on 
current template; reference updated 
throughout iRECIST text
6.1.2.6.4
Figure
Correction: Figure 1 was corrected to Figure 3
Keep with succession of figures in the 
text
6.1.5.3.2
Follow-up Visits
Correction: After 1 year, the imaging time point will occur 
every 12 weeks (± 7 days).
Typo correction; align with interval of 
imaging plan
Template
Change: using new Emory IRB protocol template
Align with Emory IRB new template
Table 5
4.2.3
Change: Table 5 updated from MISP v.12 template
Align with updated dose modification 
guidelines on MISP v.12
Version 2.0 revisions
Cover page
Cover page
Deletion: co-investigator name and contact
One co-investigator left institution
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 8 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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3.1.2
Preclinical and 
Clinical Trial Data
Correction: EHFR changed to EGFR
Typo correction
4.2
Trial Treatments
Insertion: “following the sequence”
Align to match with the approved and 
established treatment order 
sequence for this study
4.2.1
Timing of Dose 
Administration
Insertion: “We are not aware of any clinical concern of 
administering docetaxel prior to ramucirumab. To 
maximize the clinical benefit of this study treatment in 
patients who have already progressed on PD-1/PD-L1 
blockade, we will give chemotherapy with docetaxel 
upfront in an attempt to enhance tumor anti-genecity and 
tumor mutation burden. This will be followed by an anti-
angiogenic agent, ramucirumab, in an attempt to 
modulate the tumor immune microenvironment. And last, 
we will administer pembrolizumab.”
Insertion: “However, in this study, we will administer 
docetaxel prior to ramucirumab based on the rational 
provided above.”
Added rational and clarification for 
the treatment sequence
Change: footnotes d and e
Insertion:  footnotes f and g
5.1
Study Flow Chart 
(Legend and 
footnotes)
Insertion: footnotes d, f, and g in table
Clarified timepoints for tissue 
collection and for correlative studies 
blood collection 
5.1
Study Flow Chart
Deletion: Pre-screening Consent line
This study does not have a pre-
screening consent
6.1.4.2
Treatment period
Correction: Docetaxel, Ramucirumab, and 
Pembrolizumab
Align to match with the approved and 
established treatment order 
sequence for this study
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 9 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Deletion: IND language
IND language is not required for this 
IND-exempt study
Correction: 90 days instead of 30 days “For the time 
period beginning at treatment allocation through 90 days 
following cessation of treatment”
Align with MISP protocol guidance
6.2.3
Immediate 
Reporting of 
Adverse Events 
to the Principal 
Investigator and 
to Merck
Insertion: “(or 30 days following cessation of study 
intervention if the participant initiates new anticancer 
therapy, whichever is earlier)”
Align with MISP protocol guidance
Table 3
4.2
Change: Pembrolizumab moved to 3rd row in Table 3
Align to match with the approved and 
established treatment order 
sequence for this study
Table 10
8.1
Change: 
Ramucirumab 
moved 
to 
2nd 
row 
and 
pembrolizumab moved to 3rd row
Align to match with the approved and 
established treatment order 
sequence for this study
Version 2.1 revisions
Insertion: co-investigators names and contact information
Two co-investigators added to the 
study
Cover page
Cover page
Deletion: co-investigator name and contact, VA institution
Co-investigator is moving to another 
institution 
Study 
summary,
1.1, 4.3, 7.1, 
7.3
Study summary
Study design
Treatment 
allocation
Trial design
Statistical 
analysis plan
Insertion: We estimate to enroll 60 participants to account 
for screen failures in order to have 41 evaluable patients 
(study summary)
Insertion: evaluable (1.1, 4.3, 7.1, 7.3)
Insertion: We estimate to enroll 60 participants to account 
for screen failures (7.3)
To clarify the total number of 
patients accounting for screen 
failures and evaluable patients for 
analysis
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 10 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Version 2.2 revisions
Study 
summary,
7.3
Study summary
Statistical 
analysis plan
Correction: We estimate to enroll 45 participants to 
account for screen failures in order to have 41 evaluable 
patients (study summary)
Correction: We estimate to enroll 45 participants to 
account for screen failures (7.3)
To clarify the total number of 
patients including screen failures to 
account 10% above target.  Should 
this prove insufficient as the study 
proceeds, we will discuss any change 
that might prove necessary with the 
funding source
Table 4
4.2.3
Insertion: (defined as systolic blood pressure ≥180 mmHg 
and/or diastolic blood pressure ≥120 mmHg)
Added definition of severe 
hypertension
Version 2.3 revisions
3.2.4.2, 5.1, 
6.1.2.7, 
6.1.4.2
Biomarker 
Research
Study Flow Chart
Tumor Tissue 
Collection and 
Correlative 
Studies Blood 
Sampling
Treatment Period
Change: 2nd timepoint blood collection was moved from 
cycle 1 between day 8 and 15 to cycle 2 day 1 prior to drug 
administration
To eliminate the inconvenience of an 
extra visit for blood draw on 
participants and improve accrual on 
correlative studies
Change: RNA sequencing replaced by mass cytometry on 
tumor
To clarify the technology used on 
tumor infiltrating immune cells 
collected from fresh biopsy specimen 
and align with current budget
2.3, 3.2.4.2, 
6.1.2.7
Exploratory 
Objective(s)
Biomarker 
Research
Tumor Tissue 
Collection and 
Change: “after treatment” to “at end of treatment”
To align 2nd biopsy timing throughout 
protocol
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 11 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Correlative 
Studies Blood
Insertion: We will use Winship Cancer Tissue and 
Pathology (CTP) Shared Resource to ensure specimens for 
the study are properly tracked for reporting purposes and 
stored prior to distributing them to the recipient lab 
(Winship Immune Monitoring Shared Resource at the end 
of the study for analysis.  Winship CTP will follow their 
standard biorepository processes as described in 
IRB00045796 (PI: Schneider, Storage & Research Use of 
Tissue & Information).
Deletion:  Address: HSRB E330 – phone: 404-727-3701)
To clarify the need for Winship 
Cancer Tissue and Pathology (CTP) 
Shared Resource
Insertion: tube for each timepoint
To clarify that the amount of blood 
collected refer to each time 
timepoint
3.2.4.2, 5.1, 
6.1.2.7
Biomarker 
Research
Tumor Tissue 
Collection and 
Correlative 
Studies Blood
Insertion: Blood tubes will be delivered at room 
temperature, on same day if possible, or overnight, to 
Winship Cancer Tissue and Pathology (CTP) Shared 
Resource (1365B Clifton Road, 3rd Floor, 3200 – phone: 
404-778-5108). Winship CTP standard process is to aliquot 
plasma into 4 x 0.5ml aliquots and 4 x 1.0ml aliquots before 
storage at -80. PBMC are cryopreserved at ~5x10^6 
cells/aliquot and stored long-term in LN2.  Blood collected 
outside of the windows indicated below or missed blood 
collections will not constitute protocol deviations. Blood 
collection timing may vary because appointments may not 
be scheduled solely for this study.
To clarify delivery, processing, and 
storage of the research blood 
samples and include language to 
eliminate protocol deviations if 
samples are not collected or are 
collected outside these timepoints
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 12 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Insertion: Freshly obtained biopsies will be logged and de-
identified by Winship CTP (Address: B3200) before 
distribution to the recipient lab (Address: B3204). Tumor 
tissue collected outside of the windows indicated above or 
missed tumor tissue collections will not constitute 
protocol deviations. Tumor tissue collection timing may 
vary because appointments may not be scheduled solely 
for this study.
To clarify delivery of the research 
tumor samples with new room 
address and include language to 
eliminate protocol deviations if 
samples are not collected or are 
collected outside these timepoints
Insertion: in coordination with the recipient lab (Address: 
B3204 – phone 404-727-3701) and Winship CTP (Address: 
B3200 – phone: 404-778-5108).  Tumor studies will only be 
offered to participants accrued at Emory.
Insertion: foot note h:  Tissue collection will only be 
offered to participants accrued at Emory. Biopsies will be 
coordinated with the recipient lab (Address: B3204 – 
phone 404-727-3701) and Winship CTP (Address: B3200 – 
phone: 404-778-5108).
Deletion: Address: HSRB E330. We can also arrange for 
pickup if main lab number is called: 404-727-3701.
To clarify coordination of arranging 
fresh biopsies for analysis and to limit 
this option to the main research site 
for logistical reasons
Version 3.0 revisions
Cover page
Cover page
Insertion: Ascension Sacred Heart Pensacola
Emory required multi-site language
Study 
Summary
Description of 
Sites/Facilities 
Enrolling
Insertion: Winship Cancer Institute of Emory University 
(Atlanta, GA)
Emory required multi-site language
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 13 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Participants:
Ascension Sacred Heart (Pensacola, FL)
Section 3.2
Section 3.2
Insertion: We propose a prospective multicenter (Emory 
and Ascension Sacred Heart Pensacola) phase II clinical 
trial to study this combination.
Emory required multi-site language
Section 8.5
Returns and 
Reconciliation
Insertion: The IDS (Investigational Drug Service) personnel 
at Winship and Ascension Sacred Heart Pensacola will 
account for all study drugs.
Emory required multi-site language 
Section 4.1
Study Population
Insertion: We plan to have 41 participants complete the 
protocol required research procedures and estimate to 
enroll 45 participants across all sites to account for screen 
failures. Potential participants will be identified in medical 
oncology 
clinics, 
multidisciplinary 
cancer 
clinic, 
multidisciplinary tumor board at Emory University and 
Ascension Sacred Heart Pensacola. 
Emory: The number of participants who are expected to be 
enrolled and screened at Winship is 33, and the number of 
participants needed to complete the research procedures 
(i.e., number of participants excluding screen failures) is 
35.
Ascension Sacred Heart Pensacola: The number of 
participants who are expected to be enrolled and screened 
at Mayo Clinic is 8, and the number of participants needed 
to complete the research procedures (i.e., number of 
participants excluding screen failures) is 10.
Emory required multi-site language
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Section 11
Section 11
Insertion: Multi-Site language 
Adding Ascension Sacred Heart 
Pensacola to the study and needing 
to insert multi-site language 
Version 4.0 revisions
Cover page
Cover page
Study 
Summary
Description of 
Sites/Facilities 
Enrolling
Participants
Section 3.2
Section 3.2
Section 8.5
Returns and 
Reconciliation
Section 4.1
Study Population
Section 11
Section 11
Deletion: Ascension Sacred Heart Pensacola
Insertion: non-Emory collaborating site
Non-Emory collaborating site will be 
determined if necessary to complete 
accrual
Study 
summary,
1.1, 4.1, 4.3, 
7.1, 7.3
Study summary
Study Design
Study Population
Treatment 
Allocation
Trial Design
Sample size
Change:  We estimate to consent up to 45 patients to 
account for screen failures and enroll up to 30 patients to 
account for early dropout prior to 6 months on study in 
order to have 21 evaluable patients for the primary 
endpoint (Study Summary).
Change: We will include 21 evaluable patients to assess 
the safety of the combination treatment and its efficacy 
in terms of 6-month progression free survival (PFS) 
targeting a 25% increase (1.7-fold) over the historic PFS 
on REVEL study (i.e. from 37% to 62%) (Study Design)
To clarify the total number of 
patients accounting for screen 
failures, dropout prior to 6 months, 
and evaluable patients for analysis
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 15 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Change: We plan to have 21 participants complete the 
protocol required research procedures for the primary 
endpoint and estimate to consent up to 45 patients 
across all sites to account for screen failures and enroll up 
to 30 patients to account for early dropout prior to 6 
months on study (Study Population)
Deletion:  
Emory: The number of participants who are expected to 
be enrolled and screened at Winship is 33, and the 
number of participants needed to complete the research 
procedures (i.e., number of participants excluding screen 
failures) is 35.
Ascension Sacred Heart Pensacola: The number of 
participants who are expected to be enrolled and 
screened at Mayo Clinic is 8, and the number of 
participants needed to complete the research procedures 
(i.e., number of participants excluding screen failures) is 
10 (Study Population)
Change: In the first stage, 10 evaluable patients will be 
accrued. If there are 4 or fewer patients with free of 
progression at 6-month among these 10 patients, the 
study will be stopped for futility. Otherwise, 11 additional 
evaluable patients will be accrued for a total of 21 
(Treatment Allocation)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 16 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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Change: Simon’s two-stage optimum design will be used. 
The null hypothesis that the 6-month PFS rate is 37% will 
be tested against one-sided alternative hypothesis that the 
actual 6-month PFS rate is higher than 62%. In the first 
stage, 10 evaluable patients will be accrued. If there are 5 
or more patients who progressed or died prior to 6 months 
among these 10 patients, the study will be stopped early 
for futility. Otherwise, 11 additional evaluable patients will 
be accrued for a total of 21 patients.
The null hypothesis will be rejected if 11 or more remain 
free of progression or death by 6 months among 21 
evaluable patients. This design yields a type I error of 0.10 
and power of 80% when the actual 6-month PFS rate is 
62%. To account for early dropout prior to 6 months on 
study, we plan to enroll up to 30 patients. The calculation 
is based on current enrollment status including early 
dropout (among 23 enrolled, 5 dropouts without 
progression at 6 months and 2 did not complete cycle 1 of 
study treatment). (Trial Design) 
Change: We will include 21 evaluable patients to assess 
the safety of the combination treatment and its efficacy 
in term of 6-month PFS rate as defined by 25% increase 
(1.7-fold) from the historic 6-month PFS rate on REVEL 
study (37% to 62%). We estimate to consent up to 45 
patients to account for screen failures and enroll up to 30 
patients to account for early dropout prior to 6 months 
on study (Sample size)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 17 of 118                       Protocol Version: Version 4.0 Dated 7March2025
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4.1
Table 3
Insertion: infusion timing for each agent
Insertion: Sites should make every effort to target infusion 
duration of each administered agent to be as close as 
possible to the recommended infusion duration of each 
agent. However, given the variability of infusion pumps, a 
window of -5 minutes and +10 minutes will be permitted.
To clarify the infusion duration for 
each agent and add a time window to 
allow technical variabilities
4.1
Table 4
Insertion: Resume ramucirumab no sooner than 2 weeks 
after surgery and until adequate wound healing. 
Deletion: no sooner than 28 days after surgery and until 
the surgical wound is fully healed. Discontinue 
ramucirumab for wound healing complications that 
require medical intervention.
To align with ramucirumab package 
insert 3/2022
5.1
Study Flow Chart
Insertion: +3 days under column 1 of 21-day treatment 
cycle
To allow flexibility similar to other 
cycles for sites who can’t bill for 
provider and infusion chair on same 
day.
Page 3
Updated IRB approved pending status
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 18 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Table of Contents
1.0
STUDY DESIGN............................................................................................................................21
1.1
Study Design ......................................................................................................21
2.0
OBJECTIVE(S) & HYPOTHESIS(ES) ................................................................................................22
2.1
Primary Objective(s) & Hypothesis(es)..............................................................22
2.2
Secondary Objective(s) & Hypothesis(es)..........................................................22
2.3
Exploratory Objective(s) ....................................................................................22
3.0
BACKGROUND & RATIONALE......................................................................................................23
3.1
Background........................................................................................................23
3.2
Rationale............................................................................................................27
4.0
METHODOLOGY..........................................................................................................................38
4.1
Study Population ...............................................................................................38
4.2
Trial Treatments ................................................................................................44
4.3
Treatment Allocation.........................................................................................55
4.4
Stratification ......................................................................................................55
4.5
Concomitant Medications/Vaccinations (allowed & prohibited) ......................55
4.6
Participant Withdrawal/Discontinuation Criteria..............................................58
4.7
Participant Replacement Strategy.....................................................................59
4.8
Clinical Criteria for Early Trial Termination........................................................59
5.0
TRIAL FLOW CHART.....................................................................................................................60
5.1
Study Flow Chart................................................................................................60
6.0
TRIAL PROCEDURES ....................................................................................................................65
6.1
Trial Procedures.................................................................................................65
6.2
Assessing and Recording Adverse Events ..........................................................82
7.0
STATISTICAL ANALYSIS PLAN.......................................................................................................93
7.1
Trial Design ........................................................................................................93
7.2
Statistical Analysis Plan......................................................................................93
8.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES......................................94
8.1
Investigational Product......................................................................................94
8.2
Packaging and Labeling Information..................................................................95
8.3
Clinical Supplies Disclosure................................................................................96
8.4
Storage and Handling Requirements.................................................................96
8.5
Returns and Reconciliation................................................................................97
9.0
ADMINISTRATIVE AND REGULATORY DETAILS ............................................................................98
9.1
Data Reporting / Regulatory Requirements ......................................................98
10.0 ETHICS AND PROTECTION OF HUMAN SUBJECTS.......................................................................100
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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10.1
Ethical standard...............................................................................................100
10.2
Institutional review board ...............................................................................100
10.3
Informed consent ............................................................................................100
10.4
Participant and data confidentiality ................................................................101
10.5
Research use of stored samples, specimens, or data......................................101
11.0 Multi-Site or Collaborative Research.........................................................................................102
12.0 References................................................................................................................................103
13.0 APPENDICES .............................................................................................................................107
Appendix 1:.............................................................................................................................107
A)
ECOG Performance Status ...............................................................................107
B)
The New York Heart Association (NYHA) functional classification of heart 
failure
107
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ......................108
Appendix 3: Contraceptive Guidance and Pregnancy Testing................................................109
Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression .....113
APPENDIX 5   Abbreviations and definition of terms..............................................................117
       
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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STUDY SUMMARY
Abbreviated Title
Docetaxel, ramucirumab, and pembrolizumab in metastatic 
or recurrent NSCLC
Trial Phase
Phase 2
Clinical Indication
NSCLC
Trial Type
Prospective, single arm, open-label
Type of control
N/A
Route of administration
Intravenously 
Trial Blinding
N/A
Treatment Groups 
Single arm: NSCLC patients who progressed on platinum-
based and any of the FDA-approved PD-1 or PD-L1 immune 
checkpoint inhibitors, when given sequentially or in 
combination, and who were not previously exposed to 
docetaxel or ramucirumab.
Number 
of 
trial 
participants
We estimate to consent up to 45 patients to account for 
screen failures and enroll up to 30 patients to account for 
early dropout prior to 6 months on study in order to have 21 
evaluable patients for the primary endpoint.  
Estimated 
enrollment 
period
24 months
Estimated duration of trial 24 months
Duration of Participation
Until progression of the disease confirmed on 2 consecutive 
scans obtained at least 4 weeks apart, or occurrence of 
severe side effects, or if the patient or the treating physician 
believes that continuing on the study treatment is not in the 
best interest of the patient.
Estimated average length 
of treatment per patient
6 months
Description 
of 
Sites/Facilities Enrolling
Participants:
Winship Cancer Institute of Emory University (Atlanta, GA)
Non-Emory collaborating site (TBD)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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1.0 STUDY DESIGN
1.1
Study Design
This is a prospective, single arm, open-label, phase 2 study of the combination of docetaxel, 
ramucirumab, and pembrolizumab for adult patients with metastatic or recurrent NSCLC that 
progressed after receiving concomitantly or sequentially a platinum-doublet chemotherapy and 
a PD-1 or PD-L1 checkpoint inhibitor. The combination will be administered every 21 days until 
confirmed disease progression defined as progression on 2 consecutive scans at least 4 weeks 
apart, or occurrence of severe side effects, withdrawal of consent by the patient or if in the 
opinion of the treating physician continuing on the study treatment is not in the best interest of 
the patient.
We will include 21 evaluable patients to assess the safety of the combination treatment and its 
efficacy in terms of 6-month progression free survival (PFS) targeting a 25% increase (1.7-fold) 
over the historic PFS on REVEL study (i.e. from 37% to 62%). We will first evaluate safety of the 
3-drug regimen in an initial run-in of six patients. If less than 2 of 6 patients experience dose 
limiting toxicity, we will continue with the efficacy assessment of the combination. If safety 
signals are noted, we will consider dose reduction, when clinically appropriate, for the 
subsequent group of patients.
The study is divided into a Screening period, Treatment period, End of Treatment (EOT) period, 
and Follow-up period.
During Screening period patients will provide written informed consent to participate in the study 
before completing any protocol-specified procedures or evaluations not considered to be part of 
the patient’s standard care. Procedures that were performed for standard of care prior to signing 
informed consent may be used for screening purposes (e.g., full physical exam) as long as the 
procedures were completed within the 28-day screening period. After signing the ICF, patients 
will be evaluated for entry criteria during the screening period within 28 days before 
administration of study drug(s).  Rescreening after screen failure will be allowed.
Treatment will continue until unacceptable toxicity, death, disease progression per RECIST 1.1, 
Investigator’s decision to discontinue treatment, patient withdraws consent, lost to follow-up, or 
Institution decides to terminate the trial. Patients with PD per RECIST 1.1 but with otherwise 
stable or improved performance and clinical status may continue to be treated in the event of a 
perceived benefit per Investigator; see Section “Treatment beyond progression”.  Patients with 
a PR or SD will continue to receive treatment until achievement of a confirmed complete 
response (CR), disease progression, or intolerability to therapy. It is at the discretion of the 
Investigator to continue treating patients with a confirmed CR.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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2.0 OBJECTIVE(S) & HYPOTHESIS(ES)
2.1
Primary Objective(s) & Hypothesis(es)
Objective:  To determine the anti-tumor efficacy of the combination treatment using the 6-
month progression free survival rate (6-month PFS rate) by Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1).
Hypothesis: We hypothesize that the combination of docetaxel, ramucirumab, and 
pembrolizumab is safe and more effective than docetaxel and ramucirumab in patients with 
metastatic or recurrent NSCLC who have progressed on platinum-based chemotherapy given 
concomitantly or sequentially with a PD-1 or PD-L1 immune checkpoint inhibitor.
2.2
Secondary Objective(s) & Hypothesis(es) 
Objectives:
(1)
To determine the safety profile and tolerability of docetaxel and ramucirumab in 
combination with pembrolizumab in patients who progressed on platinum-based 
chemotherapy and PD-1 or PD-L1 checkpoint inhibitor given sequentially or in combination.
(2)
To determine immune related adverse events of the combination docetaxel, ramucirumab, 
and pembrolizumab.
(3)
To assess the overall response rate (ORR) of the combination docetaxel, ramucirumab, and 
pembrolizumab.
(4)
To assess the overall survival (OS) of the combination docetaxel, ramucirumab, and 
pembrolizumab.
2.3
Exploratory Objective(s)
Objectives: 
(1)
To correlate treatment response with PD-L1 22C3 expression, STK11 and KRAS mutation 
status. 
(2)
To correlate treatment response with the doublet tumor mutation burden (TMB) and PD-
L1 22C3 expression.
(3)
To perform an immunophenotypic analysis of circulating immune cells by mass cytometry 
before and after treatment and EOT.
(4)
To analyze the tumor infiltrating immune cells by mass cytometry coupled to blood mass 
cytometry, in paired biopsies before and at end of after treatment.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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3.0 BACKGROUND & RATIONALE
3.1
Background
Immunotherapy in cancer
The development of therapeutic agents that binds to the programmed cell death protein 1 (PD-
1) and programmed death-ligand 1 (PD-L1) is one of the major advances in the treatment of lung 
cancer in the last decade. In particular, pembrolizumab (formerly MK-3475 and lambrolizumab, 
trade name Keytruda®), was the first FDA-approved anti-PD-1 therapy in oncology. 
Immunotherapy is an established modality for the treatment of lung cancer. Inflammation and 
immune escape play crucial roles in the progression of disease while on immune checkpoint 
inhibitors. 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Pembrolizumab is indicated for the treatment of patients across a number of indications because 
of its mechanism of action to bind the PD-1 receptor on the T cell.  For more details on specific 
indications refer to the Investigator brochure.
In September 2014, the US Food and Drug Administration (FDA) granted accelerated approval for 
pembrolizumab as treatment of relapsed or refractory melanoma. This designation was granted 
based on early findings of efficacy and unmet medical need for melanoma patients. Since then, 
pembrolizumab and other PD-1/PD-L1 inhibitors have received FDA-approval for the treatment 
of a variety of solid tumors including lung cancer. Most pembrolizumab’s approved indications 
are based on the companion diagnostic test PD-L1 22C3 expression. In addition, pembrolizumab 
is the only tissue-agnostic immune checkpoint inhibitor (ICI) that is FDA-approved for any 
unresectable or metastatic solid tumor with mismatch repair deficiency (dMMR) or microsatellite 
instability (MSI high).
3.1.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma [Dudley et al., 2005; Hunder et al., 2008].
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  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. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001].
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain 
responsible for ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), 
and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling 
cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 
2009].  The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
[Parry et al., 2005; Francisco, 2010].  As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in lung cancer. 
Non-Small Cell Lung Cancer (NSCLC) current treatments
NSCLC represents a heterogeneous cancer, with different biology and clinical behavior. For wild 
type NSCLC, chemotherapy with platinum-doublet and PD-1 or PD-L1 checkpoint inhibitor, given 
in combination or sequentially, are the main 2 effective treatment approaches. For mutant type 
metastatic NSCLC, an oral tyrosine kinase inhibitor targeting the appropriate mutation is the 
preferred upfront treatment for these patients.
To overcome therapeutic limitations of chemotherapy, investigators have explored the use of 
anti-angiogenic agents prior to immune therapy. The development of hypoxia within a growing 
tumor activates the hypoxia-inducible factors (HIF-1a and HIF-2a) that in turn activate multiple 
intracellular signaling pathways leading to the generation and release of pro-angiogenic factor 
from within the tumor and stroma responsible of the formation of new capillaries and blood 
vessels. Thus, inhibition of the angiogenesis pathway by targeting VEGF-A and VEGFR-2 lead to 
new treatment options for NSCLC: the two monoclonal antibodies, bevacizumab (1st line) and 
ramucirumab (2nd line and beyond), are FDA-approved therapies when administered in 
combination with chemotherapy.
After progression on platinum doublets, docetaxel with or without ramucirumab, a human IgG1 
monoclonal antibody that targets the extracellular domain of VEGFR-2, was the preferred 2nd line 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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therapy before the immune therapy era with checkpoint inhibitors. The combination resulted in 
a modest improvement in overall survival (OS) compared to docetaxel alone. The REVEL study 
[Garon E.B. et al., 2014] is a randomized, double-blind, placebo-controlled, multicenter phase 3 
study of to treat patients with NSCLC that progressed on platinum doublet. 624 patients received 
docetaxel 75 mg/m2 with ramucirumab 10 mg/kg every 3 weeks and 621 patients received 
docetaxel 75 mg/m2 with placebo every 3 weeks until disease progression, unacceptable toxicity, 
withdrawal, or death. OS was the primary endpoint. Median OS was 10.5 vs. 9.1 months (HR 0.86; 
95% CI: 0.75, 0.98; p =0.023) and median PFS was 4.5 vs. 3 months (HR 0.76; 95% CI: 0.68, 0.86; 
p <0.0001) in the combination and control arms, respectively. 
The investigator-assess overall response rate (ORR) was 23% vs. 14% (odds ratio [OR] 1.89, 95% 
CI: 1.41, 2.54; p <0.0001) and the disease control rate (DCR) in 64% vs. 53% (OR 1.60, 95%CI: 1.28, 
2.01; p <0.0001) in combination and control arms, respectively. Non-squamous and squamous 
subgroups had the same response rate benefit.
TRAE of any grade were noted in 98% of the treatment arm and 95% in the control arm. The most 
common severe TRAE were neutropenia 49% vs. 40%, febrile neutropenia 16% vs. 10%, fatigue 
14% vs. 10%, leukopenia 14% vs. 12%, fatigue 14% vs. 10%, hypertension 6% vs. 2%, and diarrhea 
5% vs. 3% in the treatment and control arms, respectively. Toxicities were manageable with 
appropriate dose reductions and supportive care. Grade 3 pulmonary hemorrhage (1%) and 
death from adverse events (5% vs. 6%) were not significantly different between both arms.
3.1.2
Preclinical and Clinical Trial Data
Immune therapy has changed the paradigm of how we treat lung cancer. It is now a standard of 
care treatment for lung cancer patients in 1st line and beyond in the metastatic space and in 
consolidation after definitive therapy with concurrent chemoradiation for locally advanced, non-
metastatic, unresectable disease.
Pembrolizumab was initially approved as monotherapy for 2nd line treatment of NSCLC patients 
with PD-L1 1% in the metastatic setting [Herbst, R.S., et al., 2016] In Keynote-010, 354 patients 
were assigned to pembrolizumab 2mg/kg, 346 to pembrolizumab 10 mg/kg, and 343 to 
docetaxel. The primary endpoints were overall survival (OS) and progression free survival (PFS). 
OS was longer with pembrolizumab 10.4 (hazard ratio 0.71; 95% CI: 0.58, 0.88; p= 0.0008) 
and12.7 (hazard ratio 0.61; 95% CI: 0.49, 0.75; p< 0.0001) months, compared to 8.5 months with 
docetaxel. Similarly, PFS was significantly longer with pembrolizumab than with docetaxel (5, 5.2, 
and 4.1 months respectively). Severe treatment-related adverse events (TRAE) were less 
common with pembrolizumab than with docetaxel (13%, 16%, and 35% in the 3 arms, 
respectively).
Similarly, nivolumab was approved as monotherapy for 2nd line treatment of NSCLC patients 
disregards their PD-L1 status in the metastatic setting [Brahmer, J. et al.,2015]. In CheckMate 
017, 272 patients were randomized to receive either nivolumab or docetaxel. The primary 
endpoint was OS. Median OS was 9.2 vs. 6 months (HR 0.59; 95% CI: 0.44, 0.79; p<0.001) and 1-
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 26 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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year OS was 42% vs. 24% with nivolumab and docetaxel, respectively. Median PFS was 3.5 vs. 2.8 
months (HR 0.62; 95% CI: 0.47,0.81; p <0.001) with nivolumab and docetaxel, respectively. Grade 
3-4 TRAE were reported by patients in 7% in the nivolumab arm and 55% in the docetaxel arm. 
Later on, pembrolizumab was approved as monotherapy in the 1st line setting for wild type, 
NSCLC patients with PD-L1 ≥50% in the metastatic setting [Reck, M. et al., 2016]. In Keynote-024, 
305 previously untreated patients were randomly assigned to receive pembrolizumab 200 mg 
every 3 weeks or the investigator’s choice of platinum-based systemic therapy. Crossover was 
allowed on progression. The median PFS, primary endpoint, was longer in the pembrolizumab 
arm (10.3 months) compared to chemotherapy (6 months); (hazard ratio 0.50; 95% CI: 0.37, 0.68; 
p< 0.001). Response rate was higher in the pembrolizumab arm (44.8 vs. 27.8%). The median 
duration of response was longer in pembrolizumab arm (not reached; range, 1.9+ to 14.5+ 
months) vs. 6.3 months (range, 2.1+ to 12.6+) in the chemotherapy arm. TRAE of any grad were 
less frequent (73.4% vs. 90%) as were the severe TRAE (26.6% vs. 53.3%). Median OS was 
significantly longer in the pembrolizumab arm (30 months) compared to 14.2 months in the 
chemotherapy arm. In an updated follow up analysis, pembrolizumab continued to show 
significant OS benefit (over chemotherapy n this population despite crossover to pembrolizumab 
on progression [Reck, M., et al.,2019].
Pembrolizumab has also demonstrated superiority when given in combination with platinum-
based chemotherapy regardless of PD-L1 expression in NSCLC of nonsquamous [Gandhi, L., et al., 
2018] and squamous cell carcinoma [Paz-Ares, L., et al. 2018] histology (KeyNote-189 and -407). 
The ICI indications in the lung cancer patients are in adjuvant[8] (PACIFIC) and metastatic settings: 
in monotherapy  [Reck, M. et al 2016; Mok, T.S.K. et al. 2019; Herbst, R.S., et al., 2016; Brahmer, 
J. et al., 2015] (KeyNote-024, -042, -010, and CheckMate 017) or, in combination with 
chemotherapy [13, 14] [Gandhi, L. et al., 2018; Paz-Ares, L. et al., 2018] (KeyNote-189 and -407) 
or with another monoclonal antibody targeting angiogenesis [Socinski, M.A. et al., 2018] 
(IMpower 150). Studies using ICI with radiation therapy, immune therapies with different 
mechanism of action, tyrosine kinase inhibitor, or with surgery are in current development. 
Pembrolizumab’s approved indications in monotherapy are based on the companion diagnostic 
test PD-L1 22C3 expression (in 1st line, 50% in first line per KeyNote-024 and 1% per KeyNote-
042; in 2nd line, 1% per KeyNote-010). In addition, pembrolizumab is the only tissue-agnostic ICI 
that is FDA-approved for any unresectable or metastatic solid tumor with mismatch repair 
deficiency or microsatellite instability [Le, D.T. et al., 2015] (KeyNote-016).
Recently, the combination of anti-PD-L1, anti-angiogenic and chemotherapy: Atezolizumab with 
Bevacizumab, Carboplatin, and Paclitaxel was approved in the 1st line setting in metastatic NSCLC 
patients with no EGFR or ALK genomic tumor aberrations disregard their PD-L1 expression 
[Socinski, M.A. et al., 2018]. In IMpower 150, 356 patients were assigned in the ABCP arm and 
336 to the BCP arm. The estimated median PFS, primary endpoint, was 8.3 months for patients 
receiving the 4-drug regimen and 6.8 months for those receiving the 3-drug regimen (hazard ratio 
0.62; 95% CI 0.52, 0.74; p <0.001). This was consistent across all clinical subgroups analyzed with 
notable benefit in the small subgroup with EGFR and ALK genetic alterations. The 1-year PFS was 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 27 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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36.5 vs. 18%, respectively. The estimated median OS was 19.2 months for patients receiving the 
4-drug regimen and 14.7 months for those receiving carboplatin, paclitaxel, and bevacizumab 
(hazard ratio 0.78; 95% CI: 0.64, 0.96; p= 0.02). The overall response rates were 63.5% in the 4-
drug arm and 48% in the control arm. 3 patients (0.8%) had a grade 5 febrile neutropenia related 
to the 4-drug regimen. No new safety signals were identified with the combination and TRAE 
frequency was similar to that reported in previous trials with chemotherapy and ICI combination.
3.2
Rationale
Currently, the treatment options for NSCLC after progression on platinum-based chemotherapy 
and immunotherapy are relatively limited; docetaxel monotherapy [Fossella, F.V., et al., 2000] or 
in combination [Garon, E.B., et al., 2014] with ramucirumab remain the best available standard 
salvage treatment with a modest increase in median PFS of 3 and 4.5 months, respectively, when 
used in 2nd line prior to immune therapy era. Thus, there is an urgent and unmet need for 
innovative therapies in this population. The role of chemotherapy in combination with PD-1 
inhibition after progression on prior PD-1 or PD-L1 based regimens is not known. Anecdotal 
reports in patients progressing on ICI suggest a higher response rate to docetaxel compared to 
historical experience. Furthermore, pathologic tumor related angiogenesis promotes tumor 
growth and may also contribute to immune escape in patients treated with ICI. 
We hypothesize that the combination of docetaxel, ramucirumab, and pembrolizumab is safe 
and more effective than docetaxel and ramucirumab in patients with metastatic or recurrent 
NSCLC who progressed on platinum-based chemotherapy given concomitantly or sequentially 
with a PD-1 or PD-L1 immune checkpoint inhibitor. We propose a prospective multicenter (Emory 
and non-Emory collaborating site) phase II clinical trial to study this combination.
Rationale for combining pembrolizumab with docetaxel and ramucirumab: 
Angiogenesis and immunosuppression are two hallmarks of tumor growth. VEGF is important in 
modulating the tumor immune microenvironment [Rivera, L.B. and G. Bergers 2015; Terme, M., 
E. et al. 2013; Yang, J. et al. 2018]. It induces PD-1 expression, impedes T cell extravasation, 
inhibits the proliferation and cytotoxicity of cytotoxic T lymphocytes, impairs the differentiation, 
maturation, and activation of dendritic cells, stimulates the proliferation of T regulatory (Treg) 
cells, stimulates the accumulation and activity of myeloid-derived suppressor cells (MDSCs). The 
abnormal tumor vasculature promotes immune suppression in the tumor microenvironment. 
This effect can be reversed with anti-VEGF therapy. Furthermore, antiangiogenic therapies and 
immune checkpoint inhibitors have independently demonstrated clinical efficacy in NSCLC. 
In addition, chemotherapy enhances antigenicity of the tumor, increases tumor mutation burden 
(TMB), enhances T cell activation, PD-L1 expression, and response rate.
Therefore, combining pembrolizumab with docetaxel and ramucirumab is therefore a rational 
next step for this population with unmet need.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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o
Preclinical experience for combining anti angio-genesis and immune stimulation:
The potential of increased efficacy of combining both strategies is supported by 
preclinical findings in vivo NSCLC models where the combination significantly inhibited 
tumor growth whereas neither treatment alone had a significant effect [Shi, S., et al., 
2013]: 
by 
normalizing 
tumor 
vasculature 
and 
decreasing 
hypoxic 
tumor 
microenvironment, there was increase in cytokine-induced killer cells’ proliferation, 
cytotoxicity and migration as well decreased accumulation in suppressive immune cells in 
the tumor tissue. In addition, there was increased tumor-infiltration lymphocytes 
compared with other treatments. Ziogas et al.  [Ziogas A.C., et al., 2012] found that T cells 
secrete VEGF and express VEGFR-2 upon activation and that VEGF directly suppress T cell 
activation from ovarian cancer patients and healthy individuals is mediated by VEGFR-2.
o
Clinical experience for combining anti angio-genesis and immune stimulation:
Multiple trials investigating anti-angiogenic agents in combination with immunotherapy 
in NSCLC are ongoing. 
Previously treated: (presented at 2018 ASCO Annual Meeting)
Herbst et al presented the phase 1 clinical trial findings of the combination of 
ramucirumab and pembrolizumab at the 2018 ASCO Annual Meeting [Herbst, R.S., et al., 
2019]. 92 previously treated cancer patients with NSCLC (n= 27), gastric and gastro-
esophageal junction (n= 17) and urothelial (n= 48) cancers were treated with the 
combination of ramucirumab and pembrolizumab (Figures 1 and 2). The safety profile was 
consistent with that of each individual drug. There were no additive toxicities. The NSCLC 
cohort was treated with ramucirumab 10 mg/kg and pembrolizumab 200 mg on Day 1 
every 3 weeks after 1-3 prior lines of therapy. Median follow-up for this cohort was 32.8 
months. ORR was observed in 8 (30%) patients and stable disease was observed in 56% 
of patients with NSCLC. Fatigue (36%) was the most common treatment-related adverse 
event (TRAE) of any grade. Grade 3 or 4 TRAE occurred in 26% of patients with the most 
common being hypertension (7%). One (1%) patient on the gastro-esophageal 
adenocarcinoma had a Grade 5 TRAE; none on NSCLC cohort. This combination was safe 
and active. It will be tested in a larger, randomized trials within LUNGMAP (S1800A).
Table 1: Adverse events of the combination ramucirumab and pembrolizumab.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Signs of Efficacy
PD-L1 <1 % (n = 11)
PD-L1 1 % (n = 11)
ORR, % (95% CI)
18% (2.3-51.8)
45% (16.7-76.6)
PFS, months (95% CI)
9.7 (2.1-13.9)
6.9 (2.8-NR)
OS, months (95% CI)
17.0 (10.5-NR)
NR (4.0-NR)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Figure 1. NSCLC Cohort tumour response assessment per RECIST v1.1 by investigator review. (A): 
Treatment duration and response; (B): Change in tumour size over time.
 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Figure 2. NSCLC Cohort. (A) Progression-free survival, (B) Overall survival by PD-L1 status 
(negative/positive) (C) Progression-free survival, (D) Overall survival by PD-L1 status (negative 
<1% / strong positive 50% / weak positive 1-49%).
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Treatment Naïve: (presented at 2019 ESMO Annual Meeting)
In a phase 1 expansion cohort of ramucirumab and pembrolizumab in 26 advanced treatment-
naïve patients with NSCLC with PD-L1 22C3 1%, Herbst et al found that the combination has a 
manageable safety profile with no additive toxicities and was active. 11 (42.3%) patients had 
Grade 3 TRAEs, most commonly hypertension (15.4%) and myocardial infarction (7.7%). No 
patients discontinued because of TRAEs.
Signs of Efficacy
PD-L1 1-49 % (n = 9)
PD-L1 50 % (n = 16)
ORR, % (95% CI)
22.2% (2.8-60.0)
56.3% (29.9-80.2)
PFS, 12-month (95% CI)
33.3% (7.8-62.3)
56.2% (26.9-77.6)
OS, 12-month (95% CI)
66.7% (28.2-87.7)
75.0% (46.3-89.8)
Based on above, ramucirumab plus pembrolizumab should be further explored with 
chemotherapy. 
3.2.1
Rationale for the Trial and Selected Population
The combination of docetaxel plus ramucirumab is recommended after progression on platinum-
doublet chemotherapy for patients with metastatic or recurrent NSCLC. While taxane containing 
doublet chemotherapy has been safely combined with pembrolizumab, there is no data on the 
combination of docetaxel, ramucirumab and pembrolizumab. However, we expect that the 
proposed combination to be safe, with manageable safety profile and with no additive toxicity. 
Our expectation is based on the encouraging facts that there was no additive toxicity with the 
combination docetaxel / ramucirumab, the combination pembrolizumab / ramucirumab, and the 
combination of Atezolizumab / Bevacizumab / Carboplatin / Paclitaxel. Therefore, the study 
combination of docetaxel, ramucirumab, and pembrolizumab would not pose a significant risk 
and would not require an IND.
This study design addresses safety concerns and accommodates this patient population by 
providing access to this novel combination therapy and will allow us to understand the 
mechanism of tackling three hallmarks of cancer by combining immunotherapy, chemotherapy, 
and anti-angiogenic in NSCLC patients exposed to immunotherapy.
3.2.2
Comprehensive Adverse Events and Potential Risks List
The Adverse Event and Potential Risks list provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform presentation of events by body 
system.  
Refer to the package inserts for the comprehensive list of adverse events.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Ramucirumab 
The following adverse events, associated with the use of ramucirumab as single agent, have been 
reported: 
• Cardiovascular: Hypertension, arterial thrombosis. 
• Hematologic: neutropenia, anemia, hemorrhage. 
• Respiratory: Epistaxis 
• Gastrointestinal: Diarrhea (14%), intestinal obstruction (2%) 
• Genitourinary: Proteinuria 
• Endocrine & metabolic: Hyponatremia 
• Central nervous system: Headache
• Immunologic: Antibody development 
• Dermatologic: Skin rash
• Miscellaneous: Infusion related reaction 
• Thyroid Dysfunction: Hypothyroidism (2.6%) 
Toxicity of ramucirumab in combination with docetaxel:
In the REVEL clinical trial, patients received either ramucirumab 10 mg/kg or placebo 
intravenously in combination with docetaxel. 
The most common serious adverse reactions in patients who received ramucirumab with 
docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of 
granulocyte colony-stimulating factors was 42% in ramucirumab with docetaxel-treated patients 
versus 37% in patients who received placebo with docetaxel. 
The most common adverse reactions leading to treatment discontinuation of ramucirumab were 
infusion-related reaction (IRR) (0.5%) and epistaxis (0.3%).
The most common adverse reactions (all grades) observed in ramucirumab with docetaxel-
treated patients at a rate of ≥30% and ≥2% higher than placebo with docetaxel were neutropenia, 
fatigue/asthenia, and stomatitis/mucosal inflammation. 
Clinically relevant adverse drug reactions reported in ≥1% and <5% of ramucirumab with 
docetaxel-treated patients in REVEL were: 

Hyponatremia (4.8%) 

Proteinuria (3.3%) 
Warning and Precautions:
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Hemorrhage: ramucirumab increased the risk of hemorrhage and gastrointestinal hemorrhage, 
including Grade ≥3 hemorrhagic events. 
Gastrointestinal Perforations: ramucirumab can increase the risk of gastrointestinal perforation, 
a potentially fatal event. 
Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that 
inhibit the VEGF or VEGFR pathway. Ramucirumab, a VEGFR2 antagonist, has the potential to 
adversely affect wound healing. Ramucirumab has not been studied in patients with serious or 
non-healing wounds. 
Arterial Thromboembolic Events: Serious, sometimes fatal, arterial thromboembolic events 
(ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral 
ischemia, occurred across clinical trials. 
Hypertension: An increased incidence of severe hypertension occurred in patients receiving 
ramucirumab. Control hypertension prior to initiating treatment with ramucirumab. Monitor 
blood pressure every two weeks or more frequently as indicated during treatment. 
Infusion-Related Reactions: Prior to the institution of premedication recommendations across 
clinical trials of ramucirumab, IRRs occurred in 6 out of 37 patients (16%), including two severe 
events. The majority of IRRs across trials occurred during or following a first or second 
ramucirumab infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain 
and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, 
symptoms included bronchospasm, supraventricular tachycardia, and hypotension. 
Worsening of Pre-existing Hepatic Impairment: Clinical deterioration, manifested by new onset 
or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with 
Child-Pugh B or C cirrhosis who received single agent ramucirumab. 
Reversible 
Posterior 
Leukoencephalopathy 
Syndrome: 
Reversible 
Posterior 
Leukoencephalopathy Syndrome (RPLS) has been reported in <0.1% of 1916 patients enrolled in 
five clinical studies with ramucirumab. 
Proteinuria Including Nephrotic Syndrome: Across five clinical studies in 1916 patients with 
various cancers treated with ramucirumab, the incidence of all Grade proteinuria ranged from 3-
20%. Grade ≥3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from 
<1-3%.
Thyroid Dysfunction: Across five clinical studies in 1916 patients with various cancers treated 
with ramucirumab, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; no grade 3-5 
reported.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Embryo-fetal toxicity: Based on its mechanism of action, ramucirumab can cause fetal harm 
when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to 
critical aspects of female reproduction, embryo-fetal development, and postnatal development.
Docetaxel
The most serious adverse reactions from docetaxel are: toxic deaths, hepatotoxicity, 
neutropenia, hypersensitivity, and fluid retention. 
The most common adverse reactions across all docetaxel indications are infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, 
vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the 
indication.
Pembrolizumab
Most common adverse reactions (reported in ≥20% of patients) were:
Pembrolizumab as a single agent: fatigue, musculoskeletal pain, decreased appetite, pruritus, 
diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. 
Pembrolizumab in combination with chemotherapy: fatigue/asthenia, nausea, constipation, 
diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral 
neuropathy, mucosal inflammation, and stomatitis. 
Pembrolizumab in combination with ramucirumab: diarrhea, fatigue, hypertension, 
hypothyroidism.
3.2.3
Justification for Dose 
Ramucirumab is approved for metastatic NSCLC. The recommended dose is 10 mg/Kg 
administered intravenously every 3 weeks over 60 minutes infusion time.
Docetaxel is approved for metastatic NSCLC. For treatment after failure of prior platinum-based 
chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 
mg/m2 administered intravenously over 1 hour every 3 weeks.
Pembrolizumab (anti-PD-1): the planned dose of pembrolizumab for this study is 200 mg every 
3 weeks (Q3W).  Based on the totality of data generated in the pembrolizumab development 
program, 200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications 
and regardless of tumor type.  As outlined below, this dose is justified by:
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall survival at 
200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 
and KN006).  All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure.  The 
2 mg/kg (or 200 mg fixed dose) Q3W provided similar responses to the highest doses studied.  
Subsequently, flat dose-exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type.  
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols.
3.2.4
Rationale for Endpoints
We will study the efficacy and safety profile of the study combination in patients with NSCLC who 
progressed on platinum doublet and immune therapy. We chose the 6-month PFS as primary 
endpoint because it is a more reliable endpoint to quantify the impact of ICI and efficient to 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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assess in the context of a single institution study. The safety profile will be studied because there 
is no study that has tested the combination yet. The correlative studies will help us find predictive 
biomarkers for efficacy and impact of this combination on the immune system cells.
3.2.4.1 Efficacy Endpoints
Primary Endpoint:
6-month Progression-free Survival (PFS) rate as determined by RECIST 1.1.
Secondary Endpoints:
- Toxicity will be evaluated according to NCI CTCAE Version 5.0.
- ORR will be determined per RECIST 1.1 and iRECIST
- OS is defined from treatment start date to date of death for any cause.
3.2.4.2 Biomarker Research
Various factors that could potentially affect clinical response to treatment with Pembrolizumab 
in combination with Docetaxel and Ramucirumab will be investigated in peripheral blood in pre-
treatment, after treatment and upon progression as well on tumor specimens (optional).
Data from these investigations will be evaluated for associations with clinical efficacy data. All 
samples collected may also be used for exploratory analyses to assess biomarkers associated 
immunotherapy treatment.
We will use Winship Cancer Tissue and Pathology (CTP) Shared Resource to ensure specimens for 
the study are properly tracked for reporting purposes and stored prior to distributing them to 
the recipient lab (Winship Immune Monitoring Shared Resource at the end of the study for 
analysis. Winship CTP will follow their standard biorepository processes as described in 
IRB00045796 (PI: Schneider, Storage & Research Use of Tissue & Information).
Peripheral blood samples
Blood samples will be collected for immunophenotypic analysis of circulating immune cells by 
mass cytometry before and after treatment and EOT. The goal is to characterize treatment 
emergent changes in immune cells (T, B, myeloid cells) using a 35-marker panel. For this, we 
would collect 30 ml of blood in green top (heparin) tube for each timepoint. Blood tubes will be 
delivered at room temperature, on same day if possible, or overnight, to Winship Cancer Tissue 
and Pathology (CTP) Shared Resource (1365B Clifton Road, 3rd Floor, 3200 – phone: 404-778-
5108). Winship CTP standard process is to aliquot plasma into 4 x 0.5ml aliquots and 4 x 1.0ml 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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aliquots before storage at -80. PBMC are cryopreserved at ~5x10^6 cells/aliquot and stored long-
term in LN2. Blood collected outside of the windows indicated below or missed blood collections 
will not constitute protocol deviations. Blood collection timing may vary because appointments 
may not be scheduled solely for this study.
- At Baseline, on cycle 1 day 1 prior to drug administration (if no planned optional biopsy); 
otherwise, same day of the optional biopsy
- On Cycle 2 day 1 prior to drug administration
- At the EOT discontinuation visit (if no planned EOT optional biopsy); otherwise, same day of 
EOT optional biopsy.
Tumor Tissue
Tissue biopsies will be collected for analysis of tumor infiltrating immune cells mass cytometry 
coupled to blood mass cytometry, in paired biopsies before (within 28 days prior to C1D1) and at 
end of treatment in coordination with the recipient lab (Address: B3204 – phone 404-727-3701) 
and Winship CTP (Address: B3200 – phone: 404-778-5108). Tumor studies will only be offered to 
participants accrued at Emory. The goal is to evaluate treatment emergent changes in tumor 
microenvironment in diverse immune cell subsets. Freshly obtained biopsies will need to be 
logged and de-identified by Winship CTP (Address: B3200) before distribution to the recipient lab 
(Address: B3204). Tumor tissue collected outside of the windows indicated above or missed 
tumor tissue collections will not constitute protocol deviations. Tumor tissue collection timing 
may vary because appointments may not be scheduled solely for this study.
If the information is already known, tissue will be evaluated to measure TMB, PDL-1 22C3 
expression, STK11 and KRAS mutations (if known).
When sufficient quantities of fresh tissue is available, it will be preserved for future exploratory 
studies including genomic profiling.
4.0 METHODOLOGY
4.1
Study Population
We plan to have 21 participants complete the protocol required research procedures for the 
primary endpoint and consent up to 45 participants across all sites to account for screen 
failures and enroll up to 30 patients to account for early dropout prior to 6 months on study. 
Potential participants will be identified in medical oncology clinics, multidisciplinary cancer 
clinic, multidisciplinary tumor board at Emory University and non-Emory collaborating site. 
4.1.1
Participant Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of non-small cell lung cancer will be 
enrolled in this study.
2. Patients must have progressed on a platinum-based chemotherapy and any of the FDA-
approved PD-1 or PD-L1 immune checkpoint inhibitors, either given sequentially or in 
combination. 
3. A male participant must agree to use a contraception as detailed in Appendix 3 of this 
protocol during the treatment period plus an additional 120 days after the last dose of 
study treatment and refrain from donating sperm during this period.
4. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, 
and 
at 
least 
one 
of 
the 
following 
conditions 
applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days plus 30 days (a menstruation cycle) after the 
last dose of study treatment.
5. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.  
6. Have measurable disease based on RECIST 1.1.  Lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
8. Life expectancy > 12 weeks as determined by the Investigator.
9. Have adequate organ function as defined in the following table (Table 2).  Specimens must 
be collected within 10 days prior to the start of study treatment.
Table 2:  Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine 
OR
Measured 
or 
calculatedb 
creatinine 
≤1.5 
× 
ULN 
OR
≥30 mL/min for participant with creatinine 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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10. Palliative radiotherapy (to bone or soft tissue lesions) must be completed >1 week prior 
to start of study drug (exception: palliative radiotherapy for pain may be used any time 
prior to first dose). 
11. Clinically significant toxic effect(s) of the most recent prior anti-cancer therapy must be 
Grade 1 or resolved (except alopecia and sensory neuropathy); patients with Grade 2 
adrenal insufficiency related to prior anti-cancer therapy (defined as requiring medical 
intervention, such as concomitant steroids) or Grade 2 hypothyroidism (defined as 
requiring hormone replacement therapy) may be enrolled provided that clinical 
symptoms are adequately controlled and the daily dose is 10 mg or less of prednisone or 
equivalent. If the patient received major surgery or radiation therapy of > 30 Gy, they 
must have recovered from the toxicity and/or complications from the intervention.
12. Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial.
13. Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association (NYHA) Functional Classification (Appendix 
1 B).  To be eligible for this trial, patients should be class 2B or better.
clearance
(GFR can also be used in place of creatinine 
or CrCl)
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
ALT 
(SGPT)=alanine 
aminotransferase 
(serum 
glutamic 
pyruvic 
transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood 
cell (pRBC) transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and 
guidelines for the administration of specific chemotherapies.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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4.1.2
Participant Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. A WOCBP with a positive urine pregnancy test within 72 hours prior of the planned 
treatment on Day 1 of each cycle (see Appendix 3).  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.
2. Patients have prior exposure to docetaxel or ramucirumab.
3. Patients with proteinuria of 2+ on dipsticks or urine protein/creatinine ratio of >1 g/24-
hour.
4. Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks or 5 times the half-life time, whichever is shorter [could consider shorter interval 
for kinase inhibitors or other short half-life drugs] prior to allocation.
Note: Participants must have recovered from all AEs due to previous therapies to 
Grade ≤1 or baseline. Participants with Grade ≤2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study 
treatment.
5. Has received prior radiotherapy within 1 week of start of study treatment.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease.
6. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
7. Is currently participating in or has participated in a study of an investigational device 
within 4 weeks prior to the first dose of study treatment.
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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9. Patients with symptomatic brain metastasis (patients with treated brain metastasis 
without symptoms and not requiring steroid are allowed to participate).
10. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients.
11. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
significant cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements.
12. Patients with significant cardiovascular disease (e.g., myocardial infarction, arterial 
thromboembolism, cerebrovascular thromboembolism) within 6 months prior to start of 
study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New 
York Heart Association (Appendix 1B)  Class 3 or 4 congestive heart failure; or 
uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic 
blood pressure ≥160 mmHg) despite antihypertensive therapy.
13. Patients with any major hemorrhage or thromboembolic events within 3 months prior to 
start on this study.
14. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
15. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis or established interstitial lung disease.
16. Patients who had prior history of immune-related adverse event (irAE) that required 
treatment with steroids and permanent ICI discontinuation per NCCN guidelines.
17. Has an active infection requiring systemic therapy.
18. Has a known history of Human Immunodeficiency Virus (HIV). Note: no HIV testing is 
required unless mandated by local health authority.
19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.  
Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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20. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
21. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of trial treatment.
4.1.3
Lifestyle Restrictions
4.1.3.1 Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
4.1.3.2 Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception.
For this study, male participants 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).  
4.1.4
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  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 Merck.  If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately 
and the pregnancy must be reported to Merck and followed as described in Section 6.2.2.
4.1.5
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, 
participants who are breast-feeding are not eligible for enrollment.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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4.2
Trial Treatments
The treatment to be used in this trial is outlined below following the sequence in Table .
Table 3:  Trial Treatment Sequence
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen/Treat
ment Period
Use
Docetaxel
75 mg/m2
Q3W
IV infusion over 
60 minutes
Day 1 of each
3-week cycle
Standard of Care
Ramucirumab
10 mg/kg
Q3W
IV infusion over 
60 minutes
Day 1 of each
3-week cycle
Standard of Care
Pembrolizumab
200 mg
Q3W
IV infusion over 
60 minutes
Day 1 of each
3-week cycle
Experimental
Trial treatment should begin on the day of allocation or as close as possible to the date on which 
treatment is allocated. Sites should make every effort to target infusion duration of each 
administered agent to be as close as possible to the recommended infusion duration of each 
agent. However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes 
will be permitted.
4.2.1 Timing of Dose Administration
We are not aware of any clinical concern of administering docetaxel prior to ramucirumab. To 
maximize the clinical benefit of this study treatment in patients who have already progressed on 
PD-1/PD-L1 blockade, we will give chemotherapy with docetaxel upfront in an attempt to 
enhance tumor anti-genecity and tumor mutation burden. This will be followed by an anti-
angiogenic agent, ramucirumab, in an attempt to modulate the tumor immune 
microenvironment. And last, we will administer pembrolizumab.
Ramucirumab
Prior to each Ramucirumab infusion, premedicate all patients with an intravenous histamine-1 
receptor antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced 
a Grade 1 or 2 IRR, premedicate with a histamine-1 receptor antagonist, dexamethasone (or 
equivalent), and acetaminophen prior to each Ramucirumab infusion. 
The recommended dosage of Ramucirumab is 10 mg/kg administered by intravenous infusion 
over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. However, in this study, we 
will administer docetaxel prior to ramucirumab based on the rational provided above.
Injection: 100 mg/10 mL (10 mg/mL) or 500 mg/50 mL (10 mg/mL) clear to slightly opalescent, 
colorless to slightly yellow solution in a single-dose vial.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Docetaxel
All patients should be premedicated with oral corticosteroids such as dexamethasone 16 mg per 
day (e.g., 8 mg BID) for 3 days starting 1 day prior to Docetaxel administration in order to reduce 
the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.
For treatment after failure of prior platinum-based chemotherapy, Docetaxel was evaluated as 
monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over 1 hour 
every 3 weeks (-5 minutes and +10 minutes).
Pembrolizumab
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 5.0). Pembrolizumab 200 mg 
will be administered as a 30-minute IV infusion every 3 weeks. The Pharmacy Manual contains 
specific instructions for the preparation of the pembrolizumab infusion fluid and administration 
of infusion solution.
All trial treatments will be administered on an outpatient basis. All trial treatments may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle.
4.2.2
Definition of dose-limiting toxicities (DLT)
A DLT is defined as one of the following AEs that occur within the first 4 weeks of the study 
treatment (DLT observation period), if considered to be definitely, probably, or possibly related 
to the study regimen by the investigator; and fulfills any one of the following criteria using NCI 
CTCAE Version 5.0:
1. Nonhematologic toxicity as follows:
a) Grade 4 nonlaboratory toxicity
b) Grade 3 nonlaboratory toxicity (for example, nausea, vomiting, and diarrhea) lasting
>3 days despite optimal supportive care
c) Any Grade 3 or Grade 4 laboratory value if:
i) Medical intervention is required to treat the patient, or
ii) The abnormality persists for >1 week.
Note: Liver function abnormality: For patients with liver metastasis who begin treatment 
with Grade 2 aspartate aminotransferase (AST) or alanine amino transferase (ALT), if AST 
or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 
7 days.
2. Hematologic toxicity, as follows:
a) Grade 4 toxicity lasting ≥ 7 days, or
b) Grade 3 thrombocytopenia if associated with bleeding and requires platelet
transfusion, or
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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c) Febrile neutropenia Grade 3 or Grade 4
3. Grade 5 toxicity (that is, death)
4. Any other significant toxicity deemed by the primary investigator and Merck clinical research 
personnel to be dose limiting, for example:
a) Any toxicity that is possibly related to study treatment that requires the
withdrawal of the patient from the study during Cycle 1, or
b) A delay of > 14 days due to persistent Grade ≥ 2 toxicities in initiating Cycle 2,
with the exception of Grade 2 fatigue
Any infusion or hypersensitivity reactions occurring during the infusion of the drug are not 
considered dose-related and therefore will NOT be considered to be a DLT.
After each of the 3 patients in a dose schedule completes the observation period, a safety analysis 
will occur; the data will be reviewed by study investigators and Merck, and the findings 
documented, indicating whether each dose schedule is or is not well tolerated. The results will 
inform the decision whether or not to move onto Phase 2.
4.2.3
Dose Modification and toxicity management 
The investigator will decide whether any AE that occurs is related to either or both drugs and 
determine whether dose modification or discontinuation of one or both drugs is required per the 
guidance below.
Ramucirumab
Prior to each Ramucirumab infusion, premedicate all patients with an intravenous histamine-1 
receptor antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced 
a Grade 1 or 2 infusion-related reaction (IRR), premedicate with a histamine-1 receptor 
antagonist, dexamethasone (or equivalent), and acetaminophen prior to each Ramucirumab 
infusion. 
Reduce dose, withhold dose, or discontinue Ramucirumab to manage adverse reactions as 
described in Table 4 and are based on criteria in the Ramucirumab package insert.
Table 4: Dose Modification for Immune-related Adverse Events Associated with Ramucirumab.
Adverse Event
Dose Modification
Infusion-related reactions
Reduce infusion rate by 50% for grade 1 or 2
Permanently discontinue for grade 3 or 4
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Hypertension
Interrupt infusion for severe hypertension (defined as systolic 
blood pressure ≥180 mmHg and/or diastolic blood pressure 
≥120 mmHg) until controlled with medical management
Permanently discontinue if severe hypertension cannot be 
controlled with antihypertensive therapy 
Proteinuria
Interrupt ramucirumab for urine protein levels ≥2g/24h (first 
occurrence). Reinitiate treatment at a reduced dose of 8 mg/Kg 
every 3 weeks once the protein level returns to <2g/24h. 
If the urine protein level ≥2g/24h reoccurs, interrupt 
ramucirumab and reduce the dose to 6 mg/Kg every 3 weeks 
once the urine protein level returns to <2g/24h.
Permanently discontinue if urine protein levels >3g/24h or in 
the setting of nephrotic syndrome.
Wound healing 
complications (all grades)
Withhold ramucirumab for 28 days prior to elective surgery. 
Resume ramucirumab no sooner than 2 weeks after surgery and 
until adequate wound healing.
Arterial thromboembolic 
events (all grades)
Permanently discontinue ramucirumab
Gastrointestinal 
perforation (all grades)
Permanently discontinue ramucirumab
Grade 3 or 4 bleeding
Permanently discontinue ramucirumab
Reversible posterior 
leukoencephalopathy 
syndrome
Permanently discontinue ramucirumab for confirmed diagnosis
Docetaxel
Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, 
neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, 
or other grade 3/4 non-hematological toxicities during Docetaxel Injection treatment should 
have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients 
who develop grade ≥3 peripheral neuropathy should have Docetaxel Injection treatment 
discontinued entirely.
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 5. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Table 5: Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv5.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with 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.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Grade 3 or 4
Permanently 
discontinue
Intolerable/ 
persistent Grade 
2
Withhold
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  Gullain-
Barre Syndrome, 
encephalitis
All other 
immune-related 
AEs
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
Dose modification and toxicity management of infusion-reactions related to pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
6. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Table 6: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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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 participant is deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
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 participant is deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 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 participant 
should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment
Participant 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 of 
analgesic).
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further study 
drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record.
4.3
Treatment Allocation
This is an open-label, single-arm study. All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements will receive Docetaxel and 
Ramucirumab in combination with pembrolizumab.
Subjects will be enrolled sequentially: 6 patients will be enrolled and evaluated for safety 
data. If less than 2 patients experience dose limiting toxicity (DLT), we will continue with the 
efficacy assessment of the combination.
In the first stage, 10 evaluable patients will be accrued. If there are 4 or fewer patients with 
free of progression at 6-month among these 10 patients, the study will be stopped for futility. 
Otherwise, 11 additional evaluable patients will be accrued for a total of 21. 
Patient will be considered evaluable for safety data if the patient has received at least 1 
infusion of (agent) and had safety assessments for a minimum of 4 weeks or have had a DLT 
during the first 4 weeks of treatment.
4.4
Stratification
N/A.
4.5
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the participant's primary physician. 
4.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’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) 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial 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 trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 6.2.
4.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.  

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, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed. 

Systemic 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 may be approved after consultation with the Sponsor.
Participants 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.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards 
of medical care.  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the Investigator, the Sponsor 
and the participant.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of 
docetaxel may be modified by the concomitant administration of compounds that induce, 
inhibit, or are metabolized by cytochrome P450 3A4. 
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was 
coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, 
particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel 
Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be 
avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for 
toxicity and a Docetaxel Injection dose reduction could be considered if systemic 
administration of a potent CYP3A4 inhibitor cannot be avoided.
Avoid coadministration of study drugs with strong CYP3A4 inducers, strong CYP3A inhibitor 
or a sensitive CYP3A4 substrate.
4.5.3
Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by 
the treating investigator.  Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are outlined along with the dose modification guidelines 
in Section 4.2.3, [Table 4 and 5].  Where appropriate, these guidelines include the use of oral 
or IV treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased.  For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care.  The treatment guidelines are intended to be applied when the Investigator determines 
the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to study 
treatment, the Investigator does not need to follow the treatment guidance.  Refer to [Table 
4-5] in Section 4.2.3 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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4.6
Participant Withdrawal/Discontinuation Criteria
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  
In addition, a participant may be discontinued from study treatment by the investigator or 
the Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 6.1.4 – Other Procedures.
A participant must be discontinued from study treatment but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to 
discontinue study treatment

Confirmed radiographic disease progression outlined in Section 6.1.2.6

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Unacceptable adverse experiences as described in Section 4.2.2 and 4.2.3.

If both docetaxel and ramucirumab are discontinued, patients will be allowed to 
continue on pembrolizumab only

The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment.

The participant has a confirmed positive serum pregnancy test

Noncompliance with study treatment or procedure requirements

Recurrent Grade 2 pneumonitis

Discontinuation of treatment may be considered for participants who have attained 
a confirmed complete response (CR) and have been treated for at least 8 cycles (at 
least 24 weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab and at least 80% of the planned doses of Ramucirumab and 
Docetaxel beyond the date when the initial CR was declared. 

The participant is lost to follow-up

Completion of 35 treatments (approximately 2 years) with pembrolizumab
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Note: The number of treatments is calculated starting with the first dose.  Participants 
who stop the combination or pembrolizumab after receiving 35 doses may be eligible for 
retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 4.2.3. Participants may be retreated in the Second 
Course Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year).

Administrative reasons
4.7
Participant Replacement Strategy
Patients who are not evaluable for toxicity during the safety period will be replaced. Similarly, 
patients who are not evaluable for efficacy will be replaced.
4.8
Clinical Criteria for Early Trial Termination
Early trial 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 participants
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 participant treatment can be made.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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5.0 TRIAL FLOW CHART
5.1
Study Flow Chart
Trial Period
Screening Phase
21- day Treatment Cycles
End of 
Treatme
nta
Post-Treatment
Subsequent cycles
Treatment Cycle/Title
Main Study 
Screening 
(Visit 1)
1
Even
Odd
Discon
Safety 
Follow-
Up
Follow-Up 
Visits
Survival 
Follow-
Up
Scheduling Window (Days)
-28 to -1
+3
± 3
± 3
At time 
of Discon
30 days 
post 
Discon
Every 8 
weeks post 
Discon
Every 12 
weeks
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics, Height and 
Medical History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
Post-study anticancer therapy 
status
X
X
X
Survival Status
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 61 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Trial Period
Screening Phase
21- day Treatment Cycles
End of 
Treatme
nta
Post-Treatment
Subsequent cycles
Treatment Cycle/Title
Main Study 
Screening 
(Visit 1)
1
Even
Odd
Discon
Safety 
Follow-
Up
Follow-Up 
Visits
Survival 
Follow-
Up
Scheduling Window (Days)
-28 to -1
+3
± 3
± 3
At time 
of Discon
30 days 
post 
Discon
Every 8 
weeks post 
Discon
Every 12 
weeks
Full Physical Examination
X
X
X
Directed Physical Examination
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or 
Serum -HCGb
X
X
X
X
PT/INR and aPTT (prior to 
optional biopsies)
X
X
CBC with Differential
X
X
X
X
X
Comprehensive Serum 
Chemistry Panel
X
X
X
X
X
FT3, FT4 and TSH
X
X
X
Urinalysis
X
X
X
X
Spot urine for protein / 
creatinine
X
X
X
X
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 62 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Trial Period
Screening Phase
21- day Treatment Cycles
End of 
Treatme
nta
Post-Treatment
Subsequent cycles
Treatment Cycle/Title
Main Study 
Screening 
(Visit 1)
1
Even
Odd
Discon
Safety 
Follow-
Up
Follow-Up 
Visits
Survival 
Follow-
Up
Scheduling Window (Days)
-28 to -1
+3
± 3
± 3
At time 
of Discon
30 days 
post 
Discon
Every 8 
weeks post 
Discon
Every 12 
weeks
HBs Ag, HCV Ab, HCV viral load, 
and HIV serology (if clinically 
indicated)
X
Lipase, Amylase, LDH, CK, Hb 
A1c, ACTH, Cortisol, Prolactin, 
FSH, LH, testosterone (if 
clinically indicated)
X
X
Radiology/Efficacy Measurements
CT scan Chest / Abdomen
X
Every 6 weeks first 6 months; then, every 
9 weeks between 6-12 months; and every 
12 weeks thereafter c
X
MRI Brain (if clinically indicated)
X
Every 12 weeks
X
Bone Scan (if clinically indicated)
X
Every 12 weeks
X
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival or Newly Obtained 
Tissue Collection (Optional)
Xd
Xg
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 63 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Trial Period
Screening Phase
21- day Treatment Cycles
End of 
Treatme
nta
Post-Treatment
Subsequent cycles
Treatment Cycle/Title
Main Study 
Screening 
(Visit 1)
1
Even
Odd
Discon
Safety 
Follow-
Up
Follow-Up 
Visits
Survival 
Follow-
Up
Scheduling Window (Days)
-28 to -1
+3
± 3
± 3
At time 
of Discon
30 days 
post 
Discon
Every 8 
weeks post 
Discon
Every 12 
weeks
Correlative Studies: Blood and 
Tissueh Collection (Optional)
Xd, h
Xe
Xf
Xg, h
Abbreviations: ACTH: adrenocorticotropic hormone; CK: Creatinine kinase; ECOG = Eastern Cooperative Oncology Group; FSH: Follicle-
stimulating hormone; HBs Ag = hepatitis B surface antigen; HIV = human immunodeficiency virus; LDH: Lactate Dehydrogenase; LH: 
Luteinizing Hormone; PT = prothrombin time; PTT = partial thromboplastin time; TSH = thyroid stimulating hormone; FT4 = free 
thyroxin; FT3 = free triiodothyronine; HCV Ab = Hepatitis C virus antibody.
a: 30 days (+10 days) after the last dose of study drug. 
b: for women of childbearing potential.
c: All known sites of metastases should be evaluated at each time point. Baseline imaging will be done within 28 days from starting 
cycle 1. Subsequent tumor imaging will be performed every 6 weeks (42 days ±7 days) from Cycle 1 Day 1 during first 6 months, then 
every 9 weeks (63 days ±7 days) between 6 months and 1year, then every 12 weeks (84 days ±7 days) after 1 year. Imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts. Every effort should be made to continue tumor 
imaging using same interval for participants who discontinue study treatment without documented disease progression.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 64 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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d: The 1st time point of peripheral blood will be collected the same day of the 1st optional biopsy.
e: If no optional biopsy is planned, the 1st time point of peripheral blood will be collected on Cycle 1 Day 1 prior to treatment 
administration.
f: The 2nd time point of peripheral blood will be collected on Cycle 2 Day 1 prior to drug administration.
g: The 3rd time point of peripheral blood will be collected the same day of the End of Treatment (EOT) 2nd optional biopsy; if no plan 
for EOT optional biopsy, peripheral blood will be collected at the EOT visit.
h: Tissue collection will only be offered to participants accrued at Emory. Biopsies will be coordinated with the recipient lab (Address: 
B3204 – phone 404-727-3701) and Winship CTP (Address: B3200 – phone: 404-778-5108).
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 65 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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6.0 TRIAL PROCEDURES
6.1
Trial Procedures
The Trial Flow Chart - Section 5.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor 
and/or Merck for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the participant.  In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
6.1.1
Administrative Procedures
6.1.1.1 Informed Consent
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial.
6.1.1.1.1 General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 66 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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6.1.1.2 Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial. 
Patients will be registered after meeting all entry requirements and signing of the informed 
consent document.
Study personnel will notify Winship Central Subject Registration (WCSR) by email at 
winshipcsr@emory.edu, once subject has been consented for a trial. 
Email notification must be done within 24 hours after consent has been obtained and it will 
include scanned copies of:

Signed patient consent form

HIPAA authorization form

Emory 
Research 
Management 
System 
(ERMS; 
https://erms.emory.edu) 
Enrollment Fax Cover 
The WCSR will enter the subject into the OnCore Research Management System, which is the 
system of record for Winship Cancer Institute Clinical Trials.
Enrolling a subject requires careful screening and determination of eligibility. 
Eligible patients will be enrolled on study centrally at Winship Cancer Institute by the Study 
Coordinator.  
When all required test results are available, complete the eligibility checklist and provide the 
checklist and the supporting documentation to the IRB approved investigator for review and 
sign-off. Once the investigator (sub-investigator, Co-Investigator) has signed the eligibility 
checklist, randomization and or enrollment may proceed. OnCore and ERMS must be updated 
to reflect eligibility and on treatment status. 
6.1.1.3 Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.  
6.1.1.4 Prior and Concomitant Medications Review
6.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 67 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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participant within 28 days before starting the trial.  Treatment for the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as a prior 
medication. 
6.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 6.2.
6.1.1.5 Disease Details and Treatments
6.1.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
6.1.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
6.1.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy 
within 30 days after the last dose of trial treatment, the 30-day Safety Follow-up visit must 
occur before the first dose of the new therapy.  Once new anti-cancer therapy has been 
initiated the participant will move into survival follow-up. 
6.1.1.6 Trial Compliance (Medication/Diet/Activity/Other)
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured. Dose changes and 
interruptions of study drug must be specifically documented in the patient’s CRF.
6.1.2
Clinical Procedures/Assessments
6.1.2.1 Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 5.0 (see Appendix 2).  Toxicities will be 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 68 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
Please refer to section 6.2 for detailed information regarding the assessment and recording 
of AEs.  
6.1.2.2 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, 
6.1.2.3 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  
6.1.2.4 Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified 
in the Trial Flow Chart (Section 5.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
On infusion days, patients receiving treatment will be monitored during and after infusion:  

A 1-hour observation period is required after the first infusion. If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent 
infusion observation periods can be at the Investigator’s discretion (suggested 30 
minutes after each infusion).  
The date and time of collection and measurement will be recorded on the appropriate eCRF.  
Additional monitoring with assessment of vital signs is at the discretion of the Investigator 
per standard clinical practice or as clinically indicated.  
6.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial 
treatment as specified in the Trial Flow Chart.  ECOG classification groups are referenced in 
Appendix 1.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 69 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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6.1.2.6 Tumor Imaging and Assessment of Disease
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  PET/CT  
and MRI can be used in special circumstances. For the abdomen and pelvis, contrast-
enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated contrast 
is contraindicated, or when local practice mandates it.  MRI is the strongly preferred modality 
for imaging the brain.  The same imaging technique regarding modality, ideally the same 
scanner, and the use of contrast should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and 
improve the accuracy of the assessment of response or progression based on imaging.
Brain imaging at screening will be performed in patients who have symptoms concerning for 
brain metastases or have prior history of brain metastases.  MRI is preferred; however, CT 
imaging will be acceptable, if MRI is medically contraindicated.
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be 
used to determine participant eligibility.  Confirmation that the participant’s imaging shows 
at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly 
recommended prior to participant allocation.  
6.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
allocation.  The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1. 
Brain imaging, if performed to document the stability of existing metastases, should be by 
MRI if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
6.1.2.6.2 Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed every 6 weeks 
(42 days ±7 days) or more frequently if clinically indicated.  After 6 months, participants who 
remain on treatment will have imaging performed every 9 weeks (63 days ±7 days) until 1 
year, and every 12 weeks (84 days ±7 days) thereafter.  Imaging timing should follow calendar 
days and should not be adjusted for delays in cycle starts.  Imaging should continue to be 
performed until disease progression is identified by the Investigator. 
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a response 
is observed.  Participants will then return to regular scheduled imaging every 6 weeks, starting 
with the next scheduled imaging time point.  Participants who receive additional imaging for 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 70 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.  
Per iRECIST (Table 7, Figure 3), disease progression should be confirmed by the site 4 to 
8 weeks after first radiologic evidence of PD in clinically stable participants.  Participants who 
have unconfirmed disease progression may continue on treatment at the discretion of the 
Investigator until progression is confirmed by the site provided they have met the conditions 
detailed in Appendix 4.  Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point, if clinically stable.  Participants who 
have confirmed disease progression by iRECIST, as assessed by the site, will discontinue study 
treatment.  Exceptions are are possible upon consultation with Merck (Table 7, Figure 3 and 
Appendix 4).
6.1.2.6.3 End of Treatment and Follow-up Tumor Imaging
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (± 4-week window).  If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory.  In participants who discontinue study treatment due to 
documented disease progression and the Investigator elects not to implement iRECIST, this 
is the final required tumor imaging.
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 6-12 weeks in Year 1 or 
every 12 weeks after Year 1) to monitor disease status until the start of a new anticancer 
treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the 
study, whichever occurs first.
6.1.2.6.4 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total 
and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 71 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Table 7: Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging at 4 
to 8 weeks to confirm 
PD.
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 4 
to 8 weeks to confirm 
PD per Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per 
Investigator 
assessment
No additional 
imaging required.
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor imaging 
shows iUPD by iRECIST 
per Investigator 
assessment
Repeat imaging at 4 
to 8 weeks to confirm 
PD.  May occur at 
next regularly 
scheduled imaging 
visit.
Continue study treatment 
at the Investigator’s 
discretion.
Repeat imaging at 4 
to 8 weeks to confirm 
PD per Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor imaging 
shows iSD, iPR, or iCR 
by iRECIST per 
Investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study treatment 
at the Investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study treatment 
if condition has improved 
and/or clinically stable per 
Investigator’s discretion.  
Next tumor image should 
occur according to the 
regular imaging schedule.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in 
Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD 
= progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Figure 3. Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator
6.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling
Various factors that could potentially affect clinical response to treatment with 
Pembrolizumab in combination with Docetaxel and Ramucirumab will be investigated in 
peripheral blood in pre-treatment, after treatment and upon progression as well on tumor 
specimens (optional). 
Data from these investigations will be evaluated for associations with clinical efficacy data. 
All samples collected may also be used for exploratory analyses to assess biomarkers 
associated immunotherapy treatment.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Peripheral blood samples 
Blood samples will be collected for immunophenotypic analysis of circulating immune cells 
by mass cytometry before and after treatment and EOT. The goal is to characterize treatment 
emergent changes in immune cells (T, B, myeloid cells) using a 35-marker panel. For this, we 
would collect 30 ml of blood in green top (heparin) tube for each timepoint. Blood tubes will 
be delivered at room temperature, on same day if possible, or overnight, to Winship Cancer 
Tissue and Pathology (CTP) Shared Resource (1365B Clifton Road, 3rd Floor, 3200 – phone: 
404-778-5108). Winship CTP standard process is to aliquot plasma into 4 x 0.5ml aliquots and 
4 x 1.0ml aliquots before storage at -80. PBMC are cryopreserved at ~5x10^6 cells/aliquot 
and stored long-term in LN2. Blood collected outside of the windows indicated below or 
missed blood collections will not constitute protocol deviations. Blood collection timing may 
vary because appointments may not be scheduled solely for this study.
- At Baseline, on cycle 1 day 1 prior to drug administration (if no planned optional biopsy); 
otherwise, same day of the optional biopsy
- On Cycle 2 day 1 prior to drug administration
- At the EOT discontinuation visit (if no planned EOT optional biopsy); otherwise, same day of 
EOT optional biopsy.
Tumor Tissue
Tissue biopsies will be collected for analysis of tumor infiltrating immune cells by mass 
cytometry coupled to blood mass cytometry, in paired biopsies before (within 28 days prior 
to C1D1) and at end of treatment in coordination with the recipient lab (Address: B3204 –
phone 404-727-3701) and Winship CTP (Address: B3200 – phone: 404-778-5108). Tumor 
studies will only be offered to participants accrued at Emory. The goal is to evaluate 
treatment emergent changes in tumor microenvironment in diverse immune cell subsets. 
Freshly obtained biopsies will be logged and de-identified by Winship CTP (Address: B3200) 
before distribution to the recipient lab (Address: B3204). Tumor tissue collected outside of 
the windows indicated above or missed tumor tissue collections will not constitute protocol 
deviations. Tumor tissue collection timing may vary because appointments may not be 
scheduled solely for this study.
If the information is already known, tissue will be evaluated to measure TMB, PDL-1 22C3 
expression, STK11 and KRAS mutations (if known).
When sufficient quantities of fresh tissue is available, it will be preserved for future 
exploratory studies including genomic profiling.
6.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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The schedule regarding specific laboratory procedures/assessments to be performed in this 
trial are noted in the Study Flow Chart.  
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle. Clinical 
laboratory assessments during the treatment period may be conducted anytime within 72 
hours prior to the scheduled visit, unless otherwise specified. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol. In these instances, the AE corresponding to the laboratory abnormality will be 
recorded. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified below and in 
Table 8.

Hematology (hemoglobin, hematocrit, white blood cell count with differential and 
platelet count)

Clinical Chemistry (sodium, potassium, chloride, bicarbonate, magnesium, calcium, blood 
urea nitrogen, creatinine, glucose (random), total bilirubin, total protein, ALP, ALT, AST, 
and albumin)

LDH, CK, amylase, lipase (if clinically indicated)

Urinalysis and spot urine for protein / creatinine

Coagulation parameters: Activated partial thromboplastin time and International 
normalized ratio to be assessed prior to optional biopsies

Pregnancy test (only in women of childbearing potential)
o
Urine human chorionic gonadotropin, or
o
Serum beta-human chorionic gonadotropin 

Endocrine test
o
TSH, free T3, and free T4
o
Hb A1c, ACTH, cortisol, FSH, LH, Prolactin, and testosterone (if clinically 
indicated)

Other laboratory tests (if clinically indicated)
o
Hepatitis B surface antigen
o
Hepatitis C antibody
o
Hepatitis C viral load
o
HIV antibody
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 76 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Table 8: Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
  (β-hCG)†
Platelet count
Alanine aminotransferase (ALT) Protein
PT (INR)
WBC (total and differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
aPTT
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If 
abnormal) 
Free thriiodothyronine (FT3)
Absolute Neutrophil Count
Carbon Dioxide ‡
results are noted
Free tyroxine (FT4)
Absolute Lymphocyte Count   (CO2 or biocarbonate)
Urine pregnancy test †
Thyroid stimulating hormone (TSH)
Blood Urea Nitrogen 
24h urine protein
CK
Creatinine
Hb A1c
Calcium
Blood for correlative studies
Chloride
 ACTH
Glucose 
 FSH
Potassium  
 LH
Sodium
 Prolactin
Magnesium
 Testosterone
Total Bilirubin
 Cortisol
Direct Bilirubin (If total bilirubin 
is elevated above the upper 
limit of normal)
Hepatitis B surface antigen
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 78 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Hematology
Chemistry
Urinalysis
Other
Total protein
Hepatitis C antibody
Amylase 
HIV antibody
Lipase
Hepatitis C viral load
† 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 region.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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6.1.3.1 Withdrawal/Discontinuation
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 6.2 - Assessing and 
Recording Adverse Events.  Participants who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 4.2.3.  After discontinuing treatment 
following assessment of CR, these participants should return to the site for a Safety Follow-
up Visit (described in Section 6.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 6.1.5.3.2).
6.1.4
Visit Requirements
Visit requirements are outlined in Section 5.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 6.1 - Trial Procedures.
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations will be performed.  The purpose of obtaining 
these detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated.  
6.1.4.1 Screening
Screening procedures will be performed up to 28 days prior initiation of treatment, except 
for baseline imaging (up to 28 days allowed) unless otherwise specified.  All subjects must 
first read, understand, and sign the IRB/REB/IEC-approved ICF before any study-specific 
screening procedures are performed.  After signing the ICF, completing all screening 
procedures, and being deemed eligible for entry, subjects will be enrolled in the study.  
Procedures that are performed prior to the signing of the ICF and are considered standard of 
care may be used as screening assessments if they fall within the screening window. 
The following procedures will be performed during the Screening Visit:

Informed Consent

Review of eligibility criteria

Medical history and demographics

Complete physical exam 

ECOG Performance Status

Vitals signs [temperature, heart rate (HR), blood pressure (BP) and respiratory rate 
(RR), oxygen saturation], height and weight

Optional
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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a. Tumor tissue from diagnostic biopsy, if available, is provided for biomarker 
analysis
b. Peripheral blood samples for correlative studies at the time of the planned 
pre-treatment optional biopsy

Review of prior/concomitant medications 

Radiologic imaging studies to evaluate tumor status: computed tomography (CT) of 
the chest and abdomen, PET/CT, or MRI of chest and abdomen.  Additional imaging 
may be obtained as clinically indicated. Baseline scans may be done within 4 weeks 
prior to the first dose of study drug.
Clinical laboratory tests for:
a. Hematology 
b. Clinical chemistry 
c.
TSH, free T3, and free T4
d. Serum or urine pregnancy test (for women of childbearing potential)
e. Urinalysis and spot urine for protein / creatinine
f.
Optional:
o
Peripheral blood samples for correlative studies at the time of the planned 
pre-treatment optional biopsy
g. If clinically indicated:
o
Hb A1c, ACTH, cortisol, FSH, LH, Prolactin, and testosterone
o
LDH, CK, amylase, lipase
o
Coagulation (PT, PTT, INR) if plan for biopsy
o
Hepatitis B, Hepatitis C antibody and viral load, and HIV serologies
6.1.4.2 Treatment Period
Procedures to be conducted during the treatment phase of the study are presented in the 
Trial Flow Chart (Section 5.1). Screening procedures performed within 72 hours of Cycle 1 Day 
1 (C1D1) do not need to be repeated on C1D1.

Brief medical history

Symptom-directed physical exam 

ECOG Performance Status

Vitals signs and weight 

Review of prior/concomitant medications 

Record AEs

Treatment with Docetaxel, Ramucirumab, and Pembrolizumab

Clinical laboratory tests for:
a. Hematology 
b. Clinical chemistry
c.
TSH, free T3, free T4 (odd cycles)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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d. Serum or urine pregnancy test (for women of childbearing potential)
e. Urinalysis and spot urine for protein / creatinine
f.
Optional peripheral blood samples for correlative studies:
o
on Cycle 1 Day 1 prior to drug administration (if no plan for the optional 
biopsy)
o
 on Cycle 2 Day 1 prior to drug administration
o
At EOT visit (if no plan for the optional EOT biopsy); otherwise, will be 
collected at the same day of the planned optional EOT biopsy
g. If clinically indicated:
o
Hb A1c, ACTH, cortisol, FSH, LH, Prolactin, and testosterone
o
LDH, CK, amylase, lipase
6.1.4.3 Post-Treatment Visits
End of treatment is defined as the last planned dosing visit within the dosing period. For 
patients who discontinue drug treatment, end of treatment is considered the last visit where 
the decision is made to discontinue treatment. All required procedures may be completed 
within ± 7 days of the end of treatment visit. Repeat disease assessment is not required if 
performed within 28 days prior to the end of treatment visit.
Assessments for patients who have completed treatment and achieved disease control or 
have discontinued treatment due to toxicity in the absence of confirmed progressive disease 
are provided in the Schedule of Event.   
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until end of the study.
6.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Participants with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs 
that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  
6.1.5.3.2 Follow-up Visits
Participants 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.  After 1 year, the imaging time point will occur 
every 12 weeks (± 7 days). Every effort should be made to collect information regarding 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 82 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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disease status until the start of new anti-cancer therapy, disease progression, death, end of 
the study Information regarding post-study anti-cancer treatment will be collected if new 
treatment is initiated.
 
6.1.5.3.3 Survival Follow-up
Participants who experience confirmed disease progression or start a new anticancer 
therapy, will move into the Survival Follow-Up Phase and should be contacted by telephone 
every 12 weeks ( 3 weeks) for 2 years, then every 6 months for next 3 years, then annually 
until the subject’s death or until the subject is lost to follow-up up to 10 years to assess for 
survival status until death, withdrawal of consent, or the end of the trial, whichever occurs 
first. 
The following information will be collected: 

Disease status as: 
o
No evidence of disease on treatment (document treatment type if 
available)
o
No evidence of disease on follow-up
o
Active disease on treatment (document treatment type if available)
o
Active disease not on treatment

The patient’s survival status, and if deceased, the date of death. If known, cause 
of death.

The method by which the survival status was assessed and the date it was 
assessed.

Any subsequent anti-cancer therapy received, or imaging performed after 
completion of study.
6.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant 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 the Merck’s product, is also an adverse event.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 83 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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All adverse events, that begin or worsen after informed consent through 30 days following 
cessation of treatment, must be recorded by the investigator or designee at each 
examination on the Adverse Event case report forms/worksheets.  
The investigator will make every attempt to follow all subjects with non-serious adverse 
events for outcome.
Conditions that were already present at the time of informed consent should be recorded in 
the Medical History page of the patient’s CRF/worksheet.
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, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. Grade 1 to 5 will be used to characterize the severity 
of the Adverse Event. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1-5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be 
collected through a Death form (or EOT/SEC/Survival Information in NOVDD). The occurrence 
of adverse events should be sought by non-directive questioning of the patient (patient) 
during the screening process after signing informed consent and at each visit during the 
study. Adverse events also may be detected when they are volunteered by the patient 
(patient) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates)  
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes, 
investigational treatment, Yes, the study treatment (non-investigational), Yes, both and/or 
indistinguishable) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 84 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 6.2 and 
which seriousness criteria have been met (include for NCDS trials) 
Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)  
If the event worsens, the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported 
in the CRF noting the start date when the event improved from having been Grade 3 or Grade 
4. All adverse events should be treated appropriately. If a concomitant medication or non-
drug therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. Progression of malignancy (including fatal 
outcomes), if documented by use of appropriate method (for example, as per RECIST criteria 
for solid tumors), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 85 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck.
6.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Principal Investigator and to Merck
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant 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 Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Merck’s product 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.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Principal Investigator and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229)
6.2.2
Reporting of Pregnancy and Lactation to the Principal Investigator and to Merck
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study.
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator 
if they cause the participant to be excluded from the trial, 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 infant exposures during breastfeeding that occur from the time of 
treatment allocation/randomization through 120 days following cessation of study 
treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator.  All reported 
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 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 86 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported.
Such events must be reported within 24 hours to the Principal Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229)
6.2.3
Immediate Reporting of Adverse Events to the Principal Investigator and to Merck
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event 

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. (Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse).
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment (or 30 days following cessation of study intervention if the participant initiates new 
anticancer therapy, whichever is earlier), any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the study drug, 
must be submitted on a Winship SAE form and assessed by PI in order to determine reporting 
criteria to regulatory authorities, IRB, DSMC, FDA and/or Merck. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or the adherence to be stable. Other supporting documentation of the 
event may be requested by the study PI and should be provided as soon as possible. 
All subjects with serious adverse events must be followed up for outcome.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours 
of the investigator receiving the follow-up information. 
An SAE occurring at a different time interval or otherwise considered completely unrelated 
to a previously reported one should be reported separately as a new event. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Any SAEs experienced after the reporting period described above should only be reported to 
FDA/IRB and/or Merck if the investigator suspects a causal relationship to the study 
treatment.   
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (Pembrolizumab and/or Ramucirumab and/or Docetaxel), complete 
the SAE Report Form, and submit the completed form.  
Each reoccurrence, complication, or progression of the original event should be reported as 
a follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not, and whether the patient continued or withdrew from study 
participation. 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. 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.
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product 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 be reported immediately (within 2 working days) to Merck Global 
Safety. 
Global Safety facsimile number:  +1-215-661-6229
All participants with serious adverse events must be followed up for outcome.
6.2.3.1 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229).
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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For the time period beginning when the consent form is signed until treatment allocation, 
any ECI, or follow up to an ECI, that occurs to any participant must be reported within 2 
working days to Merck Global Safety if it causes the participant to be excluded from the trial, 
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.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
Merck product, must be reported within 2 working days to Merck Global Safety.
Events of clinical interest for this trial include:
1.  an overdose of Merck product, as defined in Section 6.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, 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 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. 
6.2.4
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 5.0. 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.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Table 9: Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V5.0 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 Merck product that:
†Results in death; or
†Is life threatening; or places the participant, 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 for an elective procedure to treat a pre-existing 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 a Merck 
product and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to 
diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the 
Sponsor within 24 hours and to Merck within 2 working days to meet certain local requirements); or
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 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days..
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 participant 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 Merck product to be discontinued?
Relationship 
to Merck 
Product 
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product 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 Merck product and the AE; the 
greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely Merck product caused the adverse event (AE):
Exposure
Is there evidence that the participant was actually exposed to Merck product 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 Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials 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
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued)
to Merck 
Product
(continued) 
Dechallenge
Was Merck product 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 the Sponsor’s product; or (3) the trial is a single-dose 
drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the participant re-exposed to Merck product 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) the trial is a single-dose drug trial); or (3) Sponsor’s product(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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding 
Merck product 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 
Merck product relationship).
Yes, there is a reasonable 
possibility of Merck 
product relationship.
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to 
the administration of Merck product is reasonable.  The AE is more likely explained by Merck 
product than by another cause.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20: A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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No, there is not a 
reasonable possibility of 
Merck product 
relationship
Participant did not receive the Merck  product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another 
cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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6.2.5
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations. 
7.0 STATISTICAL ANALYSIS PLAN
7.1
Trial Design
Simon’s two-stage optimum design will be used. The null hypothesis that the 6-month PFS rate is 37% 
will be tested against one-sided alternative hypothesis that the actual 6-month PFS rate is higher than 
62%. In the first stage, 10 evaluable patients will be accrued. If there are 5 or more patients who 
progressed or died prior to 6 months among these 10 patients, the study will be stopped early for 
futility. Otherwise, 11 additional evaluable patients will be accrued for a total of 21 patients.
The null hypothesis will be rejected if 11 or more remain free of progression or death by 6 months 
among 21 evaluable patients. This design yields a type I error of 0.10 and power of 80% when the actual 
6-month PFS rate is 62%. To account for early dropout prior to 6 months on study, we plan to enroll up 
to 30 patients. The calculation is based on current enrollment status including early dropout (among 23 
enrolled, 5 dropouts without progression at 6 months and 2 did not complete cycle 1 of study 
treatment).
7.2
Statistical Analysis Plan
Descriptive statistics will be provided for collected demographic data, safety, dosage, clinical factors, 
etc. as appropriate. Descriptive statistics on continuous data will include means, medians, standard 
deviations, and ranges, while categorical data will be summarized using frequency counts and 
percentages. Graphical summaries of the data may be presented.
The term toxicity is defined as adverse events that are classified as either possibly, probably, or 
definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal CTC 
standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and 
leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as 
well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity 
profiles will be explored and summarized. Frequency distributions, graphical techniques and other 
descriptive measures will form the basis of these analyses. Proportion of acute and late toxicity will be 
reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method. 
The treatment response (6-month PFS rate) will be reported, and its 95% confidence intervals will be 
estimated using the Clopper-Pearson method. Chi-square test will be used to compare the efficacy in 
term of treatment response between the two groups stratified by binary biomarker (PD-L1 and KRAS 
status), respectively. Two sample t-test will be used to compare the tumor mutation burden (TMB) if 
known, and PD-L1 22C3 expression, changes of circulating immune cells in peripheral blood (pre-
treatment, after treatment and on progression) between treatment responders and non-responders, 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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respectively. Logistics regression model will be further employed to test the adjusted effect of PD-L1 
22C3, STK11, KRAS, TMB (if known), immunophenotypic analysis of circulating immune cells on the 
treatment response after adjusting for other clinical factors and demographic factors. 
For progression free survival, progression or death from any cause will be defined as the event. Patients 
will be censored at time of last follow-up. For overall survival, death from any cause will be defined as 
the event. Patients will be censored at time of last follow-up. Overall survival (OS) and progression free 
survival (PFS) rates of two patient groups stratified by binary biomarker (PD-L1 and KRAS status), 
respectively will be estimated with the Kaplan-Meier method and compared using the log-rank test, 
respectively. Cox proportional hazards models will be further used in the multivariable analyses to 
assess adjusted effect of PD-L1 and KRAS status on the patients’ OS and PFS after adjusting for other 
factors. Interaction terms between these factors will also be tested for statistical significance. The 
proportional hazards assumption will be evaluated graphically and analytically with regression 
diagnostics. Violations of the proportional hazard’s assumptions will be addressed by use of time-
dependent covariates or extended Cox regression models. 
7.3 Sample size
We will include 21 evaluable patients to assess the safety of the combination treatment and its efficacy 
in term of 6-month PFS rate as defined by 25% increase (1.7-fold) from the historic 6-month PFS rate 
on REVEL study (37% to 62%). We estimate to consent up to 45 patients to account for screen failures 
and enroll up to 30 patients to account for early dropout prior to 6 months on study.  
We will evaluate the first six patients for safety data. If less than 2 patients experience dose limiting 
toxicity, we will continue with the efficacy assessment of the combination.
7.4 Analysis sets
All subjects who receive any amount of study drug will be included in the evaluation of safety, except 
for patients who take less than 80% of their prescribed doses of study drugs since they will be 
considered unevaluable for the primary endpoint.
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
8.1
Investigational Product 
Ramucirumab (CYRAMZA®)
Ramucirumab is a human monoclonal antibody (IgG1) against vascular endothelial growth factor 
receptor 2 (VEGFR2), a type II trans-membrane tyrosine kinase receptor expressed on endothelial cells. 
By binding to VEGFR2, ramucirumab prevents binding of its ligands (VEGF-A, VEGF-C, and VEGF-D), 
thereby preventing VEGF-stimulated receptor phosphorylation and downstream ligand-induced 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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proliferation, permeability, and migration of human endothelial cells. VEGFR stimulation also mediates 
downstream signalling required for angiogenesis and is postulated to be heavily involved in cancer 
progression, making it a highly likely drug target. In contrast to other agents directed against VEGFR-2, 
ramucirumab binds a specific epitope on the extracellular domain of VEGFR-2, thereby blocking all VEGF 
ligands from binding to it. 
Ramucirumab is a recombinant human IgG1 monoclonal antibody, it has an approximate molecular 
weight of 147 kDa. And it is produced in genetically engineered mammalian NS0 cells. 
Docetaxel (TAXOTERE®)
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis 
beginning with a precursor extracted from the renewable needle biomass of yew plants. Docetaxel is 
an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for 
mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly 
of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to the stabilization of microtubules, 
which results in the inhibition of mitosis in cells.
Pembrolizumab (KEYTRUDA®)
Pembrolizumab is an immunoglobulin IgG4, with a variable region against the human PD-1 receptor, a 
humanized mouse monoclonal [228-L-proline (H10-S>P)]γ4 heavy chain (134-218') disulfide and a 
humanized mouse monoclonal κ light chain dimer (226-226:229-229)-bisdisulfide. It is recombinantly 
manufactured in Chinese hamster ovary (CHO) cells.
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.
Pembrolizumab will be provided by Merck, the commercially available Docetaxel and Ramucirumab 
will be prescribed and administered per local laws and prescribing information as summarized in Table 
10.
Table 10: Product Descriptions
Product Name & Potency
Dosage Form
Docetaxel (20 mg/2 mL or 80 mg/8 mL 
or 160 mg/16 mL).
Solution for Injection
Ramucirumab 100 mg/10 mL or 500 
mg/50 mL)
Solution for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
8.2
Packaging and Labeling Information
Supplies will be labeled in accordance with regulatory requirements.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Ramucirumab
Ramucirumab injection is a clear to slightly opalescent and colorless to slightly yellow, preservative-free 
solution supplied in single-dose vials. 
Injection: 100 mg/10 mL (10 mg/mL) or 500 mg/50 mL (10 mg/mL) in a single-dose vial 

NDC 0002-7669-01: 100 mg/10 mL (10 mg/mL), individually packaged in a carton 

NDC 0002-7678-01: 500 mg/50 mL (10 mg/mL), individually packaged in a carton 
Docetaxel
Docetaxel Injection is supplied in a multiple dose vial as a sterile, pyrogen-free solution. Docetaxel 
Injection requires NO prior dilution with a diluent and is ready to add to the infusion solution. 
Docetaxel Injection 10 mg/mL is supplied as 20 mg/2 mL, 80 mg/8 mL and 160 mg/16 mL. 
Each mL of Docetaxel Injection contains 10 mg docetaxel; 80 mg polysorbate 80; 648 mg polyethylene 
glycol 300; 275.9 mg alcohol 96% (v/v), and 4 mg citric acid.
Refer to the latest package insert for complete details.
Pembrolizumab
Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa.  
Pembrolizumab will be provided as a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for IV infusion.  

Pembrolizumab solution is provided in single-dose vials containing 100 mg/4 mL (25 mg/mL).  
Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in L-histidine (1.55 
mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 

The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of the infusion solution.  An infusion of pembrolizumab in this study 
will require 2 vials of solution.   
Pembrolizumab will be supplied in commercial packaging, which includes the package insert or patient 
information leaflet. Refer to the latest package insert for complete details.
8.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial 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.
8.4
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 trial medication must be recorded by an authorized person at the trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Ramucirumab
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until 
time of use. Do not freeze or shake the vial. 
Docetaxel
Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to protect from bright light. 
Freezing does not adversely affect the product. 
After initial puncture, Docetaxel Injection multiple dose vials are stable for 28 days when stored 
between 2ºC to 8ºC and at room temperature, with or without protection from light. Docetaxel 
Injection infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours in either 
0.9% Sodium Chloride solution or 5% Dextrose solution. Use within 4 hours including storage and 
administration. Do not freeze infusion solution.
Pembrolizumab
Storage of Reconstituted and Diluted Solutions The product does not contain a preservative. Store the 
reconstituted and diluted solution from the pembrolizumab 50 mg vial either: 
At room temperature for no more than 6 hours from the time of reconstitution. This includes room 
temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion. 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. 
Store the diluted solution from the pembrolizumab 100 mg/4 mL vial either: 
At room temperature for no more than 6 hours from the time of dilution. This includes room 
temperature storage of the diluted solution, and the duration of infusion. 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If 
refrigerated, allow the diluted solution to come to room temperature prior to administration. Discard 
after 6 hours at room temperature or after 24 hours under refrigeration. 
Do not freeze.
8.5
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 participants and the amount remaining at 
the conclusion of the trial. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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The study drug provided for this study will be used only as directed in the study protocol. 
The IDS (Investigational Drug Service) personnel at Winship and non-Emory collaborating site will 
account for all study drugs.
Drug accountability should be performed until the patient stops study treatment completely. Study site 
personnel will account for all study drugs received at the site.
Study drug supplies must be kept in an appropriate, secure locked area and stored in accordance with 
the conditions specified on the labels. The Investigator, pharmacist, or designee must maintain an 
accurate record of dispensing the study drug/s in a Drug Accountability Log.
The Drug Accountability Log may record specifics to study drug dispensation such as: 
• Records of product delivery, inventory, temperature monitoring, destruction, and return.
• Dosages prepared, time prepared, doses dispensed. 
• Doses and/or vials destroyed. 
• The Drug Accountability Log will be reviewed by the monitor during site visits and at the completion 
of the study.
Drug accountability will be noted by the field monitor during site visits and at the completion of the 
study. 
The study drug supply will be disposed of as per Winship’s Investigational Pharmacy (IDS) SOP.
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver. This information must be captured in the source 
document at each patient visit.  Dose changes and interruptions of study drug must be specifically 
documented in the patient source documents and eCRF.
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, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept.
9.0
ADMINISTRATIVE AND REGULATORY DETAILS
9.1
Data Reporting / Regulatory Requirements
Data Reporting
Study participants are responsible for submitting data and/or data forms in the clinical management 
system - Online Collaborative Research Environment (ONCORE) - per Winship SOP 4.2 Data Completion 
Metrics.  Data completion will be reviewed monthly. In situations where there are significant delays of 
data completion, the Associate Director of Clinical Research or the Director of Clinical Trials may 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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temporarily suspend enrollment. Data entry is to be completed within the designated timeframe, not 
to exceed 30 days of the subject visit. 
Queries will be resolved by the research staff within the time frame specified by the protocol, not to 
exceed 2 weeks. 
Source data and documents
In accord with section 1.51 of the ICH E6 document all information in original records and certified 
copies of original records or clinical findings, observations, or other activities necessary for the 
reconstruction and evaluation of the trial is considered source data. Source data are contained in source 
documents, which can be original records or certified copies of hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects' diaries of evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-
rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial.
Case Report Forms (CRFs) - Source data may be collected in the source documents or entered directly 
onto the case report forms.
Protocol Adherence
By signing the Form FDA 1572, the Investigator agrees to conduct the study according to the protocol 
and the FDA regulations set forth in 21 CFR Parts 50, 54, 56, and 312.
Retention of Study Documents
All documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence will be maintained for at least 2 years after the investigation is completed.
Data and Safety Monitoring Plan
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide 
oversight for the conduct of this study. The DSMC functions independently within Winship Cancer 
Institute to conduct internal monitoring functions to ensure that research being conducted by Winship 
Cancer Institute Investigators produces high-quality scientific data in a manner consistent with good 
clinical practice (GCP) and appropriate regulations that govern clinical research. Depending on the risk 
level of the protocol, the DSMC review may occur every 6 months or annually. Since this study is deemed 
Moderate Risk, initial study monitoring will occur within 1 year from the date of the first subject 
accrued, with 2 of the first 5 subjects being reviewed. Subsequent monitoring will occur in routine 
intervals per the Winship Data and Safety Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with the 
protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and 
availability of source documents, AEs/SAEs, and essential regulatory documents. Following the 
monitoring review, monitors will provide a preliminary report of monitoring findings to the PI and other 
pertinent individuals involved in the conduct of the study. The PI is required to address and respond to 
all the deficiencies noted in the preliminary report. Prior to the completion of the final summary report, 
monitors will discuss the preliminary report responses with the PI and other team members (when 
appropriate). A final monitoring summary report will then be prepared by the monitor. Final DSMC 
review will include the final monitoring summary report with corresponding PI response, submitted 
CAPA (when applicable), PI Summary statement, and available aggregate toxicity and safety data. 
The DSMC will render a recommendation and rating based on the overall trial conduct. The PI is 
responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB. 
Continuing Review submissions will include the DSMC recommendation letter. Should any revisions be 
made to the protocol-specific monitoring plan after initial DSMC approval, the PI will be responsible for 
notifying the DSMC of such changes. The Committee reserves the right to conduct additional audits if 
necessary.
10.0 ETHICS AND PROTECTION OF HUMAN SUBJECTS
10.1 Ethical standard
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research, and are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements patient data protection. 
10.2 Institutional review board
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented 
participants need to be re-consented.
10.3 Informed consent
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Informed consent is a process that is initiated prior to the individual consent to participate in the study 
and continues throughout the individual’s participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be 
IRB approved and the participant will be asked to read and review the document. The investigator will 
explain the research study to the participant and answer any questions that may arise. All participants 
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will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, 
and potential risks of the study and of their rights as research participants.  Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing.
The participants should have the opportunity to discuss the study with their surrogates or think about 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study.
10.4 Participant and data confidentiality
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records.
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and research staff 
will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived.
10.5 Research use of stored samples, specimens, or data
Samples and data collected under this protocol may be used for future exploratory studies including 
genomic profiling. Access to stored samples will be limited to IRB-approved investigations. Samples and 
data will be stored using codes assigned by the investigators or their designees. Data will be kept in 
password-protected computers. Only investigators will have access to the samples and data.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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All stored samples will be maintained in the laboratory to which it was sent initially for analysis. Study 
participants who request destruction of samples will be notified of compliance with such request and 
all supporting details will be maintained for tracking.
11.0   Multi-Site or Collaborative Research 
The research will be conducted at Emory University and non-Emory collaborating site. 
All sites will have the current protocol document and each IRB will review each site’s consent form and all 
required approvals will be obtained at each site.  Any protocol modifications will be communicated to all sites 
with the appropriate regulatory agencies notified for their respective reviews and approvals.  All engaged 
participating sites will safeguard date, including secure transmission of data, as required by local information 
security policies.  All local site investigators will conduct the study in accordance with applicable federal 
regulations and local laws.  All non-compliance with the study protocol or applicable requirements will be 
reported in accordance with local policy.  
Site initiation at subsites
At the time of study initiation at a subsite, the coordinating center multi-site coordinator (with additional staff 
as needed) will perform a site initiation teleconference. During this teleconference, the Emory team will review 
the study, enrollment, reporting, and regulatory compliance. 
Subsite data collection
Subsite data must be submitted to the coordinating center multi-site coordinator as outlined in the protocol-
specific monitoring plan. The protocol-specific monitoring plan will be provided by the coordinating center multi-
site coordinator to external participating prior to site activation. Access to the coordinating center OnCore 
database will be provided to external participating sites for direct electronic data entry. All data submitted must 
be accompanied by supporting source documents, where applicable and as outlined in the protocol-specific 
monitoring plan. All data must be entered in the timeframe required at each site, but no later than 14 days 
following registration and each visit completion. All queries are to be resolved within 4 weeks of issue. The 
coordinating center multi-site coordinator will provide OnCore training and request access to the appropriate 
staff at the participating site.
Monthly investigator conference calls
The subsite research coordinators will maintain a spreadsheet which will be de-identified and will summarize 
patient data for subjects actively being treated on the trial well as a roadmap detailing pending tests/treatments 
for each individual subject. The spreadsheet will be shared with the coordinating center PI (or designee) via e-
mail. Teleconferences will be conducted at least once monthly between the PI (or designee) at Emory and the 
research team at the participating site(s). 
The purpose of the meetings is to discuss the enrollment, regulatory updates, monitor toxicities, and evaluate 
the progress of the trial. Scheduled teleconferences may stop after all patients have completed assigned protocol 
therapy. The coordinating center (or designee) will communicate with participating sites via monthly email as 
needed. 
The minutes from the teleconference will be maintained in the regulatory binder for the study. In addition, 
electronic copies will be sent via email to the research teams at subsite.  
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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Monitoring
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial follows the 
currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s).
Subsite self-monitoring: The participating site will have internal monitoring meetings. These meetings which will 
include the participating site investigator (or designee), the clinical research coordinator and the regulatory 
affairs coordinator as applicable, will meet at least on a monthly basis to review and discuss study data to ensure 
subject safety. Chart reviews will be performed on selected cases by participating site staff to confirm that the 
data collection is accurate regarding study conduct, data collection, documentation and completion. 
Central monitoring: Study-specific monitoring plans are specified per site, with the only difference between sites 
whether the site submits source data on paper or provides the coordinating center multi-site team remote access 
to that site’s local electronic medical record.  Centralized monitoring will occur minimally quarterly, no more 
frequently than monthly. Monitoring will be centralized, including data reporting and research sample 
acquisition. The coordinating center multi-site coordinator will perform on-site and/or remote monitoring visit 
within the first three months of enrollment of the first subject. Quarterly monitoring visits will occur (on site up 
to once per year and at least three times remotely) until subject follow-up is terminated. Monthly reviews of 
data will be conducted to ensure compliance or identify discrepancies; specifically, to assess compliance with the 
protocol, verify informed consent forms, verify compliance with SAE reporting procedures, monitor the tracking 
of study drug (pharmacy visit, storage and accounting of study drug), retrieve regulatory documentation, and 
perform quality control by comparing data from the CRF to the source documents of the center.
Auditing
For sites with an auditing mechanism in place that are able to share documentation of their auditing standards 
and processes followed, an agreement may be requested for the site to perform local auditing and provide formal 
audit reports to the coordinating center.
 
12.0 References

Brahmer, J., et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-
Cell Lung Cancer. N Engl J Med, 2015. 373(2): p. 123-35.

Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 
2004;173:945-54.

Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.

Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy 
for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 
2005;23(10):2346-57.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47.

Fossella, F.V., et al., Randomized phase III trial of docetaxel versus vinorelbine or 
ifosfamide in patients with advanced non-small-cell lung cancer previously treated with 
platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer 
Study Group. J Clin Oncol, 2000. 18(12): p. 2354-62.

Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.

Gandhi, L., et al., Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung 
Cancer. N Engl J Med, 2018. 378(22): p. 2078-2092.

Garon, E.B., et al., Ramucirumab plus docetaxel versus placebo plus docetaxel for 
second-line treatment of stage IV non-small-cell lung cancer after disease progression 
on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 
trial. Lancet, 2014. 384(9944): p. 665-73.

Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.

Herbst, R.S., et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-
positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled 
trial. Lancet, 2016. 387(10027): p. 1540-50.

Herbst, R.S., et al., Ramucirumab plus pembrolizumab in patients with previously treated 
advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial 
carcinoma (JVDF): a multicohort, non-randomized, open-label, phase 1a/b trial. Lancet 
Oncol 2019;20(8):1109-23.

Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.

Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 
2015. 372(26): p. 2509-20.

Mok, T.S.K., et al., Pembrolizumab versus chemotherapy for previously untreated, PD-
L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): 
a randomised, open-label, controlled, phase 3 trial. Lancet, 2019. 393(10183): p. 1819-
1830.

Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 2001;98(24):13866-
71.

Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 
2005;25(21):9543-53.

Paz-Ares, L., et al., Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell 
Lung Cancer. N Engl J Med, 2018. 379(21): p. 2040-2051.

Reck, M., et al., Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell 
Lung Cancer. N Engl J Med, 2016. 375(19): p. 1823-1833.

Reck, M., et al., Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-
Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor 
Proportion Score of 50% or Greater. J Clin Oncol, 2019. 37(7): p. 537-546.

Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.

Rivera, L.B. and G. Bergers, Intertwined regulation of angiogenesis and immunity by 
myeloid cells. Trends Immunol, 2015. 36(4): p. 240-9.

Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet 
Oncol. 2017;18(3):e143-e152. Epub 2017 Mar 2.

Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-
cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and 
downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.

Shi, S., et al., Combining antiangiogenic therapy with adoptive cell immunotherapy 
exerts better antitumor effects in non-small cell lung cancer models. PLoS One, 2013. 
8(6): p. e65757.

Socinski, M.A., et al., Atezolizumab for First-Line Treatment of Metastatic Nonsquamous 
NSCLC. N Engl J Med, 2018. 378(24): p. 2288-2301.

Terme, M., E. Tartour, and J. Taieb, VEGFA/VEGFR2-targeted therapies prevent the 
VEGFA-induced proliferation of regulatory T cells in cancer. Oncoimmunology, 2013. 
2(8): p. e25156.

Yang, J., J. Yan, and B. Liu, Targeting VEGF/VEGFR to Modulate Antitumor Immunity. 
Front Immunol, 2018. 9: p. 978.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and functional 
analysis of the costimulatory receptor programmed death-1. Immunity 2004;20:337-47.

Ziogas, A.C., et al., VEGF directly suppresses activation of T cells from ovarian cancer 
patients and healthy individuals via VEGF receptor Type 2. Int J Cancer, 2012. 130(4): p. 
857-64.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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13.0 APPENDICES
A) 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.
B) The New York Heart Association (NYHA) functional classification of heart failure
Class I (Mild)
Patients with cardiac disease but without resulting in limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation 
(rapid or pounding heartbeat), dyspnea (shortness of breath), or anginal 
pain (chest pain)
Class II (Mild)
Patients with card iac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain
Class III 
(Moderate)
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Class IV 
(Severe)
Patients with cardiac disease resulting in the inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.
Appendix 1:
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_8.5x11.pdf)
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE)
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if they agree 
to one of the following during the protocol defined time frame in section X: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a 
long term and persistent basis) and agree to remain abstinent
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year 
as described in Table 10 when having penile-vaginal intercourse with a woman of childbearing 
potential who is not currently pregnant.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration.
Appendix 3: Contraceptive Guidance and Pregnancy Testing
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
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Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception that has a low user dependency consistently and correctly as 
described in Table 11 during the protocol-defined time frame.  
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Table 11:
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b 
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently 
and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 6 months after the last dose of study treatment .
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test and in 
accordance with local requirements.  When applicable this test should be repeated a maximum of 24-
hours before the first dose/vaccination.
Following initiation of treatment additional pregnancy testing will be performed at monthly intervals 
during the treatment period and at least 120 days plus 30 days (a menstruation cycle) after the last dose 
of study treatment and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected.
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether 
to continue a participant on study treatment until repeat imaging is obtained (using iRECIST for 
participant management (see Table 5 and Figures 1 and 3).  This decision by the Investigator should be 
based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, 
per Investigator assessment.  I
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and ≥ 5 mm 
from nadir
o
Please note: the iRECIST publication uses the terminology “sum of measurements”, but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease).  For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size thresholds and 
rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 lesions 
Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters of these 
lesions will be calculated and kept distinct from the sum of diameters for target lesions at baseline.  All 
other new lesions will be followed qualitatively as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which iUPD is 
seen.  This may correspond to the next visit in the original visit schedule.  The assessment of the 
subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, 
and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 115 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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
None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a 
response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule.  
If PD is confirmed, participants will be discontinued from study treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment may 
be considered.  In this case, if study treatment is continued, tumor imaging should continue to be 
performed following the intervals as outlined in Section 5.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by any of the 
following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) either 
for the first time, or after resolution of previous pseudo-progression.  The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD.
o
If non-target lesions had shown previous unequivocal progression, and this progression has 
not resolved, iUPD results from any significant further growth of non-target lesions, taken 
as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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o
Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum 
of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression must be 
confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, except in one 
respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the burden of 
new lesions has increased from its smallest value (for new target lesions, their sum of diameters is ≥5 
mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a 
decrease in the new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes 
iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour et al, 2017].
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
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The following abbreviations and special terms are used in this study Protocol.
Abbreviation 
or 
special term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BP
Blood pressure
CL
Clearance
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EOT
End of Treatment 
FDA
Food and Drug Administration
FT3
Free thriiodothyronine
GCP
Good Clinical Practice
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICI
immune checkpoint inhibitor 
DMSC
Data Monitoring Safety Committee
IgG
Immunoglobulin G
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
  APPENDIX 5   Abbreviations and definition of terms
Complion Document ID: 9472875

Protocol Title:  WINSHIP4950-20 - A phase 2 study of docetaxel, ramucirumab, and pembrolizumab for patients 
with metastatic or recurrent non-small cell lung cancer who progressed on platinum-doublet and PD-1/PD-L1 blockade
Page 118 of 118                       Protocol Version: Version 4.0 Dated 13JAN2025
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Abbreviation 
or 
special term
Explanation
IV
Intravenous
mAb
Monoclonal antibody
MRI
Magnetic resonance imaging
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PR
Partial response
Q3W
Every 3 weeks
QT
QT interval 
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious adverse event
SD
Stable disease
T3
Triiodothyronine
T4
Thyroxine
TMB
Tumor mutation burden 
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
WOCBP
Woman of childbearing potential
Complion Document ID: 9472875