Clinical trial NCT03971474
Conditions: Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8
Sponsor: SWOG Cancer Research Network
Start date: 2019-05-28; Completion date: 2024-01-01
Enrollment: 166 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II Lung-MAP non-Match treatment trial studies how well ramucirumab and pembrolizumab work versus standard of care in treating patients with non-small cell lung cancer that is stage IV or has come back. Immunotherapy with monoclonal antibodies, such as ramucirumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in standard of care chemotherapy for non-small cell lung cancer, such as docetaxel, gemcitabine hydrochloride, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ramucirumab and pembrolizumab together may work better in treating patients with non-small lung cancer compared to standard of care.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare overall survival between patients previously treated with platinum-based chemotherapy and immunotherapy for stage IV or recurrent non-small cell lung cancer randomized to ramucirumab and MK-3475 (pembrolizumab) versus standard of care (SoC).

SECONDARY OBJECTIVES:

I. To compare response rates between the arms, including complete response (CR) and partial response (PR) (confirmed and unconfirmed).

II. To compare the disease control rate (CR, PR, confirmed and unconfirmed and stable disease \[SD\]).

III. To evaluate the duration of response (DoR) among responders within each arm.

IV. To evaluate the frequency and severity of toxicities within each arm. V. To compare investigator assessed-progression-free survival (IA-PFS) between the arms.

VI. To evaluate the clinical outcomes (overall survival \[OS\], IA-PFS, response) by randomization stratification factors by comparing outcomes within the ramucirumab and MK-3475 (pembrolizumab) arm, performing a sub-group analysis of the arms, and by evaluating an interaction between the factors and treatment arm.

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To evaluate if PD-L1 expression levels are associated with clinical outcomes (OS, IA-PFS, and response).

II. To evaluate if tumor mutation burden (TMB) as determined by the Foundation Medicine Inc (FMI) Foundation One panel is associated with clinical outcomes.

III. To collect, process, and bank cell-free (circulating cell-free deoxyribonucleic acid \[cfDNA\]) at baseline and progression for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor DNA (ctDNA).

IV. To establish a tissue/blood repository to pursue future studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients may receive docetaxel intravenously (IV) over 10-30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, pemetrexed IV over 10 minutes on day 1 (non-squamous NSCLC patients only), or ramucirumab IV over 60 minutes combined with docetaxel IV over 10-30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive ramucirumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment (prior to disease progression), patients are followed up every 3 months for the first year, and then every 6 months for up to 3 years from date of randomization. After completion of study treatment (after disease progression), patients are followed up every 6 months for 2 years, then at the end of year 3 from the date of randomization.

Arms: arm 1: Patients receive docetaxel IV over 10-30 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 or ramucirumab IV over 60 minutes and docetaxel IV over 10-30 minutes on day 1. Patients with non-squamous NSCLC receiving docetaxel and gemcitabine hydrochloride, also receive pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ramucirumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Docetaxel intervention 2: Gemcitabine intervention 3: Gemcitabine Hydrochloride intervention 4: Pembrolizumab intervention 5: Pemetrexed intervention 6: Pemetrexed Disodium intervention 7: Ramucirumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
S1800A 
 
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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY T 
 
S1800A: (Non-Match Immunotherapy Combination Sub-Study)  
 
SWOG CANCER RESEARCH NETWORK 
TITLE  
LUNGMAP, A MASTER PROTOCOL TO EVALUATE BIOMARKER-DRIVEN THERAPIES AND 
IMMUNOTHERAPIES IN PREVIOUSLY TREATED NON-SMALL CELL LUNG CANCER (LUNG-MAP 
SCREENING STUDY) 
 
S1800A, A PHASE II RANDOMIZED STUDY OF RAMUCIRUMAB PLUS PEMBROLIZUMAB (MK-3475) 
VERSUS STANDARD OF CARE FOR PATIENTS PREVIOUSLY TREATED WITH IMMUNOTHERAPY 
FOR STAGE IV OR RECURRENT NON-SMALL CELL LUNG CANCER (LUNG-MAP NON-MATCHED 
SUB-STUDY) 
NCT #03971474 
This is an FDA Registration Trial. Additional site requirements include: 
• 
maintenance of a Trial Master File (https://www.swog.org/sites/default/files/docs/2017-
10/Guidance%20on%20FDA%20Inspection.pdf)  
• 
completion of a protocol specific Delegation of Task Log (DTL) (see Section 13.2) 
• 
additional monitoring (see LUNGMAP Appendix 18.2) 
 
LUNGMAP and its sub-studies are being conducted under SWOG IND 143217 and CIRB. The 
LUNGMAP study is considered a single study under one IND, consisting of the screening protocol 
and multiple sub-studies. Each sub-study protocol operates independently and has its own 
version date. However, for regulatory purposes, all LUNGMAP sub-study protocols should be 
processed as a single study for Continuing Review.  
 
 
STUDY CHAIRS: 
AGENTS: 
Karen L. Reckamp, M.D. (Medical Oncology) 
NCI Supplied Investigational Agents: 
NCTN Group: SWOG 
Ramucirumab (NSC 749128) 
Cedars-Sinai Medical Center  
Pembrolizumab (MK-3475) (NSC 776864) 
8700 Beverly Blvd, SCCT 1S27 
 
Los Angeles, California 90048 
Commercially Available Agents: 
Phone: 310/423-5362 
Docetaxel (NSC 628503) 
FAX:  310/423-7182 
Gemcitabine hydrochloride (NSC 613327) 
E-mail: karen.reckamp@cshs.org 
Pemetrexed (NSC 698307) 
 
 
Konstantin H. Dragnev, M.D. (Medical Oncology) 
BIOSTATISTICIANS: 
NCTN Group: Alliance 
Mary Redman, Ph.D. 
Dartmouth Cancer Center 
Katherine Minichiello, M.S. 
One Medical Center Drive 
SWOG Statistics and Data Management Center  
Lebanon, NH  03756 
1100 Fairview Ave N, M3-C102 
Phone:  603/650-6345 
P.O. Box 19024 
FAX:  603/650-7791 
Seattle, WA 98109-1024 
E-mail: konstantin.h.dragnev@hitchcock.org  
Phone: 206/667-4623 
 
FAX: 206/667-4408 
 
E-mail: mredman@fredhutch.org   
 
E-mail: kmini@fredhutch.org   
 
 
 
 
 
 


 
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PARTICIPANTS 
 
 
 
 
 
 
 
 
 
U.S.-Only Participants: 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 


 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
TABLE OF CONTENTS ............................................................................................................................... 3 
PROTOCOL CONTACT INFORMATION ..................................................................................................... 5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objective ............................................................................................................................. 8 
1.2 
Secondary Objectives ...................................................................................................................... 8 
1.3 
Translational Medicine Objectives ................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................... 8 
2.1 
Lung-MAP ........................................................................................................................................ 8 
2.2 
General Background ........................................................................................................................ 8 
2.3 
Study Design .................................................................................................................................... 9 
2.4 
Ramucirumab and Pembrolizumab (MK-3475)................................................................................ 9 
2.5 
PD-L1 Test ..................................................................................................................................... 10 
2.6 
Circulating tumor DNA (ctDNA) ..................................................................................................... 10 
2.7 
Inclusion of Women and Minorities and Planned Enrollment Report ............................................ 11 
3.0 
DRUG INFORMATION .................................................................................................................. 11 
3.1 
Docetaxel (Taxotere®) (NSC-628503)........................................................................................... 11 
3.2 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) .................................................................. 13 
3.3 
Pemetrexed (Alimta®) (NSC 698037)............................................................................................ 15 
3.4 
Ramucirumab (Cyramza™, IMC-1121B, LY3009806) (NSC 749128, IND 143217) ..................... 17 
3.5 
Pembrolizumab (MK-3475) (NSC-776864) (IND 143217) ............................................................. 20 
3.6 
DRUG ORDERING & ACCOUNTABILITY FOR INVESTIGATIONAL AGENTS .......................... 27 
4.0 
STAGING CRITERIA ..................................................................................................................... 28 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 30 
5.1 
Disease Related Criteria ................................................................................................................ 30 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 32 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 33 
5.4 
Specimen Submission Criteria ....................................................................................................... 35 
5.5 
Regulatory Criteria ......................................................................................................................... 35 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 35 
7.0 
TREATMENT PLAN ...................................................................................................................... 36 
7.1 
Disease Assessment ...................................................................................................................... 36 
7.2 
Pre-Medication and Supportive Care ............................................................................................. 36 
7.3 
Treatments ..................................................................................................................................... 37 
7.4 
Criteria for Removal from Protocol Treatment ............................................................................... 41 
7.5 
Discontinuation of Treatment ......................................................................................................... 41 
7.6 
Follow-Up Period ............................................................................................................................ 41 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 41 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 41 
8.2 
General Considerations ................................................................................................................. 41 
8.3 
Dose Modifications for Chemotherapy ........................................................................................... 42 
8.4 
Dose Modifications for Ramucirumab ............................................................................................ 42 
8.5 
Dose Modifications for Pembrolizumab (MK-3475) ....................................................................... 46 
8.6 
Dose Modification Contacts ........................................................................................................... 50 
8.7 
Adverse Event Reporting ............................................................................................................... 50 
9.0 
STUDY CALENDAR ...................................................................................................................... 51 
9.1 
Arm A: Investigator’s Choice of Standard of Care ......................................................................... 51 
9.2 
Arm B: Ramucirumab plus Pembrolizumab (MK-3475) ................................................................. 55 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 58 
10.3 
Best Response ............................................................................................................................... 61 
10.4 
Performance Status ....................................................................................................................... 62 
10.5 
Time to Death ................................................................................................................................. 62 
10.6 
Investigator-Assessed Progression-Free Survival ......................................................................... 62 
10.7 
Progression-Free Survival by Central Review ............................................................................... 62 


 
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10.8 
Duration of Response (DoR) .......................................................................................................... 62 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 63 
11.1 
Study Design and Endpoint Justification........................................................................................ 63 
11.2 
Primary Objective ........................................................................................................................... 63 
11.3 
Sample Size, Accrual Duration, and Estimated Analysis Times .................................................... 63 
11.4 
Design, Sample Size Justification .................................................................................................. 63 
11.5 
Interim Analysis Plan ...................................................................................................................... 64 
11.6 
Accrual Justification ....................................................................................................................... 67 
11.7 
Data and Safety Monitoring ........................................................................................................... 68 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 68 
12.1 
Radiology Review .......................................................................................................................... 68 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 68 
13.1 
Registration Timing ........................................................................................................................ 68 
13.2 
Investigator/Site Registration ......................................................................................................... 68 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 69 
14.1 
Data Submission Requirements .................................................................................................... 69 
14.2 
Master Forms ................................................................................................................................. 69 
14.3 
Data Submission Procedures ........................................................................................................ 69 
14.4 
Data Submission Overview and Timepoints .................................................................................. 71 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 73 
15.1 
SWOG Specimen Tracking System (STS) .................................................................................... 73 
15.2  
Correlative Studies and Banking  (Optional for Patients) .............................................................. 73 
15.3 
LUNGMAP ctDNA Assay – Peripheral Whole Blood (REQUIRED FOR PATIENTS prior to 
treatment initiation) ...................................................................................................................... 74 
15.4 
Specimen Flow Diagram ................................................................................................................ 76 
15.5 
Radiology Review (Required) ........................................................................................................ 76 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 77 
16.1 
Serious Adverse Event Reporting Requirements .......................................................................... 79 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 85 
18.0 
APPENDIX ..................................................................................................................................... 88 
18.5 
PD-L1 22C3 IHC Assay ................................................................................................................. 88 
18.1 
New York Heart Association Classification .................................................................................... 89 
18.2 
Instructions for the SWOG Biospecimen Bank .............................................................................. 90 
18.3 
Child-Pugh Scoring ........................................................................................................................ 91 
18.4 
Live Vaccines Examples ................................................................................................................ 92 
18.5 
PD-L1 22C3 IHC Assay ................................................................................................................. 93 
 


 
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PROTOCOL CONTACT INFORMATION  
 
Patient Advocate: 
Judy Johnson, MBA 
E-mail: judyjohnson.519@gmail.com  
Phone: 314/477-6139 
 
Eligibility, RAVE, Data Submission: 
SWOG Statistics and Data Management Center  
E-mail: LUNGMAPquestion@crab.org 
Phone: 206/652-2267 
 
Regulatory, Protocol, Informed Consent: 
SWOG Operations Office  
E-mail: protocols@swog.org 
Phone: 210/614-8808 
 
Medical Queries (treatment or toxicity related 
questions): 
 
E-mail: S1800AMedicalQuery@swog.org 
 
Investigational Drug questions: 
Requests for Investigator’s Brochures: 
 
See Protocol Section 3.0 
 
Temperature Excursion Reports: 
 
See Protocol Section 3.4f for ramucirumab 
CTMM@lilly.com  
 
See Protocol Section 3.5f for pembrolizumab 
 
 
Specimen Tracking System (STS) Amendments, 
Errors, Connectivity Issues and Technical issues 
with the SWOG CRA Workbench: 
 
technicalquestion@crab.org  
 
Foundation Medicine, Inc. (for ordering ctDNA 
blood collection kits only): 
 
FMI Client Services  
E-mail: lung.map@FoundationMedicine.com 
 
 
Cancer Therapy and Evaluation Program – 
Identity and Access Management (CTEP-IAM): 
 
To review CTEP-IAM account (new requests, 
reset passwords): 
https://ctepcore.nci.nih.gov/iam/index.jsp 
 
Access to iMedidata Rave or Delegation of Task 
Log (DTL): 
 
See Protocol Section 14.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
 
Questions related to 
Oncology Patient Enrollment Network (OPEN): 
 
See LUNGMAP Protocol Section 13.2 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
 
Patient Transfers: 
 
patienttransfer@crab.org 
 
TRIAD installations: 
 
https://triadinstall.acr.org/triadclient/   
Questions: TRIAD-Support@acr.org  
 
Adverse Event Reporting questions: 
 
See Protocol Section 8.7 
E-mail: adr@swog.org 
 
Source Documentation Portal – Central Monitoring: 
 
centralmonitorquestion@crab.org 


 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
 
(Sign in at www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN).  
 
OPEN is accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email: 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
 
 
Data collection for this study 
will be done exclusively 
through Medidata 
Rave. Refer to the data 
submission section of the 
protocol for further 
instructions.  
 
Other Tools and Reports: 
Institutions participating 
through the CTSU continue 
to have access to other tools 
and reports available on the 
SWOG CRA Workbench via 
the SWOG website 
(www.swog.org). 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log in 
with a CTEP-IAM username and password.  
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center (SDMC) by phone or email: 
 
206/652-2267 
LUNGMAPQuestion@crab.org 
 
For treatment or toxicity related questions contact S1800AMedicalQuery@swog.org. 
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission)  
Contact the CTSU Help Desk by phone or e-mail: 
 
 
CTSU General Information Line: 
888-823-5923 
S1400contact@westat.com  
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
 


 
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SCHEMA 
 
Registration Ω 
 
Screening Study testing for determining Sub-Study Assignment 
S1800A Randomization € Δ 
 
 
 
 
 
Arm A 
 
Investigator’s Choice of Standard of 
Care ¥ 
(Cycle length = 21 days) 
 
 
 
Progression 
 
 
 
 
 
 
 
 
 
Arm B 
 
 
Ramucirumab plus 
Pembrolizumab (MK-3475) 
(Cycle length = 21 days) 
  
Progression 
 
 
 
 
Ω See LUNGMAP Section 5.1 for registration information. Note: Patients may have been enrolled 
on the legacy S1400 screening/pre-screening study. 
€ 
Notification of sub-study assignment will be provided by the SWOG Statistics and Data 
Management Center (SDMC) (see LUNGMAP Section 11.0 for details). 
Δ 
See Section 11.0 for a more detailed statistical design.  
¥ 
This is the Investigator’s Choice of Standard of Care as outlined in Section 7.2a. 
 
 
 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To compare overall survival between patients previously treated with platinum-based 
chemotherapy and immunotherapy for Stage IV or recurrent non-small cell lung cancer 
randomized to ramucirumab and pembrolizumab (MK-3475) versus standard of care 
(SoC). 
 
1.2 
Secondary Objectives 
 
a. 
To compare response rates between the arms, including complete response (CR) 
and partial response (PR) (confirmed and unconfirmed). 
 
b. 
To compare the disease control rate (CR, PR, confirmed and unconfirmed and SD) 
 
c. 
To evaluate the duration of response (DoR) among responders within each arm.  
 
d. 
To evaluate the frequency and severity of toxicities within each arm.  
 
e. 
To compare IA-PFS between the arms. 
 
f. 
To evaluate the clinical outcomes (OS, IA-PFS, response) by randomization 
stratification factors (See Section 6.0) by comparing outcomes within the 
ramucirumab and pembrolizumab (MK-3475) arm, performing a sub-group 
analysis of the arms, and by evaluating an interaction between the factors and 
treatment arm.  
 
1.3 
Translational Medicine Objectives 
 
a. 
To evaluate if PD-L1 expression levels are associated with clinical outcomes (OS, 
IA-PFS, and response). 
 
b. 
To evaluate if tumor mutation burden (TMB) as determined by the FMI Foundation 
One panel is associated with clinical outcomes. 
 
c. 
To collect, process, and bank cell-free (cfDNA) at baseline and progression for 
future development of a proposal to evaluate comprehensive next-generation 
sequencing of circulating tumor DNA (ctDNA).  
 
Note: The proposal to use these specimens would be submitted as an amendment 
to CTEP for approval prior to SDMC reviewing the results. 
 
d. 
To establish a tissue/blood repository to pursue future studies. 
 
2.0 
BACKGROUND 
 
2.1 
Lung-MAP 
 
The Lung-MAP study is an umbrella protocol which contains a screening component and 
multiple independently conducted and analyzed treatment sub-studies for patients with 
previously treated stage IV or recurrent NSCLC. This protocol is specifically designed for 
patients not eligible for one of the biomarker-driven sub-studies in Lung-MAP who have 
previously received (and progressed during or following) both platinum-based 
chemotherapy and immune checkpoint inhibitor therapy.  
 
2.2 
General Background 
 


 
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The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals 
of immunotherapy agents in both treatment-naïve and previously treated cancer and 
irrespective of histology. (1, 2, 3, 4, 5) Tumors may modulate and evade the host immune 
response through several mechanisms, including down regulation of tumor-specific antigen 
expression and presentation, secretion of anti-inflammatory cytokines, and upregulation of 
inhibitory ligands. T-cell checkpoint regulators such as cytotoxic T-lymphocyte antigen 4 
(CTLA-4) and programmed death-1 (PD-1, CD279) are cell surface molecules that play a 
critical role in down-regulating T-cell activation and proliferation. T-cell checkpoint 
inhibitors’ anti-tumor activity depends on disruption of immune tolerance to tumor cell 
antigens. Following on the success of CTLA-4 and anti-PD-1 pathway-targeted agents in 
several cancers, the field of tumor immunotherapy is rapidly expanding with several new 
promising approaches. Overall, enhancement of the magnitude and potency of tumor 
antigen-specific adaptive cellular responses by CD8 and CD4 T cells is now considered a 
major goal in cancer immunotherapy. Knowing that single-agent immunotherapies have 
already demonstrated activity, it is plausible, that combination therapies could lead to a 
greater depth of response, and an increase in overall survival (OS) as has been noted with 
the combination of anti-PD-1 and anti-CTLA-4 in subjects with previously untreated 
NSCLC. (6) In addition, the biggest current need is for those patients with primary or 
acquired resistance.   
 
2.3 
Study Design 
 
We now understand that the kinetics of immune-mediated anti-tumor activity may be 
delayed compared to that of cytotoxic chemotherapy or targeted therapy. Immunotherapy 
mediates tumor regression indirectly through activation of immune responses and/or 
inhibition of suppressive immune elements. This may result in delayed tumor regression, 
with some patients even experiencing the progression of existing disease or the 
appearance of new lesions prior to eventual disease regression. Furthermore, many 
immunotherapy agents do not impact PFS, but are associated with significant 
improvements in overall survival. (7)  
 
Knowing that single-agent immunotherapies have already demonstrated activity, it is 
plausible that combination therapies could lead to a greater depth of response, and/or an 
increase in overall survival (OS) as has been noted with the combination of anti-PD-1 and 
anti-CTLA-4 in subjects with previously untreated NSCLC. (8)   
 
2.4 
Ramucirumab and Pembrolizumab (MK-3475) 
 
An immunosuppressive tumor microenvironment exists within lung tumors. Vascular 
Endothelial Growth Factor (VEGF) has been shown to modulate the tumor immune 
microenvironment. CD25+ FOXP3+ CD4+ T cells (Treg) play an important role in 
developing immune tolerance within tumors. VEGF impedes T cell extravasation by limiting 
T cell adhesion to the luminal surfaces of blood vessels, inhibits the proliferation and 
cytotoxicity of cytotoxic T lymphocytes (CTLs), and stimulates the proliferation of T 
regulatory (Treg) cells. (9) VEGF also induces programmed death ligand 1 (PDL1) 
expression on dendritic cells. VEGFR2 has been shown to be expressed by FOXP3 high 
Treg and exists in peripheral blood mononuclear cells and lymphocytes within malignant 
effusions.  Therefore, inhibition of VEGFR may inhibit the immunosuppressive function of 
Treg. (10) VEGFR2 has also been shown to reduce tumor induced Treg proliferation.  (11)  
In a transgenic breast cancer model, VEGFR inhibition led to modulation of cytokines 
related to tumor cell infiltration.  In addition, VEGFR2 inhibition decreased infiltration of 
suppressive immune cells while increasing mature dendritic cells. (12) VEGF has a 
systemic effect on myeloid-derived suppressor cells (MDSCs) and suppresses dendritic 
cell maturation. VEGF drives the recruitment and infiltration of angiogenic and immune-
suppressive MDSCs and macrophages. MDSCs and macrophages then produce reactive 
oxygen species, nitric oxide, and arginase to suppress T cell proliferation, viability, and 
activity. High levels of VEGF have been associated with the accumulation of immature 
myeloid DC in cancer patients. (13) By contrast, inhibition of VEGF restores many of these 


 
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phenotypes. (14)  Sunitinib is a multi-kinase inhibitor that has multiple targets including 
VEGFR and c-kit. Treatment with sunitinib led to a 50% reduction in the peripheral blood 
levels of MDSC in renal cell cancer patients. The decline was associated with improved 
Th1 lymphocyte function and decreased numbers of Tregs. (15)  Furthermore, the 
simultaneous blockade of PD1 and VEGFR2 synergistically inhibited tumor growth by 
reducing tumor neovascularization and resulted in upregulation of proinflammatory 
cytokines. (16)   
 
Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain 
of vascular endothelial growth factor receptor 2 (VEGFR2), blocking VEGF binding and 
receptor activation. (17)  In a Phase III trial in patients with advanced NSCLC, the 
combination of ramucirumab and docetaxel demonstrated improved overall response rate 
(ORR), progression free survival and overall survival compared to docetaxel alone. (18) 
Such benefit was also seen in patients who progressed rapidly on first-line therapy who 
historically would have a poor prognosis in the second line setting in a post-hoc analysis.  
(19)  In advanced renal cell carcinoma, the combination of axitinib and pembrolizumab 
(MK-3475) resulted in a 71% ORR.  (20)   In an early Phase I a/b trial, 27 NSCLC patients 
who previously progressed on chemotherapy received the combination of ramucirumab 
and pembrolizumab (MK-3475), which demonstrated a 30% ORR with 77% of evaluable 
patients experiencing some tumor shrinkage. (21) The doublet demonstrated encouraging 
antitumor activity independent of PD-L1 and histology, numerically better than anti-PD-1 
monotherapy. In an updated presentation at ASCO 2018 by Roy Herbst et al, data in the 
NSCLC cohort was reported by PDL1 status. (22)  Overall response rate was 18% in PDL1 
<1% and 45% in ≥1% with duration of response not reached in either group, and disease 
control rate was 82% versus 91% in PDL1 <1% and ≥1%, respectively. For patients with 
PDL1 <1%, progression free survival (PFS) was 9.7 months and overall survival (OS) was 
17 months.  For those with PDL1 ≥1%, PFS was 6.9 months and OS was not reached.  
Toxicity in the NSCLC subgroup showed 26% with grade 3/4 adverse events, 7% with 
hypertension, 4% with fatigue, 4 % with infusion reaction and 4% with proteinuria. Dual 
blockade with ramucirumab and pembrolizumab (MK-3475) may lead to improved tumor 
responses and prolonged survival in patients with metastatic lung cancer. In addition, a 
study evaluating maintenance nivolumab with or without bevacizumab following first-line 
platinum-based doublet chemotherapy was evaluated in patients with advanced NSCLC. 
the median OS survival was not reached in either arm. In the combination arm, median 
PFS was 37.1 weeks, while nivolumab alone resulted in median PFS of 16 weeks for 
squamous cell carcinoma and 21.4 weeks for nonsquamous NSCLC. (23) The combination 
was well tolerated. The preclinical rationale in addition to early clinical data support the 
evaluation of this combination.  
2.5 
PD-L1 Test 
Testing for Programmed death-ligand 1 (PD-L1) expression by Immunohistochemistry 
(IHC) was performed on all fresh tumor biopsies and archival tumor materials on 
LUNGMAP screening protocol, prior to LUNGMAP Revision #4.  This was done by 
Foundation Medicine utilizing the 22C3 pharmDx (Dako) antibody which is already FDA 
approved and a reliable biomarker for selection of patients that are more likely to benefit 
from checkpoint inhibitor therapy. 
2.6 
Circulating tumor DNA (ctDNA) 
In addition, the detection rates of mutations observed in ctDNA isolated from patient 
plasma at baseline and progression will be evaluated in comparison to mutations observed 
in tumor tissue.  It is expected that mutations identified in plasma will be synonymous with 
those detected in tissue, with the following exceptions: a subset of patients may have 
insufficient amounts of ctDNA in circulation for detection, and secondly, a subset of patients 
may have additional mutations detected in plasma that are associated with metastases 
and not present in the original tissue biopsy.  The overarching goal of the Lung-MAP liquid 
biopsy program, planned across multiple sub-studies, is to assess whether positive 


 
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identification of mutations in ctDNA can be utilized for molecular assignment.  In this sub-
study, the primary objective is to correlate detection frequencies between tissue and 
plasma. 
 
2.7 
Inclusion of Women and Minorities and Planned Enrollment Report 
 
This study was designed to include women and minorities but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below.  
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
1 
3 
0 
0 
4 
Native Hawaiian or Other 
Pacific Islander 
0 
1 
0 
0 
1 
Black or African American 
5 
6 
0 
0 
11 
White 
55 
69 
1 
2 
127 
More Than One Race 
0 
0 
0 
0 
0 
Total 
61 
80 
1 
2 
144 
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures 
 
For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. For S1800A, 
the investigational drugs are ramucirumab (Arm B only) and pembrolizumab (MK-3475) and are 
being provided under an IND held by SWOG. [Note: Ramucirumab will be supplied for both Arm A 
(Investigator’s Choice of Standard of Care) and Arm B (Investigational Combination).] of For INDs 
filed by SWOG, the protocol serves as the Investigator Brochure for the performance of the 
protocol. In such instances, submission of the protocol to the IRB should suffice for providing the 
IRB with information about the drug. However, in cases where the IRB insists on having the official 
Investigator Brochure from the company, requests may be submitted to the CTSU website by 
completing the CTSU Request for Clinical Brochure. 
 
3.1 
Docetaxel (Taxotere®) (NSC-628503) 
   [Commercially Available Drug] 
a. PHARMACOLOGY 
 
Mechanism of Action: Docetaxel promotes the assembly of microtubules and 
stabilizes their formation by inhibiting depolymerization. This stabilization creates 
a microtubule which is non-functional. Cell death is promoted by the disruption of 
normal cell shape, motility, attachment, and intracellular transport. Docetaxel is 
cytotoxic predominately in the S-phase of the cell cycle. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Intravenous administration of docetaxel results in 100% 
bioavailability. Area under the curve (AUC) of docetaxel was dose 


 
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proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times 
of 1 to 2 hours.  
 
2. 
Distribution: The initial rapid decline represents distribution to the 
peripheral compartments and the late (terminal) phase is due, in part, to a 
relatively slow efflux of docetaxel from the peripheral compartment. Mean 
steady state volume of distribution was 113 L. In vitro studies showed that 
docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, 
albumin, and lipoproteins.  
 
3. 
Metabolism: Docetaxel is primarily metabolized in the liver by cytochrome 
P450 3A4 and 3A5 isoenzymes (CYP3A4/5).  
 
4. 
Elimination: Docetaxel elimination follows a three-compartment model 
with an initial distribution half-life of 3 to 5 minutes, an intermediate 
elimination half-life of 36 to 60 minutes, and a terminal half-life of 10 to 18 
hours. Mean total body clearance was 21 L/h/m2.Approximately 6% of 
unchanged drug is eliminated by the kidney in 24 hours, with the majority 
(80%) of excretion occurring in feces at 7 days.  
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Docetaxel:  The most common adverse effects 
occurring in > 20% of people receiving docetaxel include: fluid retention, 
alopecia, nail disorders, skin reactions (rash, pruritis), nausea, vomiting, 
diarrhea, 
constipation, 
mucositis, 
infections, 
anemia, 
asthenia, 
neutropenia, neuropathy, fever, amenorrhea, erythema of the extremities 
with edema, pain and lacrimation with or without conjunctivitis. 
 
Adverse effects occurring in ≤ 20% of people receiving docetaxel include: 
cutaneous skin reactions, abdominal pain, thrombocytopenia, febrile 
neutropenia, 
hepatotoxicity, 
venous 
thromboembolism, 
pulmonary 
embolism, myalgia, anorexia, dysgeusia, dyspnea, and cardiac 
dysrhythmias. 
 
Rare (< 3%) but potentially serious adverse effects include: 
hypersensitivity 
reactions 
(rash/erythema, 
hypotension, 
wheezing, 
shortness of breath, swelling of the face or throat), acute myeloid 
leukemia, and interstitial lung disease or pneumonia. 
 
Patients receiving docetaxel infusions may experience alcohol intoxication 
from the ethanol included in the formulation. 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Excretion in breast milk 
is unknown and breast feeding is not recommended during treatment. 
 
3. 
Drug Interactions: Cytochrome P450 3A4/5 inducers, inhibitors, or 
substrates may alter docetaxel metabolism. In patients receiving treatment 
with docetaxel, close monitoring for toxicity and a docetaxel dose 
reduction could be considered if systemic administration of a potent 
CYP3A inhibitor cannot be avoided.  Patients should use caution with 
sleep aids or narcotic analgesics due to possible additive sedation from 
the alcohol present in the docetaxel formulation. Due to potential drug 
interactions, a complete patient medication list, including docetaxel, 


 
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should be screened prior to initiation of and during treatment with 
docetaxel.   
 
d. 
DOSING & ADMINISTRATION 
 
See treatment plan in Section 7.0. 
 
e. 
HOW SUPPLIED  
 
Docetaxel is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 
3.2 
Gemcitabine hydrochloride (Gemzar®) (NSC-613327) 
   [Commercially Available Drug] 
a. 
PHARMACOLOGY 
 
Mechanism 
of 
Action: 
Gemcitabine 
(2'-Deoxy-2', 
2'-difluorocytidine 
monohydrochloride), like cytarabine, is a nucleoside analog of deoxycytidine.  This 
antimetabolite, a pyrimidine analog inhibiting both DNA and RNA viruses, is cell-
cycle-specific in blocking the cells at the G1/S and is retained in human tumor cells 
for long periods.  Studies suggest that gemcitabine is activated by deoxycytidine 
kinase. Deoxycytidine has been shown to reverse the growth inhibitory activity of 
gemcitabine. 
 
b. 
PHARMACOKINETICS 
 
1. 
Distribution: Gemcitabine plasma protein binding is negligible. The volume 
of distribution is increased with the infusion length. In a pharmacokinetics 
study of patients with various solid tumors, the volume of distribution of 
gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long 
infusions (70 to 285 minutes), the volume of distribution rose to 370 L/ m2.   
 
2. 
Metabolism: Gemcitabine is metabolized intracellularly to form active 
gemcitabine di- and tri-phosphates.  The gemcitabine di- and tri-
phosphates do not appear to circulate in plasma in measurable amounts.  
Gemcitabine is metabolized by the liver to form the inactive uracil 
derivative, 2'-deoxy-2',2'-difluorouridine (dFdU).  The inactive metabolite 
does not appear to accumulate with weekly dosing; however, it is excreted 
by the kidneys and may accumulate in patients with decreased renal 
function. 
 
3. 
Elimination: Following a single 1,000 mg/m2/30 min [14C]-gemcitabine 
infusion, 92% to 98% of the dose was recovered within 1 week after 
gemcitabine administration.  Urinary excretion of the parent drug and the 
dFdU metabolite accounted for 99% of the excreted dose, and less than 
1% of the dose was excreted in feces.  The renal clearance of gemcitabine 
is less than 10%; therefore, the parent drug appears to be almost 
completely metabolized to the inactive dFdU. 
 
Clearance of gemcitabine is affected by age and gender and is lower in 
women and the elderly.  Differences in either clearance or volume of 
distribution based on patient characteristics or the duration of infusion 
result in changes in half-life and plasma concentrations. Studies showed 


 
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that gemcitabine half-life for short infusions ranged from 42 to 94 minutes, 
for long infusions it varied from 245 to 638 minutes, depending on age and 
gender, reflecting a greatly increased volume of distribution with longer 
infusions. The terminal phase half-life for the active metabolite, 
gemcitabine triphosphate, in mononuclear cells ranges from 1.7-19.4 
hours. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Gemcitabine:  
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in >20% to 100% of subjects treated with 
gemcitabine include: flu-like symptoms, nausea, vomiting, rash, alopecia, 
infection, myelosuppression including anemia, leukopenia, neutropenia, 
and thrombocytopenia, muscle weakness, hematuria, paresthesia, 
sensory neuropathy, fatigue, somnolence, hearing loss, peripheral edema. 
 
Adverse effects reported in 4% to 20% of subjects include: diarrhea, 
constipation, stomatitis, dyspnea, capillary leak syndrome, posterior 
reversible encephalopathy syndrome (PRES). 
 
Adverse effects reported in 3% or less of subjects include: arrhythmias, 
supraventricular arrhythmias, congestive heart failure, myocardial 
infarction, desquamation and bullous skin eruptions, gangrene, 
cerebrovascular accident, hepatic failure, adult respiratory distress 
syndrome (ARDS), anaphylaxis, renal failure, pulmonary fibrosis, 
pulmonary edema, and, Interstitial, pneumonitis. 
 
2. 
Pregnancy and Lactation: Category D. Gemcitabine may cause fetal harm 
when administered to a pregnant woman.  This agent has produced 
teratogenic effects in mice and rabbits when administered at a dose of < 
2 mg/m2.  Adverse effects included decreased fetal viability, weight and 
morphologic defects.  There is no data on gemcitabine administration 
during human pregnancy, and it is not currently known if metabolites are 
excreted in human milk.  However, many drugs are excreted in human 
milk, and there is a potential for adverse effects in nursing infants.  
Therefore, the use of gemcitabine should be avoided in pregnant or 
nursing women because of the potential hazard to the fetus or infant. 
 
3. 
Drug Interactions: Per gemcitabine package insert, no formal drug 
interaction studies have been performed to date.  When gemcitabine was 
administered with carboplatin or paclitaxel there was minimal or no effect 
on the pharmacokinetics of the studied drugs. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Gemcitabine is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
f. 
STORAGE, PREPARATION & STABILITY 


 
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Refer to the current FDA-approved package insert. 
 
3.3 
Pemetrexed (Alimta®) (NSC 698037) 
   [Commercially Available Drug] 
NOTE: Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be 
used to treat patients with squamous cell NSCLC.  
a. 
PHARMACOLOGY 
 
Mechanism of Action: Pemetrexed for injection is a folate analog metabolic 
inhibitor that exerts its action by disrupting folate dependent metabolic processes 
essential for cell replication. In vitro studies have shown that pemetrexed inhibits 
thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide 
ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes 
involved in the de novo biosynthesis of thymidine and purine nucleotides. 
Pemetrexed is taken into cells by membrane carriers such as the reduced folate 
carrier and membrane folate binding protein transport systems. Once in the cell, 
pemetrexed 
is 
converted 
to 
polyglutamate 
forms 
by 
the 
enzyme 
folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and 
are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-
dependent process that occurs in tumor cells and is thought to occur to a lesser 
extent, in normal tissues. Polyglutamated metabolites are thought to have an 
increased intracellular half-life resulting in prolonged drug action in malignant 
cells. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: The pharmacokinetics of pemetrexed administered as a 
single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-
minute period have been evaluated in 426 cancer patients with a variety 
of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum 
plasma concentration (Cmax) increase proportionally with dose. The 
pharmacokinetics of pemetrexed do not change over multiple treatment 
cycles. 
 
2. 
Distribution: Pemetrexed has a steady-state volume of distribution of 16.1 
liters. In vitro studies indicate that pemetrexed is approximately 81% 
bound to plasma proteins. Binding is not affected by degree of renal 
impairment. 
 
3. 
Metabolism: Pemetrexed is not metabolized to an appreciable extent and 
is primarily eliminated in the urine, with 70% to 90% of the dose recovered 
unchanged within the first 24 hours following administration. 
 
4. 
Elimination: The clearance of pemetrexed decreases, and exposure 
(AUC) increases, as renal function decreases. The total systemic 
clearance of pemetrexed is 91.8 mL/min and the elimination half-life of 
pemetrexed is 3.5 hours in patients with normal renal function (creatinine 
clearance of 90 mL/min). 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Pemetrexed: Refer to the current FDA-approved 
package insert for the most comprehensive and up to date information on 
adverse reactions. 
 


 
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Adverse effects reported in > 20% of subjects treated with pemetrexed 
include: 
anemia, 
fatigue, 
constipation, 
nausea, 
vomiting, 
mucositis/stomatitis, thrombocytopenia, bleeding, infection, neutropenia, 
and desquamation. 
 
Adverse effects reported in 4% to 20% of subjects include: diarrhea, 
edema, increased serum creatinine, increased serum ALT, increased 
serum AST, interstitial pneumonitis, pulmonary fibrosis, pruritus, rash, and 
erythema multiforme.  
 
Serious adverse effects reported in ≤ 3% of subjects include: bowel 
obstruction, neuropathy, alopecia, and thrombosis/embolism. 
 
2. 
Pregnancy and Lactation:  Pregnancy Category D. Pemetrexed can cause 
fetal harm when administered to a pregnant woman. Pemetrexed 
administered intraperitoneally to mice during organogenesis was 
embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the 
recommended human dose. If pemetrexed is used during pregnancy, or if 
the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus. Women of childbearing 
potential should be advised to avoid becoming pregnant. Women should 
be advised to use effective contraceptive measures to prevent pregnancy 
during treatment with pemetrexed. Due to the potential for serious adverse 
reactions in the nursing infant, a decision should be made to discontinue 
pemetrexed or to discontinue breast-feeding during therapy, taking into 
account the benefits of treatment to the mother.  
 
3. 
Drug Interactions: Although ibuprofen (400 mg four times a day) can 
decrease the clearance of pemetrexed, it can be administered with 
pemetrexed in patients with normal renal function (creatinine clearance 
≥80 mL/min). No dose adjustment of pemetrexed is needed with 
concomitant non-steroidal anti-inflammatory drugs (NSAIDs) in patients 
with normal renal function. Caution should be used when administering 
NSAIDs concurrently with pemetrexed to patients with mild to moderate 
renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs 
with short elimination half-lives (e.g., diclofenac, indomethacin) should be 
avoided for a period of 2 days before, the day of, and 2 days following 
administration of pemetrexed. In the absence of data regarding potential 
interaction between pemetrexed and NSAIDs with longer half-lives (e.g., 
meloxicam, nabumetone), patients taking these NSAIDs should interrupt 
dosing for at least 5 days before, the day of, and 2 days following 
pemetrexed administration. If concomitant administration of NSAIDs is 
necessary, patients should be monitored closely for toxicity, especially 
myelosuppression, renal, and gastrointestinal toxicity. 
 
Due to potential drug interactions, a complete patient medication list, 
including pemetrexed, should be screened prior to initiation of and during 
treatment with pemetrexed. See Section 8.0 Toxicities to be Monitored and 
Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
Pemetrexed is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 


 
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f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 
3.4 
Ramucirumab (Cyramza™, IMC-1121B, LY3009806) (NSC 749128, IND 143217) 
[Investigational Drug] 
Ramucirumab will be supplied for both Arm A (Investigator’s Choice of Standard of Care) 
and Arm B (Investigational Combination). See Section 3.4e for additional details. 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Ramucirumab is a recombinant human IgG1 monoclonal 
antibody that specifically binds to vascular endothelial growth factor receptor 2 
(VEGFR2). The binding of ramucirumab to VEGFR2 prevents its interaction with 
activating ligands (VEGF-A, VEGF-C, and VEGF-D) and as a result, ramucirumab 
inhibits ligand-stimulated activation of VEGF Receptor 2 and its downstream 
intracellular signaling components, including Erk1/Erk2, neutralizing ligand-
induced proliferation and migration of human endothelial cells. Ramucirumab 
inhibited angiogenesis in an in vivo animal model.  
 
b. 
PHARMACOKINETICS 
 
4. 
Absorption: Ramucirumab is given via intravenous infusion. 
 
5. 
Distribution: In population pharmacokinetic models involving 2,820 
patients, the mean volume of distribution (Vd) of ramucirumab at steady 
state was 4.47 L.  
 
6. 
Metabolism: As a monoclonal antibody, ramucirumab is largely confined 
to the extracellular space, and elimination is primarily by catabolism. 
 
7. 
Elimination: The mean clearance of ramucirumab was 0.0132 L/hour. The 
mean terminal half-life was 10.2 days. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects: The below summary is based on patients receiving 
single-agent ramucirumab for gastric cancer (N=236). The type and 
frequency of adverse events observed vary when ramucirumab is 
administered in combination with other antineoplastic agents. Refer to the 
current FDA-approved package insert for the most comprehensive and 
up to date information on adverse reactions. 
 
 


 
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2. 
 
 
Version: April 2022 
Adverse Events with 
Possible Relationship to Ramucirumab 
Likely (> 20%) 
Less Likely  
(4 – ≤ 20%) 
Rare but Serious  
(≤ 3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia* 
Neutropenia 
 
 
CARDIAC DISORDERS 
 
Hypertension* 
 
Arterial 
thromboembolic 
events (myocardial 
infarction, cardiac 
arrest, 
cerebrovascular 
accidents, and 
cerebral ischemia) 
 
GASTROINTESTINAL DISORDERS 
Abdominal pain* 
 
Diarrhea* 
 
Intestinal obstruction 
Gastrointestinal 
perforation 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Hypokalemia* 
Hyponatremia* 
 
 
NERVOUS SYSTEM DISORDERS 
 
Headache* 
 
RENAL AND URINARY DISORDERS 
 
Proteinuria  
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Epistaxis 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Rash 
 
 
 
* Serious events reported 
 
Important adverse events, including serious adverse events, observed with 
ramucirumab across clinical trials and disease states: hemorrhage, infusion 
related reactions, gastrointestinal hemorrhage, impaired wound healing, Posterior 
Reversible Encephalopathy Syndrome (PRES), nephrotic syndrome, thyroid 
dysfunction, and worsening of pre-existing hepatic impairment. 
3. 
Pregnancy and Lactation:  
 
There are no available data on ramucirumab use in pregnant women. 
Based on its mechanism of action, ramucirumab can cause fetal harm. 
Avoid the use of ramucirumab in pregnant women and advise a pregnant 


 
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woman of the potential risk to a fetus. Animal models link angiogenesis, 
VEGF and VEGF Receptor 2 to critical aspects of female reproduction, 
embryofetal development, and postnatal development. Contraception 
should be used during treatment and for at least three months after the 
last dose of ramucirumab. Based on animal models, ramucirumab may 
potentially impair female fertility.  
 
Studies have not been conducted to assess ramucirumab’s impact on milk 
production, its presence in breast milk, or its effects on the breast-fed child. 
Ramucirumab is excreted in human milk and, due to potential risks to the 
nursing infant, do not breastfeed during treatment with ramucirumab and 
avoid breastfeeding for 2 months after the last dose of ramucirumab.   
 
4. 
Drug Interactions: No clinically meaningful changes in the exposure of 
either ramucirumab or its concomitant drugs in the currently approved 
combinations, including paclitaxel, docetaxel, irinotecan (or its active 
metabolite, SN-38), and erlotinib were observed in patients with solid 
tumors.  Studies indicate that it is unlikely for drug-drug interactions with 
concomitant administration of ramucirumab and durvalumab.   
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
Ramucirumab is administered through a separate infusion line. The use of a 
protein sparing 0.22 micron in-line filter is recommended. The line should be 
flushed with sterile sodium chloride (0.9%) solution for injection at the end of the 
infusion. Do not administer as an intravenous push or bolus. 
 
e. 
HOW SUPPLIED 
 
1. 
Ramucirumab will be supplied free of charge.  It will be provided by Eli Lilly 
and Company and distributed by CTEP PMB. Sites will be provided a 
commercially labeled ramucirumab for investigational use. 
2. 
Ramucirumab is supplied in single-use, 50-mL glass vials. Each vial 
contains 500 mg of ramucirumab at a concentration of 10 mg/mL in a 
sterile, preservative-free solution. Each vial is stoppered with a chlorobutyl 
elastomer stopper laminated with FluroTec® (West Pharmaceutical 
Services, Inc., Exton, PA), and secured with an aluminum 2-piece flip-top 
seal. 
Ramucirumab formulated in an aqueous solution at a concentration of 10 
mg/mL. The buffer contains 10mM histidine, 75mM sodium chloride, 
133mM glycine, and 0.01% polysorbate 80.  
 
Ramucirumab is a clear to slightly opalescent and colorless to slightly 
yellow liquid without visible particles. The pH is 6.0. 
 
All excipients used for the manufacture of ramucirumab are of 
pharmacopeial grade. Ramucirumab molecular weight is 146.8 kDa. 
 
See Section 3.6 for Drug Ordering and Accountability. 
 
 
f. 
  STORAGE, PREPARATION & STABILITY 
 


 
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1. 
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. 
Keep the vial in the outer carton in order to protect from light. DO NOT 
FREEZE OR SHAKE the vial.   
 
In case of temperature excursion outside of the storage range at the site, 
contact CTMM@lilly.com to obtain the Temperature Excursion Data 
Collection Form (TEDCF).  Complete and submit the TEDCF to the 
location indicated on the form within one business day of resolution of the 
temperature excursion. Please use the following information when filling 
out the form: 
• 
Trial Alias: I4T-US-I015   
• 
Site Number: 101 
• 
Site monitor name(s) and e-mail: This should be a person at the 
site level to contact with outcome (i.e. research coordinator). 
 
Determine the cause of the excursion and implement preventive actions 
to prevent future occurrence. Study drug should be returned to acceptable 
storage conditions and segregated from active stock.  Clearly mark the 
material as quarantined and do not dispense/use (note directly on 
package) until further instruction is provided by Eli Lilly and Company. 
 
2. 
Preparation: 
• 
Inspect vial contents for particulate matter and discoloration prior to 
dilution.  If particulate matter or discolorations are identified, discard 
the vial. 
 
• 
Withdraw the required volume of ramucirumab and further dilute with 
only 0.9% Sodium Chloride Injection in an intravenous infusion 
container to a final volume of 250 mL. DO NOT use dextrose 
containing solutions. 
 
• 
Gently invert the container to ensure adequate mixing. DO NOT 
FREEZE OR SHAKE the infusion solution. DO NOT dilute with other 
solutions or co-infuse with other electrolytes or medications. 
 
• 
Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F 
to 46°F) or 4 hours at room temperature (below 25°C [77°F]). 
 
• 
Discard vial with any unused portion of ramucirumab, as the product 
contains no preservatives. 
 
3. 
Compatibility information: DO NOT mix with dextrose containing solutions 
or infuse with electrolyte solutions or other medications. 
 
3.5 
Pembrolizumab (MK-3475) (NSC-776864) (IND 143217) 
[Investigational Available Drug] 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Pembrolizumab (MK-3475) is a humanized MAb of the 
IgG4/kappa isotype.  The programmed cell death 1 (PD-1) receptor is an inhibitory 
receptor expressed by T cells.  When bound to either of its ligands, PD-L1 or PD-
L2, activated PD-1 negatively regulates T-cell activation and effector function.  The 
pathway may be engaged by tumor cells expressing PD-1 ligands to suppress 
immune control.  Pembrolizumab (MK-3475) blocks the negative immune 


 
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regulatory signaling by binding to the PD-1 receptor, inhibiting the interaction 
between PD-1 and its ligands and thereby promoting the host immune system to 
recognize tumor cells as foreign bodies to be eliminated.  
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: N/A 
 
2. 
Distribution: Limited distribution and protein binding (Vd= ~7.5 liters) 
 
3. 
Metabolism: 
Pembrolizumab 
(MK-3475) 
follows 
general 
protein 
degradation pathways in the body. Cytochrome p450 enzymes are not 
involved in metabolism. 
 
4. 
Elimination: Elimination half-life after IV administration was approximately 
26 days. Steady state concentration levels were achieved within ~18 
weeks of repeated dosing, with ~2.2-fold accumulation in exposure during 
administration Q3W relative to exposure observed following single dose 
administration. In the dose range studied for efficacy (2 to 10 mg/kg), 
pembrolizumab (MK-3475) exposure increases in a dose-proportional 
manner, with clearance being independent of time or pembrolizumab (MK-
3475) concentration. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects: 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
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 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
3793 patients. Below is the CAEPR for pembrolizumab (MK-3475). 
 
Version 2.6, July 15, 20211 
 
 Adverse Events with Possible  
 Relationship to pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia2 
Lymph node pain2 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
CARDIAC DISORDERS 
 
 
Myocarditis2 
Pericarditis2 
ENDOCRINE DISORDERS 
 
Adrenal insufficiency2 
Endocrine disorders - 
Other (thyroiditis)2 
Hyperthyroidism2 
 


 
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 Adverse Events with Possible  
 Relationship to pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Hypophysitis2 
Hypopituitarism2 
Hypothyroidism2 
EYE DISORDERS 
 
 
Uveitis2 
Eye disorders - Other (Vogt-
Koyanagi-Harada 
syndrome) 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
Colitis2 
Diarrhea2 
Mucositis oral2 
Nausea 
Pancreatitis2 
Small intestinal 
mucositis2 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
Chills2 
Fever2 
 
HEPATOBILIARY DISORDERS 
 
Hepatobiliary disorders - 
Other (autoimmune 
hepatitis)2 
Hepatobiliary disorders - 
Other (sclerosing cholangitis) 
IMMUNE SYSTEM DISORDERS 
 
Immune system 
disorders - Other 
(pseudoprogression/tum
or inflammation)2 
Immune system 
disorders - Other 
(sarcoidosis)2 
Anaphylaxis2 
Cytokine release syndrome2 
Immune system disorders - 
Other (acute graft-versus-
host-disease)2,3 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis)2 
Serum sickness2 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
 Infusion related reaction 
INVESTIGATIONS 
 
Alanine  
aminotransferase 
increased2 
Alkaline phosphatase 
increased 
Aspartate 
aminotransferase 
increased2 
GGT increased 
Serum amylase increased 


 
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 Adverse Events with Possible  
 Relationship to pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Blood bilirubin 
increased 
CPK increased 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Hyponatremia 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia2 
Arthritis2 
Avascular necrosis2 
Back pain 
Joint effusion2 
Joint range of motion 
decreased 
Musculoskeletal and 
connective tissue 
disorder - Other 
(tenosynovitis)2 
Myalgia2 
Myositis2 
 
NERVOUS SYSTEM DISORDERS 
 
 
Guillain-Barre syndrome2 
Nervous system disorders - 
Other (myasthenic 
syndrome)2 
Nervous system disorders - 
Other (neuromyopathy)2 
Nervous system disorders - 
Other (non-infectious 
encephalitis)2 
Nervous system disorders - 
Other (non-infectious 
meningitis)2 
Nervous system disorders - 
Other (non-infectious 
myelitis) 
Nervous system disorders - 
Other (polyneuropathy)2 
Paresthesia 
Peripheral motor 
neuropathy2 
RENAL AND URINARY DISORDERS 
 
 
Renal and urinary disorders 
- Other (autoimmune 


 
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 Adverse Events with Possible  
 Relationship to pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 Cough 
Pleuritic pain2 
Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Bullous dermatitis2 
Erythroderma 
Pruritus2 
Rash acneiform2 
Rash maculo-papular2 
Skin and subcutaneous 
tissue disorders - Other 
(dermatitis)2 
Skin hypopigmentation2 
Urticaria2 
Erythema multiforme2 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Stevens-Johnson syndrome2 
Toxic epidermal necrolysis 
VASCULAR DISORDERS 
 
 
Vasculitis2 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates 
will be distributed to all Principal Investigators at the time of revision.  The current 
version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, 
the name of the investigator, the protocol and the agent should be included in the 
e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving 
pembrolizumab (MK-3475).  Adverse events potentially related to pembrolizumab 
(MK-3475) may be manifestations of immune-mediated adverse events. In clinical 
trials, most immune-mediated adverse reactions were reversible and managed 
with interruptions of pembrolizumab (MK-3475), administration of corticosteroids 
and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with 
pembrolizumab (MK-3475) who received hematopoeitic stem cell transplants. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Adverse events reported on pembrolizumab (MK-3475) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable 
possibility that pembrolizumab (MK-3475) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Disseminated intravascular coagulation; 
Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; 
Heart failure; Myocardial infarction; Pericardial effusion; Pericardial tamponade; 
Ventricular arrhythmia 


 
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EYE DISORDERS - Eye pain 
GASTROINTESTINAL 
DISORDERS 
- 
Abdominal 
distension; 
Ascites; 
Constipation; Duodenal hemorrhage; Dysphagia; Gastritis; Gastrointestinal 
disorders - Other (diverticulitis); Gastrointestinal disorders - Other (intestinal 
obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal 
hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema 
face; Edema limbs; Facial pain; Gait disturbance; General disorders and 
administration site conditions - Other (general physical health deterioration); 
Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen 
decreased; Lymphocyte count decreased; Neutrophil count decreased; Platelet 
count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperglycemia; 
Hyperkalemia; 
Hypertriglyceridemia; 
Hyperuricemia; 
Hypoalbuminemia; Hypokalemia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; 
Generalized muscle weakness; Musculoskeletal and connective tissue disorder - 
Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; 
Dysarthria; Edema cerebral; Encephalopathy; Headache; Hydrocephalus; 
Lethargy; Meningismus; Nervous system disorders - Other (brainstem herniation); 
Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; 
Proteinuria; Renal and urinary disorders - Other (hydronephrosis); Urinary 
incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; 
Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumothorax; Respiratory 
failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin 
and subcutaneous tissue disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic 
event 
 
Note: Pembrolizumab (MK-3475) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 
 
2. 
Pregnancy and Lactation: The central function of the PD-1/PD-L1 pathway 
is to maintain immune tolerance to the fetal allograft, and its important role 
in maintaining pregnancy has been recently emphasized in literature. The 
PD-L1 molecule expressed at the uteroplacental interface effectively 
protects the concepti from maternal T cell-mediated immunity. Blockade 
of PD-L1 signaling has been shown in murine models of allogeneic 
pregnancy to abrogate feto-maternal tolerance to the concepti and to 
result in an increase in fetal resorption. The evidence from these 
experimental results indicates that there is a theoretical risk associated 
with the administration of pembrolizumab (MK-3475) to women of child-
bearing potential (WOCBP). It is therefore anticipated that the inhibition of 
PD-1 
by 
treatment 
with 
anti-PD-1 
monoclonal 
antibody 
(i.e., 


 
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pembrolizumab) during pregnancy would have detrimental effects that 
might include increased rates of abortion and stillbirth. 
 
It is not known whether pembrolizumab (MK-3475) is excreted in human 
milk.  Because of the potential for drugs to be excreted in human milk, the 
risk to the nursing infant cannot be excluded and therefore pembrolizumab 
(MK-3475) should not be administered to nursing mothers. 
 
Contraception should be used during treatment and for at least four 
months after the last dose of pembrolizumab (MK-3475).  
 
3. 
Drug Interactions: No studies on pharmacodynamic drug interactions have 
been performed.  Due to potential drug interactions, a complete patient 
medication list, including pembrolizumab (MK-3475), should be screened 
prior to initiation of and during treatment with pembrolizumab (MK-3475). 
See Section 8.0 Toxicities to be Monitored and Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
1. 
Pembrolizumab (MK-3475) will be supplied free of charge.  It will be 
provided by Merck & Co., Inc. and distributed by Pharmaceutical 
Management Branch (PMB), CTEP/DCTD/NCI (PMB). 
 
2. 
Pembrolizumab (MK-3475) injection is a sterile, preservative-free, clear to 
slightly opalescent, colorless to slightly yellow solution for intravenous use. 
Each vial contains 100 mg of pembrolizumab (MK-3475) in 4 mL of 
solution. Each 1 mL of solution contains 25 mg of pembrolizumab (MK-
3475) and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), 
sucrose (70 mg), and Water for Injection, USP. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Refer to the package label for expiration. 
 
2. 
Pembrolizumab (MK-3475) should be stored under refrigeration at 2°C - 
8°C (36°F – 46°F) and protected from light in the original box.  Do not 
freeze or shake the vials. 
 
Solution: 
- 
Prepare the IV infusion using aseptic technique in a 
biological safety cabinet or hood. 
- 
Pembrolizumab (MK-3475) should be prepared in 0.9% 
Sodium Chloride Injection, USP (normal saline) with a final 
concentration between 1mg/mL and 10mg/mL.   
- 
Pembrolizumab (MK-3475) is compatible with the following 
bags: PVC plasticized with DEHP, non-PVC (polyolefin), 
EVA, PE lined polyolefin. 
- 
After adding the required amount of drug into the infusion 
bag, gently invert the bag 10-15 times to mix the solution.  
- 
Pembrolizumab (MK-3475) should NOT be mixed with other 
reconstitution diluents.  Pembrolizumab (MK-3475) is infused 
over 30 minutes and is to be administered through a sterile, 
low protein-binding 0.2 to 5 micron in-line filter.  The following 
infusion set materials are compatible with pembrolizumab 


 
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(MK-3475): PVC plasticized with DEHP, PVC and TOTM, 
polyethylene lined PVC, PVC plasticized with DEHT or 
polyurethane sets.  Maximum rate of infusion should not 
exceed 6.7ml/min using an infusion pump.  Lines may be 
primed with normal saline.  
- 
Administer prepared solutions immediately after preparation. 
If not administered immediately, prepared solutions may be 
stored refrigerated for up to 24 hours. Pembrolizumab (MK-
3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 hours. This includes room 
temperature storage of liquid drug product solution in vials, 
room temperature storage of infusion solution in the IV bag, 
and the duration of infusion. If refrigerated, allow the IV 
admixture to come to room temperature prior to use. 
- 
Parenteral drug product should be visually inspected for 
particulate matter and discoloration prior to administration.  
Discard the drug product vial if extraneous particulate matter 
other than translucent to white proteinaceous particles is 
observed. 
- 
Discard any unused portion of pembrolizumab (MK-3475) 
vials immediately as the vials do not contain preservatives. 
- 
Do not administer the product as an IV push or bolus.  
 
3. 
If a storage temperature excursion is identified, promptly return 
pembrolizumab to between 2-8°C (36°F – 46°F) and quarantine the 
supplies.  Contact Merck Sharp & Dohme Corp., by referencing the phone 
number listed on the commercial package insert, to obtain instructions and 
clinical complaint form. 
 
4. 
Do not co-administer other drugs through the same infusion line.  
 
5. 
Repackaging or other specific dispensing requirements: None 
 
3.6 
DRUG ORDERING & ACCOUNTABILITY FOR INVESTIGATIONAL AGENTS 
 
For Commercial Agents 
Commercial agents are labeled with an expiration date and that date should be followed. 
 
a. 
Drug Ordering Investigational Agents provided by PMB 
Confirmation of patient’s enrollment is required for initial drug supply. 
 
Drug ordering: NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that drug be shipped directly to the 
institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained).  The 
CTEP assigned protocol number (S1800A) must be used for ordering all CTEP 
supplied investigational agents.  The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual submission of 
FDA Form 1572 and a CV.  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution.  
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application 
< 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx >.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account < 


 
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Version Date 8/4/2022 
https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account 
status and a “current” password.   For questions about drug orders, transfers, 
returns, or accountability, call 240/276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
b. 
Drug Handling and Accountability  
 
1. 
Drug Accountability:  The investigator, or a responsible party designated 
by the investigator, must maintain a careful record of the receipt, 
disposition, and return of all drugs received from the PMB using the Drug 
Accountability Record Form available on the NCI home page 
(http://ctep.cancer.gov).  
 
2. 
Electronic logs are allowed as long as a print version of the log process is 
the exact same appearance as the current NCI DARF.  
 
c. 
Drug Return and/or Disposition Instruction   
 
1. 
All undispensed drug supplies should be returned to the PMB.  When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB 
sends a stock recovery letter), investigators should return the study drug 
to the PMB using the NCI Return Agent Form available on the NCI home 
page (http://ctep.cancer.gov).  
 
2. 
Drug Expiration: PMB will send a stock recovery letter when the agent is 
no longer suitable for use  
 
d. 
Contact Information and Useful Links 
 
Questions about drug orders, transfers, returns or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday between 
8:30 am and 4:30 pm Eastern Time or by email: PMBAfterHours@mail.nih.gov. 
 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• 
PMB policies and guidelines:  
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
• 
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application: 
https://ctepcore.nci.nih.gov/OAOP  
• 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account: 
https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
PMB email: PMBAfterHours@mail.nih.gov 
 
4.0 
STAGING CRITERIA 
 
Patients must have Stage IV or recurrent disease as outlined below (AJCC Cancer Staging Manual, 
8th Edition, 2017): 
 
Stage IVA 
Any T Any N M1a 
 
 
Any T Any N M1b 
 
Stage IVB 
Any T Any N M1c 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in 
sputum or bronchial washings but not visualized by imaging or bronchoscopy 
T0 
No evidence of primary tumor 


 
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Tis 
Carcinoma in situ 
 
 
Squamous cell carcinoma in situ (SCIS) 
Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤ 3 cm in 
greatest dimension 
T1 
Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the 
main bronchus) 
T1mi 
Minimally invasive adenocarcinoma: adenocarcinoma (≤ 3 cm in greatest dimension) with 
a predominantly lepidic pattern and ≤ 5 mm invasion in greatest dimension 
T1a 
Tumor ≤ 1 cm in greatest dimension. A superficial, spreading tumor of any size whose 
invasive component is limited to the bronchial wall and may extend proximal to the main 
bronchus also is classified as T1a, but these tumors are uncommon.  
T1b 
Tumor ˃ 1 cm but ≤ 2 cm in greatest dimension 
T1c 
Tumor ˃ 2 cm but ≤ 3 cm in greatest dimension 
T2 
Tumor ˃ 3 cm but ≤ 5 cm or having any of the following features: 
• Involves the main bronchus regardless of distance to the carina, but without 
involvement of the carina 
• Invades visceral pleura (PL1 or PL2) 
• Associated with atelectasis or obstructive pneumonitis that extends to the hilar 
region, involving part or all of the lung 
T2 tumors with these features are classified as T2a if ≤ 4 cm or if the size cannot be 
determined and T2b if ˃ 4 cm but ≤ 5 cm. 
T2a 
Tumor ˃ 3 cm but ≤ 4 cm in greatest dimension 
T2b 
Tumor ˃4 cm but ≤ 5 cm in greatest dimension 
T3 
Tumor ˃ 5 cm but ≤ 7 cm in greatest dimension or directly invading any of the following:  
parietal pleural (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal 
pericardium, or separate tumor nodule(s) in the same lobe as the primary 
T4 
Tumor ˃ 7 cm or tumor of any size invading one or more of the following:  diaphragm, 
mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, 
vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that 
of the primary 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastases 
N1 
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and 
intrapulmonary nodes, including involvement by direct extension 
N2 
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s)  
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
M1a 
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or malignant pleural or 
pericardial effusion. nodules or malignant pleural (or pericardial) effusion. ** 
M1b 
Single extrathoracic metastasis in a single organ (including involvement of a single 
nonregional node) 
M1c 
Multiple extrathoracic metastases in a single organ or in multiple organs 
 
** 
Most pleural (and pericardial) effusions with lung cancer are due to tumor.  In a few 
patients, however, multiple microscopic examinations of pleural (pericardial) fluid are 
negative for tumor, and the fluid is non-bloody and is not an exudate.  If these elements 
and clinical judgment dictate that the effusion is not related to the tumor, the effusion should 
be excluded as a staging descriptor. 
 
 
 


 
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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  For each criterion requiring test results and dates, please record this 
information on the Onstudy Form and submit via Medidata Rave® (see Section 14.0). Any potential 
eligibility issues should be addressed to the Statistics and Data Management Center (SDMC) in 
Seattle at 206/652-2267 or LUNGMAPquestion@crab.org prior to randomization.  NCI policy does 
not allow for waiver of any eligibility criterion  
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient patient scheduling without exceeding the guidelines.  
If Day 7, 14, 21, 28 or 42 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have been assigned to S1800A by the SWOG Statistics and Data 
Management Center (SDMC). Patients who were screened under S1400 (legacy 
screening/pre-screening study) must have had prior PD-L1 testing by the Dako 
22C3 PharmDx IHC assay, and must have results available for stratification 
purposes. 
 
b. 
Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK 
gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they 
have progressed following all standard of care targeted therapy.  
 
c. 
Patients must not have an active autoimmune disease that has required systemic 
treatment in past two years (i.e., with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs).  Replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency) is not considered a form of systemic treatment and is 
allowed. 
 
d. 
Patients must not have any history of primary immunodeficiency. 
 
e. 
Patients must not have experienced the following: 
• 
Any Grade 3 or worse immune-related adverse event (irAE). Exception: 
asymptomatic nonbullous/nonexfoliative rash. 
• 
Any unresolved Grade 2 irAE. 
• 
Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 
immunotherapy. 
Exception to the above: Toxicities of any grade that requires replacement therapy 
and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) are allowed. 
 
f. 
Patients must not have any history of organ transplant that requires use of 
immunosuppressives. 
 
g. 
Patients must not have clinical signs or symptoms of active tuberculosis infection. 
 
h. 
Patients must not have history of (non-infectious) pneumonitis that required 
steroids or current pneumonitis/interstitial lung disease. 
 
i. 
Patients must not have had a serious or nonhealing wound, ulcer, or bone fracture 
within 28 days prior to sub-study randomization. 


 
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j. 
Patients must not have a history of gastrointestinal perforation or fistula within six 
months prior to sub-study randomization. 
 
k. 
Patients must not have Grade 3-4 gastrointestinal bleeding (defined by NCI 
CTCAE v5) within three months prior to sub-study randomization.  
 
l. 
Patients must not have any known allergy or reaction to any component of the 
investigational formulations.   
 
If there is a known allergy or reaction to standard of care formulations, patients 
must be able to safely receive at least one of the standard of care options. 
 
m. 
Patients must not have any Grade III/IV cardiac disease as defined by the New 
York Heart Association Criteria (i.e., patients with cardiac disease resulting in 
marked limitation of physical activity or resulting in inability to carry on any physical 
activity without discomfort), unstable angina pectoris, and myocardial infarction 
within six months prior to sub-study randomization, or serious uncontrolled cardiac 
arrhythmia (see S1800A Section 18.1).  
 
Patients must not have experienced any arterial thromboembolic events, including 
but not limited to myocardial infarction, transient ischemic attack, cerebrovascular 
accident, or unstable angina, within six months prior to sub-study randomization. 
 
n. 
Patients must not have documented evidence of acute hepatitis or have an active 
or uncontrolled infection. 
 
o. 
Patients with known human immunodeficiency virus (HIV) infection are eligible, 
provided they are on effective anti-retroviral therapy and have undetectable viral 
load at their most recent viral load test and within 6 months prior to randomization.  
 
p. 
Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible 
provided viral load is undetectable on suppressive therapy, if indicated. 
 
q. 
Patients with a history of hepatitis C virus (HCV) infection must have been treated 
and cured. For patients with HCV infection who are currently on treatment, they 
are eligible if they have an undetectable HCV viral load. 
 
r. 
Patients must not have undergone major surgery within 28 days prior to sub-study 
randomization, or subcutaneous venous access device placement within 7 days 
prior to randomization. Any patient with postoperative bleeding complications or 
wound complications from a surgical procedure performed in the last two months 
should be excluded. The patient must not have elective or planned major surgery 
to be performed during the course of the clinical trial. 
 
s. 
Patients must not have gross hemoptysis within two months of sub-study 
randomization (defined as bright red blood or ≥1/2 teaspoon) or with radiographic 
evidence of intratumor cavitation or has radiologically documented evidence of 
major blood vessel invasion or encasement by cancer. 
 
t. 
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease free for five years. 
 
u. 
Patients must not have been diagnosed with venous thrombosis less than 3 
months prior to randomization. Patients with venous thrombosis diagnosed more 
than 3 months prior to randomization must be on stable doses of anticoagulants.  


 
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v. 
Patients must not have any of following:  
• 
cirrhosis at a level of Child-Pugh B (or worse) (See Appendix 18.3); 
• 
cirrhosis (any degree) and a history of hepatic encephalopathy; or 
• 
clinically meaningful ascites resulting from cirrhosis. Clinically meaningful 
ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.  
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must have received at least one line of anti-PD-1 or anti-PD-L1 therapy 
for Stage III, IV or recurrent disease and at most one line of anti-PD-1 or anti-PD-
L1 therapy for Stage IV or recurrent disease, given alone or in combination with 
platinum-based chemotherapy, an anti-CTLA4 therapy, or other immune-
modulatory therapy. Patients must have experienced disease progression during 
or after this regimen. Disease progression during or after anti-PD-1 or anti-PD-L1 
therapy must have occurred more than (>) 84 days following initiation (Cycle 1 Day 
1) of anti-PD-1 or PD-L1 therapy (combination or monotherapy).  
 
Patients who received consolidation anti-PD-1 or anti-PD-L1 therapy following 
concurrent chemoradiation for Stage III disease as their only line of anti-PD-1 or 
anti-PD-L1 therapy, are eligible if they experienced disease progression more than 
(>) 84 days but less than (<) 365 days from their first date of anti-PD-1 or anti-PD-
L1 therapy.  
 
Patients must have been exposed to platinum-based chemotherapy for Stage IV 
or recurrent disease and experienced disease progression during or after this 
regimen, with the following exception: patients that received adjuvant platinum-
based chemotherapy post-surgical resection for Stage I-III disease meet this 
criterion if disease progression occurred within one year from the last dose that the 
patient received that therapy. 
 
Prior tyrosine kinase inhibitor therapy for patients with targetable alterations is 
allowed if criteria 5.2a above is also met.  
 
b. 
Patients must have progressed (in the opinion of the treating investigator) following 
the most recent line of therapy.  
 
c. 
Patients must not have received any prior systemic therapy (systemic 
chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-
study randomization. Patients must have recovered (≤ Grade 1) from any side 
effects of prior therapy, except for alopecia. Patients must not have received any 
radiation therapy within 14 days prior to sub-study randomization. (See Section 5.3 
for criteria regarding therapy for CNS metastases). 
 
d. 
Patients must not have received nitrosoureas or mitomycin-c within 42 days prior 
to sub-study randomization. 
 
e. 
Patients must not have received systemic treatment with corticosteroids (> 10 mg 
daily prednisone or equivalent) or other immunosuppressive medications within 
seven days prior to sub-study randomization. Inhaled or topical steroids, and 
adrenal replacement doses ≤ 10 mg daily prednisone or equivalent are permitted 
in the absence of active autoimmune disease. 
 
f. 
Patients must not have received a live attenuated vaccination within 28 days prior 
to sub-study randomization. (See Appendix 18.4) 
 
g. 
Patients must not be planning to receive any concurrent chemotherapy, 
immunotherapy, biologic or hormonal therapy for cancer treatment while receiving 


 
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treatment on this study. Concurrent use of hormones for non-cancer-related 
conditions (e.g., insulin for diabetes and hormone replacement therapy) is 
acceptable. 
 
h. 
Patients must not be receiving chronic antiplatelet therapy, including aspirin, 
nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and 
others), dipyridamole or clopidogrel, or similar agents within 7 days prior to 
randomization. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. 
 
i. 
Patient must not have received radiotherapy within 14 days before the first dose 
of study treatment or received lung radiation therapy of >30 Gy within 6 months 
before the first dose of study treatment. 
Note: Participants must have recovered from all radiation-related toxicities to 
Grade 1 or less, not require corticosteroids, and not have had radiation 
pneumonitis. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have measurable disease (see S1800A Section 10.1) documented 
by CT or MRI. The CT from a combined PET/CT may be used to document only 
non-measurable disease unless it is of diagnostic quality as defined in S1800A 
Section 10.1c. Measurable disease must be assessed within 28 days prior to sub-
study randomization. Pleural effusions, ascites and laboratory parameters are not 
acceptable as the only evidence of disease. Non-measurable disease must be 
assessed within 42 days prior to sub-study randomization. All disease must be 
assessed and documented on the Baseline Tumor Assessment Form. Patients 
whose only measurable disease is within a previous radiation therapy port must 
demonstrate clearly progressive disease (in the opinion of the treating investigator) 
prior to sub-study randomization. See S1800A Section 15.0 and LUNGMAP 
Section 15.6 for guidelines and submission instructions for required central 
radiology review. CT and MRI scans must be submitted for central review via 
TRIAD. 
 
b. 
Patients must have a CT or MRI scan of the brain to evaluate for CNS disease 
within 42 days prior to sub-study randomization. Patient must not have 
leptomeningeal disease, spinal cord compression or brain metastases unless: (1) 
metastases have been locally treated and have remained clinically controlled and 
asymptomatic for at least 14 days following treatment, and prior to sub-study 
randomization, AND (2) patient has no residual neurological dysfunction and has 
been off corticosteroids for at least seven days prior to sub-study randomization. 
 
c. 
Patients must be able to safely receive at least one of the investigator’s choice of 
standard of care regimens described in Section7.3a, per the current FDA-approved 
package insert(s). 
 
d. 
Patients must have an ANC ≥ 1,500/mcl, platelet count ≥ 100,000 mcl, and 
hemoglobin ≥ 9 g/dL obtained within 28 days prior to sub-study randomization. 
 
e. 
Patients must have adequate hepatic function as defined by serum bilirubin ≤ 
Institutional Upper Limit of Normal (IULN) and either ALT or AST ≤ 2 x IULN within 
28 days prior to sub-study randomization (if both ALT and AST are done, both must 
be < 2 IULN). For patients with liver metastases, bilirubin and either ALT or AST 
must be ≤ 5 x IULN (if both ALT and AST are done, both must be ≤ 5 x IULN). 
 
f. 
Patients must have a serum creatinine ≤ the IULN or calculated creatinine 
clearance ≥ 50 mL/min using the following Cockroft-Gault Formula. This specimen 


 
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must have been drawn and processed within 28 days prior to sub-study 
randomization. 
 
Calculated Creatinine Clearance = (140 - age) X (weight in kg†)  
    72 x serum creatinine* 
 
Multiply this number by 0.85 if the patient is a female.  
 
† The kilogram weight is the patient weight with an upper limit of 140% of the IBW. 
* Actual lab serum creatinine value with a minimum of 0.8 mg/ dL. 
 
Creatinine Calculator:  
https://crawb.crab.org/TXWB/CreatinineClearanceCalculator.aspx  
 
g. 
Patients’ urinary protein must be ≤1+ on dipstick or routine urinalysis (UA). 
Random analysis of urine protein with a normal value is sufficient. If urine dipstick 
or routine analysis indicated proteinuria ≥2+, then a 24-hour urine is to be collected 
and demonstrate <1000 mg of protein in 24 hours to allow participation in the study. 
 
h. 
Patients must not have a history of uncontrolled or poorly-controlled hypertension 
defined as SBP > 150 mmHg or DBP > 90 mmHg within 28 days prior to sub-study 
randomization. Patients are permitted to be receiving multiple anti-hypertensive 
medications (unless otherwise indicated in the study).  All blood pressure 
measurements within the 14 days prior to registration must be SBP < 150 and DBP 
< 90.  An exception can be made by a healthcare provider for a patient with a single 
blood pressure elevation who upon rechecking has a normal blood pressure.    
 
i. 
For patients where an International Normalized Ratio (INR) is clinically indicated, 
INR must be ≤ 1.5 seconds above the institutional upper limit of normal (IULN) 
(unless receiving anticoagulation therapy) documented within 28 calendar days 
prior to sub-study randomization. For patients where a partial thromboplastin time 
(PTT) is clinically indicated, PTT must be ≤ 5 seconds above the institutional upper 
limit of normal (IULN) (unless receiving anticoagulation therapy) documented 
within 28 calendar days prior to sub-study randomization. 
 
j. 
If receiving warfarin, the patient must have an INR ≤3.0. For warfarin, heparin and 
low molecular weight heparin (LMWH) there should be no active bleeding (that is, 
no bleeding within 14 days prior to first dose of protocol therapy) or pathological 
condition present that carries a high risk of bleeding (for example, tumor involving 
major vessels or known varices). 
 
k. 
Patients must have Zubrod performance status 0-1 (see S1800A Section 10.4) 
documented within 28 days prior to sub-study randomization. 
 
l. 
Pre-study history and physical exam must be obtained within 28 days prior to sub-
study randomization. 
 
m. 
Patients must not be pregnant or nursing. Women/men of reproductive potential 
must have agreed to use an effective contraceptive method during the study and 
4 months after completion of study treatment. A woman is considered to be of 
"reproductive potential" if she has had menses at any time in the preceding 12 
consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any 
point a previously celibate patient chooses to become heterosexually active during 
the time period for use of contraceptive measures outlined in the protocol, he/she 


 
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is responsible for beginning contraceptive measures during the study and 4 
months after study completion. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must agree to have blood specimens submitted for circulating tumor DNA 
(ctDNA) as outlined in Section 15.3. 
 
b. 
Patients must also be offered participation in banking and in the correlative studies 
for collection and future use of specimens as described in S1800A Section 15.0.  
 
5.5 
Regulatory Criteria 
 
a. 
As a part of the OPEN registration process (see LUNGMAP Section 13.4 for OPEN 
access instructions) the treating institution's identity is provided in order to ensure 
that the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 
b. 
Patients with impaired decision-making capacity are eligible as long as their 
neurological or psychological condition does not preclude their safe participation 
in the study (e.g., tracking pill consumption and reporting adverse events to the 
investigator). 
 
c. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Randomization between treatment arms will be performed using a dynamic balancing algorithm.   
 
Randomization will be stratified based on the following factors: 
 
a. 
PD-L1 Status 
 
1. 
negative (<1%) versus; 
 
2. 
positive (>= 1%) or unknown PD-L1 status 
 
Provided by PD-L1 testing performed at FMI as part of the LUNGMAP screening protocol 
unless patient was screened under the S1400 (legacy screening/pre-screening study). The 
S1400 patients must have had prior PD-L1 testing by the Dako 22C3 PharmDx IHC assay 
and must have results available for stratifying.  
 
b. 
Histology  
 
1. 
Patients with squamous cell lung cancer, including mixed histology with any 
squamous component. 
 
2. 
Patients with non-squamous cell lung cancer (adenocarcinoma, large cell, NSCLC 
NOS). 
 
c. 
If patient is randomized to standard of care arm, does the planned treatment include 
ramucirumab?  
_ Yes 
_ No  


 
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7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Drs. Karen L. Reckamp and 
Konstantin H. Dragnev at S1800AMedicalQuery@swog.org.  For dosing principles or questions, 
please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at 
https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf.  
 
7.1 
Disease Assessment 
 
See Section 9.0 for disease assessment time points. Disease assessment timing is to be 
based on calendar timing counted as weeks after registration, not based on cycles or drug 
administration. 
 
Disease Assessment During Treatment 
• 
For patients on Arm A: CT or MRI (the same method used at pre-study to meet the 
eligibility criteria in Section 5.3) must be repeated every 6 weeks (± 7 day window), 
for the first year regardless of treatment delays, then every 12 weeks until disease 
progression. The 6 weeks should start from Cycle 1 Day 1. 
 
• 
For patients on Arm B: CT or MRI (the same method used at pre-study to meet the 
eligibility criteria in Section 5.3) must be repeated every 6 weeks (± 7 day window), 
for the first year regardless of treatment delays, then every 12 weeks until disease 
progression and discontinuation of protocol treatment. The 6 weeks should start 
from Cycle 1 Day 1. 
 
Pre-study Brain CT/MRI is required 42 days prior to randomization per Section 5.3. If 
patient has brain metastases at baseline, scans must use the same modality as baseline 
and be repeated every 12 weeks (± 7 day window) while on treatment. 
Disease Assessment During Off Protocol Treatment, Prior to Progression 
After off protocol treatment prior to progression, disease assessments must continue every 
12 weeks (± 7 day window) until progression. 
 
If patient has brain metastases at baseline, continue brain CT or MRI scans (same modality 
as baseline) after off protocol treatment prior to progression, as clinically indicated.  For 
alignment with the protocol and good clinical practice, recommended frequency of brain 
scans after off protocol treatment (and prior to progression) is at least every 12 weeks, 
unless more frequent scans are clinically appropriate.  
 
7.2 
Pre-Medication and Supportive Care 
 
Pre-medication associated with standard drug administration and supportive care 
(including anti-diarrheals, antibiotics, diuretics, growth factors, or other medications) may 
be given as indicated by the current American Society of Clinical Oncology (ASCO) 
guidelines. 
 
Pre-medication with a histamine H1 antagonist is recommended prior to infusion of 
ramucirumab. Recommended premedication agents include an intravenous histamine H1 
antagonist such as diphenhydramine hydrochloride (or equivalent). Additional 
premedication may be provided at investigator discretion.  
 
For patients who have experienced a Grade 1 or 2 infusion-related reaction, pre-medication 
antihistamine (e.g. diphenhydramine) in addition to dexamethasone and acetaminophen 
may be used prior to infusion on subsequent infusions. Dosing and administration route of 
pre-medications may be given per institutional policy. 
 


 
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Intranasal and inhaled corticosteroids are allowed during protocol therapy. Corticosteroids 
to manage immune-related adverse events during protocol therapy will be permitted. 
 
7.3 
Treatments 
 
Patients will be randomized to one of the following treatment arms: 
 
Arm A:  Investigator’s Choice of Standard of Care  
 
Arm B:  Ramucirumab plus Pembrolizumab (MK-3475) 
 
a. 
Arm A: Investigator’s Choice of Standard of Care 
Treating Investigator and patient will choose the appropriate SoC drug (docetaxel, 
gemcitabine, pemetrexed, or ramucirumab plus docetaxel) based on patient’s 
previous therapy and disease.  
 
Note: 
• 
Pemetrexed is only FDA-approved for non-squamous cell NSCLC.  
• 
Patients who take docetaxel or ramucirumab plus docetaxel, must have 
adequate hepatic function per the current FDA-approved package insert.  
• 
Women of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to Cycle 1 Day 1. 
 
1. 
Docetaxel 
 
Agent 
Dose 
Route 
Day 
Schedule* 
 
 
 
 
 
Dexamethasone 
8 mg 
BID ** 
Oral, 
beginning 
24 hours 
prior to 
docetaxel 
Day 0-2 
Q 21 days 
 
 
 
 
 
Docetaxel 
75 mg/m2 
IV 
Day 1 
Q 21 days 
 
* NOTE: A cycle of treatment is 21 days.  Disease assessment must occur 
every 6 weeks.  Treatment will continue until any criteria in Section 7.3 
is met. 
 
**Dexamethasone may be administered per local institutional guidelines. 
Recommended dose listed above. 
 
2. 
Gemcitabine hydrochloride  
 
Agent 
Dose 
Route 
Day 
Schedule* 
 
 
 
 
 
Gemcitabine 
1000 
mg/m2 
IV  
30 (± 5) 
minutes 
Days 1, 8 
Q 21 days 
 
 
 
 
 
 
* NOTE: A cycle of treatment is 21 days.  Disease assessment must occur 
every 6 weeks.  Treatment will continue until any criteria in Section 7.3 
is met. 
 
3. 
Pemetrexed * 
 


 
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Agent 
Dose 
Route 
Day 
Schedule* 
Folic Acid 
400-1000 
mcg 
Oral,  
Daily; beginning 7 
days before  
first 
dose 
of 
pemetrexed and  
continuing until 4 
weeks after the  
last 
dose 
of 
pemetrexed 
 
 
 
 
 
Vitamin B12  
1 mg ** 
Intramuscular 
Day 
-7 
Q 63 days 
(every 3rd 
cycle) 
 
 
 
 
 
Dexamethasone 
4 mg BID** 
Oral, 
beginning 24 
hours prior to 
pemetrexed 
Day 
0-2 
Q 21 days 
 
 
 
 
 
Pemetrexed 
500 mg/m2 
IV 10 
minutes 
Day 
1 
Q 21 days 
 
NOTES:  
 
* Pemetrexed is not FDA-approved for squamous cell NSCLC and should 
not be used to treat patients with squamous cell NSCLC.  
  
 A cycle of treatment is 21 days.  Disease assessment must occur every 
6 weeks.  Treatment will continue until any criteria in Section 7.3 is met. 
 
** Dexamethasone and Vitamin B12 may be administered per local 
institutional guidelines.  Recommended dose listed above.  
4. 
Ramucirumab plus Docetaxel 
 
Agent 
Dose 
Route 
Day 
Schedule b 
 
 
 
 
 
Ramucirumab a 
10 mg/kg 
IV over 30-
60 minutes d 
Day 1 
Q 21 days 
 
 
 
 
 
Dexamethasone 
8 mg 
BID c 
Oral, 
beginning 
24 hours 
prior to 
docetaxel 
Day 0-2 
Q 21 days 
 
 
 
 
 
Docetaxel 
75 mg/m2 e 
IV 
Day 1 
Q 21 days 
 
NOTES:  
 
a Pre-medication with a histamine H1 antagonist is recommended prior to 
infusion of ramucirumab. Recommended premedication agents include 
an intravenous histamine H1 antagonist such as diphenhydramine 
hydrochloride (or equivalent). Additional premedication may be provided 
at investigator discretion.  
 
b  A cycle of treatment is 21 days.  Disease assessment must occur every 
6 weeks.  Treatment will continue until any criteria in Section 7.3 is met. 


 
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c  Dexamethasone may be administered per local institutional guidelines.  
Recommended dose listed above. 
d Ramucirumab will be administered over an approximately 60-minute 
intravenous (IV) infusion. If the first infusion is tolerated, all subsequent 
ramucirumab infusions may be administered over 30 minutes. Please 
refer to the package insert for the administration of ramucirumab 
 The actual doses of ramucirumab administered will be determined by 
measuring the patient's weight at the beginning of each cycle. If the 
patient’s weight fluctuates by more than 10% from the weight used to 
calculate the dose at baseline, the dose must be recalculated using the 
most recent weight and this weight will become the baseline weight 
going forward. Recalculation of the ramucirumab dose for weight 
fluctuations of <10% is permitted but not required. 
e Docetaxel may be administered per local institutional guidelines.  
Recommended dose listed above, but the use of a starting dose of 60 
mg/m2 is allowed at treating investigator’s discretion.  Ramucirumab is 
administered prior to docetaxel consistent with FDA-approved package 
labeling for ramucirumab. Per a study noted in the ramucirumab 
package insert “Due to an increased incidence of neutropenia and febrile 
neutropenia in patients enrolled in East Asian sites, Study 3 was 
amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo 
plus docetaxel) at East Asian sites received a starting dose of docetaxel 
at 60 mg/m every 3 weeks.”  Sites should provide a justification in the 
patient’s chart for using a starting dose of docetaxel at 60 mg/m2.  
 
 


 
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b. 
Arm B: Ramucirumab plus Pembrolizumab (MK-3475) 
 
Note that women of childbearing potential must have a negative serum pregnancy 
test within 7 days prior to Cycle 1 Day 1. 
 
Agent 
Dose 
Route 
Day 
Schedule b 
 
 
 
 
 
Ramucirumab a  
10 mg/kg 
IV over 30-60 
minutes c 
Day 1 
Q 21 days 
 
 
 
 
 
Pembrolizumab 
(MK-3475) 
200 mg 
IV over 30 
minutes 
Day 1 
Q 21 days or up to 
35 cycles without 
disease 
progression 
 
NOTES:  
 
a Pre-medication with a histamine H1 antagonist is recommended prior to infusion 
of ramucirumab. Recommended premedication agents include an intravenous 
histamine H1 antagonist such as diphenhydramine hydrochloride (or equivalent). 
Additional premedication may be provided at investigator discretion.  
 
b  A cycle of treatment is 21 days.  Disease assessment must occur every 6 weeks.  
Treatment will continue until any criteria in Section 7.3 is met. 
 
c   Ramucirumab will be administered prior to pembrolizumab (MK-3475), over an 
approximately 60-minute intravenous (IV) infusion. If the first infusion is 
tolerated, all subsequent ramucirumab infusions may be administered over 30 
minutes. Please refer to the package insert for the administration of 
ramucirumab.  
 
 The actual doses of ramucirumab administered will be determined by measuring 
the patient's weight at the beginning of each cycle. If the patient’s weight 
fluctuates by more than 10% from the weight used to calculate the dose at 
baseline, the dose must be recalculated using the most recent weight and this 
weight will become the baseline weight going forward. Recalculation of the 
ramucirumab dose for weight fluctuations of < 10% is permitted but not required.  
 
 
 Pembrolizumab (MK-3475) 200 mg (fixed dose) will be administered over a 30-
minute IV infusion. Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window between -5 minutes and +10 minutes is 
permitted (that is, infusion time is between 25 and 40 minutes).  
 
 The first 2 cycles will require a 1-hr observation period i) between ramucirumab 
and pembrolizumab (MK-3475) administration, and ii) after pembrolizumab (MK-
3475) infusion. For all cycles thereafter, no observation period will be required 
unless clinically indicated. 
 
 Patients will receive 35 cycles of pembrolizumab (MK-3475). Maintenance 
ramucirumab may continue for patients past 35 cycles until reaching a 
discontinuation criterion (Section 7.3), as long as the participant is receiving 
benefit. 
 


 
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7.4 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease as defined in Section 10.2 in S1800A.  However, a 
patient on Arm B may continue protocol treatment as long as the patient is 
continuing to clinically benefit from treatment in the opinion of the treating 
investigator. Patients should still be removed from protocol treatment for criteria 
below. 
 
* Upon progression, the Request for New Sub-Study Assignment Form may be 
submitted under the patient’s screening (LUNGMAP or S1400) to receive a new 
sub-study assignment (see Section 14.0). 
 
b. 
Symptomatic deterioration (as defined in Section 10.2 of S1800A). 
 
c. 
Unacceptable toxicity. 
 
d. 
Treatment delay for any reason > 84 days (or as noted in Section 8.0) 
 
e. 
The patient may withdraw from this study at any time for any reason. 
 
7.5 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Protocol 
Treatment Notice. 
 
7.6 
Follow-Up Period 
 
All patients will be followed until death or 3 years after sub-study randomization, whichever 
occurs first. 
 
Note: Patients who enroll on a new sub-study following progression must continue follow-
up on this sub-study, in addition to follow-up on the new sub-study. 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
8.2 
General Considerations 
 
a. 
Patients on Arm B will receive pembrolizumab (MK-3475) for up to 35 cycles. 
 
b. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
c. 
Dose reductions are allowed on ramucirumab only. Dose re-escalations are not 
allowed. 
 
d. 
Dose interruptions and discontinuations are allowed to manage toxicity.  If the 
toxicity is clearly related to only one of the drugs, the other agent may be continued. 
If the relationship cannot be established, there should be an option to hold both. 
 


 
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e. 
If one drug is discontinued due to toxicity, patient may remain on other study drugs 
as long as the remaining therapy is well tolerated and according to the treating 
physician the patient is still deriving clinical benefit.   
 
f. 
The maximum dose delay for any reason is 84 days. 
 
8.3 
Dose Modifications for Chemotherapy 
 
Treatment and dose modifications are at the discretion of the treating investigator. 
 
NOTE: Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be 
used to treat patients with squamous cell NSCLC.  
8.4 
Dose Modifications for Ramucirumab 
 
Dose modifications should be made based on the observed toxicity, as 
summarized in the tables below.  
 
Table 1: Dose Reductions for Ramucirumab 
 
DRUG 
DOSE LEVEL 
DOSE 
 
Ramucirumab 
Full 
10 mg/kg 
 
-1 Level 
8 mg/kg 
 
-2 Level 
6 mg/kg 
 
-3 Level 
5 mg/kg 
 
-4 Level  
Discontinue 
 
 
Note: Once a dose reduction is applied, the reduced dose is maintained unless 
further dose reduction is needed. 
 
 
 


 
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Table 2: Dose Interruptions for Ramucirumab 
Toxicity 
Grade 
Dose 
Interruptions 
Toxicity Management 
Infusion-
Related 
Reactions 
Any Grade 
 
Manage per institutional standard 
at the discretion of treating 
investigator. 
Monitor patients for signs and 
symptoms of infusion-related 
reactions (e.g., fever and/or 
shaking chills, flushing and/or 
itching, alterations in heart rate 
and blood pressure, dyspnea or 
chest discomfort, skin rashes 
etc.) and anaphylaxis (e.g., 
generalized urticaria, 
angioedema, wheezing, 
hypotension, tachycardia, etc.). 
< Grade 2 
The infusion rate 
of study 
drug/study 
regimen may be 
decreased by 
50% or 
temporarily 
interrupted until 
resolution of the 
event. 
Subsequent 
infusions may be 
given at 50% of 
the initial infusion 
rate. 
Acetaminophen and/or 
antihistamines may be 
administered per institutional 
standard at the discretion of the 
investigator. 
 
Consider premedication per 
institutional standard prior to 
subsequent doses.  
 
 
> Grade 3 
Permanently 
discontinue 
ramucirumab. 
Manage severe infusion-related 
reactions per institutional 
standards (e.g., IM epinephrine, 
followed by IV diphenhydramine 
and ranitidine, and IV 
glucocorticoid). 
 
 
Table 3: Dose Modifications for Ramucirumab 
Toxicity 
Grade 
Dose Modifications 
Hypertension 
Grade 1 
No dose modification. Consider 
increased BP monitoring; start 
anti-hypertensive medication if 
appropriate. 
Grade 2 Asymptomatic 
No dose modification. Begin 
anti-hypertensive therapy and 
continue ramucirumab. 
 
Grade 2 Symptomatic 
Hold ramucirumab until 
symptoms resolve. Start or 
adjust anti-hypertensive 
medication. 
 


 
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Toxicity 
Grade 
Dose Modifications 
Grade 3 
Hold ramucirumab until 
resolution of symptoms and 
returns to Grade 2. 
Grade 4 
Permanently discontinue 
ramucirumab. 
 
Hypothyroidism 
Grade 2-4 
No dose modification. Therapy 
with ramucirumab can be 
continued while treatment for 
the thyroid disorder is instituted. 
 
 
Impaired Wound Healing 
Prior to planned 
surgery 
Withhold ramucirumab 28 days 
prior.. 
After surgery 
Do not administer ramucirumab 
for at least 14 days following 
major surgical procedure and 
until adequate wound healing.  
The safety of resumption after 
resolution of wound healing has 
not been established. 
Wound-healing 
complications 
developed during 
study treatment 
Do not administer ramucirumab 
for at least 14 days following 
major surgical procedure and 
until adequate wound healing.  
The safety of resumption after 
resolution of wound healing has 
not been established. 
 
Proteinuria 
Grade 1 
No dose modification. 
Grade 2 
2+ proteinuria on urine 
dipstick 
Check 24-hour urine protein 
levels.   
• 
If > 2 gram/24 hours, hold 
ramucirumab until 
resolution to < 2 gram/24 
hours.  Restart 
ramucirumab at the next 
lower dose.   
• 
If the protein level ≥2 g/24 
hours reoccurs, interrupt 
ramucirumab and reduce 
the dose to the next lower 
level once the urine protein 
level returns to <2 g/24 
hours. 
> Grade 3 
> 3.5 gram/24 hours 
Permanently discontinue 
ramucirumab. If patient 
experiences nephrotic 
syndrome, permanently 
discontinue ramucirumab. 
 
Non-life threatening and 
reversible 
Grade 3 
Hold ramucirumab until 
resolved to Grade 0-1. 


 
S1800A 
 
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Version Date 8/4/2022 
Toxicity 
Grade 
Dose Modifications 
• If resolved to Grade 0-1, may 
reduce ramucirumab by one 
dose level. 
If NOT resolved to Grade 0-1 
within 21 days, discontinue 
ramucirumab at treating 
investigator’s discretion. 
 
Other Adverse Events 
Grade 4 
Permanently discontinue 
ramucirumab immediately, with 
the exception of Grade 4 fever 
or Grade 4 laboratory 
abnormality, in which case: 
First occurrence: Delay 
ramucirumab until resolved to 
Grade 0-1. 
• If resolved to Grade 0-1, may 
resume ramucirumab original 
dose at the discretion of the 
treating investigator. 
• If NOT resolved to Grade 0-1 
within 21 days, discontinue 
ramucirumab at treating 
investigator’s discretion. 
Second occurrence: Delay 
ramucirumab until resolved to 
Grade 0-1.  
• If resolved to Grade 0-1, 
reduce ramucirumab by one 
dose level. 
If NOT resolved to Grade 0-1 
within 21 days, discontinue 
ramucirumab at treating 
investigator’s discretion. 
 
 
Table 4: Dose Discontinuations for Ramucirumab 
Toxicity 
Grade 
Dose Discontinuation 
Arterial Thromboembolic 
Events,  
Any Grade 
Permanently discontinue 
ramucirumab. 
Gastrointestinal Perforation 
Any Grade 
Permanently discontinue 
ramucirumab. 
Gastrointestinal 
Hemorrhage/Bleeding 
≥ Grade 3 
Permanently discontinue 
ramucirumab. 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
Any Grade 
Permanently discontinue 
ramucirumab. 
 
Congestive heart failure 
≥ Grade 3 
Permanently discontinue 
ramucirumab. 
 


 
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Version Date 8/4/2022 
Liver injury/liver failure or 
Hepatic encephalopathy 
and/or hepatorenal syndrome 
resulting from liver cirrhosis 
Any Grade 
Permanently discontinue 
ramucirumab. 
 
Fistula formation 
Any Grade 
Permanently discontinue 
ramucirumab. 
 
 
8.5 
Dose Modifications for Pembrolizumab (MK-3475) 
 
Adverse events (both non-serious and serious) associated with pembrolizumab (MK-3475) 
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 one 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. 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 the 
following tables. 
 
NOTE: Due to the possible effect of treatment with pembrolizumab (MK-3475)on the 
immunologic response to infectious disease vaccines, patients must not have had any 
infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, 
meningococcal, 
tetanus 
toxoid) 
1 
week 
before 
or 
after 
any 
dose 
of pembrolizumab (MK-3475). 


 
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Table 1: Dose Interruptions for Pembrolizumab (MK-3475) 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive 
treatment should begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 
weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
 
Toxicity 
 
Grade 
(CTCAE V5.0) 
 
Action with 
Pembrolizumab 
irAE Management with 
corticosteroids and/or other 
therapies 
Monitor and follow-up 
Diarrhea/ 
Colitis 
Grade 2 or 3 
 
Withhold  
 
• 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. 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
 
AST or ALT 
evaluation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5-1 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) 
Grade 3 b or 4 c 
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 


 
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Toxicity 
 
Grade 
(CTCAE V5.0) 
 
Action with 
Pembrolizumab 
irAE Management with 
corticosteroids and/or other 
therapies 
Monitor and follow-up 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of β-cell failure 
Withhold d  
• 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. 
 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated   
• Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
 
Hyperthyroidis
m  
Grade 2 
Continue 
• Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate 
• Monitor for signs and symptoms of thyroid disorders  
 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d  
 
Hypothyroidism  
Grade 2, 3, 4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care. 
• Monitor for signs and symptoms of thyroid disorders  
 
 
Myocarditis 
Grade 1 or 2 
Withhold  
• Based on severity of AE 
administer corticosteroids 
 
• Ensure adequate evaluation to confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
 


 
S1800A 
 
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Version Date 8/4/2022 
Toxicity 
 
Grade 
(CTCAE V5.0) 
 
Action with 
Pembrolizumab 
irAE Management with 
corticosteroids and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
•  Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics 
for opportunistic infections 
• 
Monitor participants for signs and symptoms of pneumonitis 
• 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue  
 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1 – 2 mg/kg or 
equivalent) followed by 
taper. 
• 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
 
All Other 
Immune Related 
AEs 
Persistent 
Grade 2 
Withhold 
• Based on type and severity 
of AE administer 
corticosteroids. 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes. 
Grade 3  
Withhold or 
discontinue  
based on the 
event e  
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x 
baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or 
≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal 
necrolysis. 
 


 
S1800A 
 
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8.6 
Dose Modification Contacts   
 
For treatment or dose modification questions, please contact Drs. Karen L. Reckamp and 
Konstantin H. Dragnev at S1800AMedicalQuery@swog.org.  For dosing principles or 
questions, please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical 
Trials" at  
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 
8.7 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 


 
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9.0 
STUDY CALENDAR 
 
9.1  
Arm A: Investigator’s Choice of Standard of Care 
 
  
PRE-STUDY 
(w/in 28 days 
prior to 
randomization, 
unless 
otherwise 
noted) 
Cycle Length = 21 days 
(+/- 3 days) 
At Off Tx 
Off Tx FU Prior to 
Prog  
Off Tx FU After 
Prog 7  
 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles 5 
PHYSICAL 
History & Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 6 
  
Weight & 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 6 
  
Vital Signs 
(BP, HR, Temp) 
X 
  
  
  
  
  
  
  
  
Toxicity Notation 
  
X 
X 
X 
X 
X 
X 
X 9 
X 9 
Smoking Status 
Assessment 
X 
  
  
  
  
  
X 
  
  
LABORATORY 
  
If labs obtained w/in 14 days 
prior to tx, tests need not be 
repeated on C1D1, unless 
otherwise noted. 
Up to 48 hours prior to Day 1 tx 
  
  
  
CBC/Diff/Platelets/ 
Hgb 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
Serum Bilirubin 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
ALT or AST 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
Serum 
Creatinine/Calc 
CrCl 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
 
INR and PTT 17 
X  
(w/in 28 days 
prior to 
randomization) 
 
 
 
 
 
 
 
 
TSH w/ Reflex to 
Free T4 
 X 18 
 
 
 
X 18 
X 18 
(every 3rd 
cycle) 
 
X 9 
X 9 
Urine Protein 
Check 
X 
 
X 13 
X 13 
X 13 
X 13 
 
X 9 
X 9 


 
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Version Date 8/4/2022 
 
  
PRE-STUDY 
(w/in 28 days 
prior to 
randomization, 
unless 
otherwise 
noted) 
Cycle Length = 21 days 
(+/- 3 days) 
At Off Tx 
Off Tx FU Prior to 
Prog  
Off Tx FU After 
Prog 7  
 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles 5 
 
HIV viral load test 
19 
X 
(within 6 
months) 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test 
  
X 4 
(w/in 7 
days prior 
to C1D1) 
  
  
  
  
  
  
  
X-RAYS & SCANS 
CT or MRI for 
Disease 
Assessment  
X 
  
  
X 1  
  
X 1  
  
X 6  
  
Brain CT/MRI 2 
X 
  
  
  
  
X 2  
  
X 2  
  
SPECIMEN SUBMISSION 
Whole Blood - 
ctDNA 
 
X 14 
(pre-tx)  
  
  
  
  
  
  
X 14 
Buffy Coat 
/Plasma for 
Banking 8 
X8 
(pre-tx) 
  
X 8 
X 8 
X 8 
  
  
  
X 8 
Arm A Treatment Choices      
(21 day cycle) 
Choice 1 
Dexamethasone 
10 
  
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
  
  
  
Docetaxel 
  
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
  
  
  
 
 Choice 2 


 
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Version Date 8/4/2022 
 
  
PRE-STUDY 
(w/in 28 days 
prior to 
randomization, 
unless 
otherwise 
noted) 
Cycle Length = 21 days 
(+/- 3 days) 
At Off Tx 
Off Tx FU Prior to 
Prog  
Off Tx FU After 
Prog 7  
 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles 5 
Gemcitabine 11 
  
X  
(Days 1 
and 8) 
X  
(Days 1 
and 8) 
X  
(Days 1 
and 8) 
X  
(Days 1 
and 8) 
X  
(Days 1 
and 8) 
  
  
  
 Choice 3 – Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC. 
 
Folic Acid 16 
 
X  
(7 days 
prior to tx) 
X  
(7 days 
prior to tx) 
X  
(7 days 
prior to tx) 
X  
(7 days 
prior to tx) 
X  
(7 days 
prior to tx) 
X  
(until 4 
wks after 
last dose) 
 
 
Vitamin B12  12 
  
X  
(7 days 
prior to tx) 
 
 
X  
(7 days 
prior to tx) 
X  
(7 days 
prior to tx) 
  
  
  
Dexamethasone 
10 
  
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
  
  
  
Pemetrexed 15 
  
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
  
  
  
Choice 4 
Ramucirumab  
  
X  
(Day 1) 
X  
(Day 1) 
X  
(Day 1) 
X  
(Day 1) 
X  
(Day 1) 
  
  
  
 
Dexamethasone 
10 
  
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
X  
(Days 0-2) 
 
 
 
Docetaxel 
  
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
X 
(Day 1) 
  
  
  
NOTE:  Forms are found on the CTSU website (www.ctsu.org).  Forms submission guidelines are found in Section 14.0. 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2019-07/BestPracticesupdate.pdf 
 
 
 
 


 
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Footnotes for Calendar Arm A: Investigator’s Choice of Standard of Care 
1 
CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3 of S1800A) must be repeated every 6 weeks (± 7 day window), 
for the first year regardless of treatment delays, then every 12 weeks until disease progression and discontinuation of protocol treatment. The 6 weeks should 
start from Cycle 1 Day 1. See Sections 5.3 and 7.1 for additional details.  
2 
Brain CT/MRI is required per Sections 5.3 and 7.1. If patient has brain metastases at baseline, scans must use the same modality as baseline and be repeated 
every 12 weeks (+/- 7 days) while on treatment. If patient has brain metastases at baseline, continue brain CT or MRI scans (same modality as baseline) after 
off protocol treatment prior to progression, as clinically indicated.  For alignment with the protocol and good clinical practice, recommended frequency of brain 
scans after off protocol treatment (and prior to progression) is at least every 12 weeks, unless more frequent scans are clinically appropriate. 
3 
If the pre-study tests are obtained within 14 days prior to treatment, tests need not be repeated on Cycle 1 Day 1. 
4 
Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1. 
5 
During continued treatment, items marked under physical and laboratory should be performed prior to every subsequent cycle unless otherwise noted.  
Disease assessments and image submission are to take place every 6 weeks (± 7 days) regardless of treatment delays. Treatment and evaluation will 
continue until any one of the criteria in Section 7.3 S1800A is met. 
6 
After off protocol treatment prior to progression, patients should be followed by repeating indicated studies every 12 weeks or more often as clinically indicated 
until progression. Disease assessments should continue per Section 7.1. 
7 
After off protocol treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 6 
months for 2 years then at end of year 3 from date of randomization.  
8 
With patient's consent, additional research blood for banking will be collected at pre-study (prior to treatment initiation), on weeks 4, 7, and 10, and at first 
progression (defined in Section 10 of S1800A) after study treatment (see Section 15.0 of S1800A). First progression blood should be collected by the time of 
the next visit after documenting progression and prior to starting any non-protocol therapy. 
9 
Assessments should continue if clinically indicated and until resolution of all acute adverse events. 
10 
Dexamethasone should be given twice daily the day before, the day of, and the day after therapy, per institutional guidelines. 
11 
Gemcitabine must be given on Days 1 and 8 of every cycle per Section 7.2 
12 
Vitamin B12 should be given one week prior to pemetrexed every 3rd cycle. 
13 
Urine protein should be performed throughout treatment as clinically indicated.  
14 
ctDNA must be collected per Section 15.3.  First progression blood should be collected by the time of the next visit after documenting progression and prior 
to starting any non-protocol therapy. Note: Kits must be ordered and will take up to 3 days to arrive. 
15 
Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC.  
16 
Folic Acid should be given daily beginning 7 days prior to first dose of pemetrexed until 4 weeks after last dose of pemetrexed. 
17 
INR and PTT should be performed if clinically indicated, per Section 5.3i.  
18 
For all patients: As clinically indicated, collect TSH pre-study and every 3rd cycle while on treatment to monitor for late endocrine toxicity from prior immune 
checkpoint inhibitor therapy. For patients receiving ramucirumab:,  Collect TSH pre-study, if clinically indicated.  While on treatment, monitor thyroid function 
every 3rd cycle. For all patients: If TSH is abnormal, reflex to Free T4 and other work up per investigator discretion. See Section 8.4 for ramucirumab dose 
modifications.  
19 
See Section 5.1 for details. 


 
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9.2 
Arm B: Ramucirumab plus Pembrolizumab (MK-3475) 
 
  
PRE-STUDY 
(w/in 28 days 
prior to 
randomization, 
unless 
otherwise noted) 
Cycle Length = 21 days 
(+/- 3 days) 
At Off Tx 
Off Tx FU Prior to 
Prog  
Off Tx 
FU After 
Prog 7  
 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles 5 
PHYSICAL 
History & Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 6 
  
Weight & 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 6 
  
Vital Signs 
(BP, HR, Temp) 
X 
 X 
 X 
 X 
 X 
 X 
  
  
  
Toxicity Notation 
  
X 
X 
X 
X 
X 
X 
X 9 
X 9 
Smoking Status 
Assessment 
X 
  
  
  
  
  
X 
  
  
LABORATORY 
  
If labs obtained w/in 14 days 
prior to tx, tests need not be 
repeated on C1D1. 
Up to 48 hours prior to Day 1 tx 
  
  
  
CBC/Diff/Platelets/ 
Hgb 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
Serum Bilirubin 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
ALT or AST 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
Serum 
Creatinine/Calc CrCl 
X 
X 3 
X 
X 
X 
X 
X 
X 9 
X 9 
 
INR and PTT 12 
X 
(w/in 28 days 
prior to 
randomization) 
 
 
 
 
 
 
 
 
 TSH w/ Reflex to 
Free T4 
 X 13 
 
 
 
X 13 
X 13 
(every 3rd 
cycle)  
 
X 9 
X 9 
Urine Protein Check 
X 
 
X 10 
X 10 
X 10 
X 10 
 
X 9 
X 9 


 
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Version Date 8/4/2022 
 
  
PRE-STUDY 
(w/in 28 days 
prior to 
randomization, 
unless 
otherwise noted) 
Cycle Length = 21 days 
(+/- 3 days) 
At Off Tx 
Off Tx FU Prior to 
Prog  
Off Tx 
FU After 
Prog 7  
 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles 5 
 
HIV viral load test 14 
X 
(within 6 
months) 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test 
  
X 4 
(w/in 7 
days prior 
to C1D1) 
  
  
  
  
  
  
  
X-RAYS & SCANS 
CT or MRI for 
Disease Assessment  
X 
  
  
X 1  
  
X 1  
  
X 6  
  
Brain CT/MRI 2 
X 
  
  
  
  
X 2  
  
X 2  
  
SPECIMEN SUBMISSION 
Whole Blood - ctDNA 
 
 X 11 
(pre-tx) 
  
  
  
  
  
  
 X 11 
Buffy Coat /Plasma 
for Banking 8 
X8 
(pre-tx) 
  
X 8 
X 8 
X 8 
  
  
  
X 8 
Arm B Treatment 
(21 day cycle) 
Ramucirumab  
  
X  
X  
X  
X  
X  
  
  
  
Pembrolizumab (MK-
3475) 
  
X 
X 
X 
X 
X 
(up to 35 
cycles) 
  
  
  
 
 
 


 
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Version Date 8/4/2022 
NOTE:  Forms are found on the CTSU website (www.ctsu.org).  Forms submission guidelines are found in Section 14.0. 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment 
for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines 
as outlined in https://www.swog.org/sites/default/files/docs/2019-07/BestPracticesupdate.pdf 
 
Footnotes for Calendar Arm B: Ramucirumab plus Pembrolizumab (MK-3475) 
1 
CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3 of S1800A) must be repeated every 6 weeks (± 7 day window), 
for the first year regardless of treatment delays, then every 12 weeks until disease progression and discontinuation of protocol treatment. The 6 weeks 
should start from Cycle 1 Day 1. See Sections 5.3 and  7.1 for additional details. 
2 
Brain CT/MRI is required per Sections 5.3 and 7.1. If patient has brain metastases at baseline, scans must use the same modality as baseline and be 
repeated every 12 weeks (+/- 7 days) while on treatment. If patient has brain metastases at baseline, continue brain CT or MRI scans (same modality as 
baseline) after off protocol treatment prior to progression, as clinically indicated.  For alignment with the protocol and good clinical practice, recommended 
frequency of brain scans after off protocol treatment (and prior to progression) is at least every 12 weeks, unless more frequent scans are clinically 
appropriate. 
3 
If the pre-study tests are obtained within 14 days prior to treatment, tests need not be repeated on Cycle 1 Day 1. 
4 
Women of child bearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1. 
5 
During continued treatment, items marked under physical and laboratory should be performed prior to every subsequent cycle unless otherwise noted.  
Disease assessments and image submission are to take place every 6 weeks (± 7 days) regardless of treatment delays. Treatment and evaluation will 
continue until any one of the criteria in Section 7.3 S1800A is met. 
6 
After off protocol treatment prior to progression, patients should be followed by repeating indicated studies every 12 weeks or more often as clinically 
indicated until progression. Disease assessments should continue per Section 7.1.  
7 
After off protocol treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 6 
months for 2 years then at end of year 3 from date of randomization.  
8 
With patient's consent, additional research blood for banking will be collected at pre-study (prior to treatment initiation), on weeks 4, 7, and 10, and at first 
progression (defined in Section 10 of S1800A) after study treatment (see Section 15.0 of S1800A). First progression blood should be collected by the 
time of the next visit after documenting progression and prior to starting any non-protocol therapy. 
9 
Assessments should continue if clinically indicated and until resolution of all acute adverse events. 
10 
Urine protein should be performed throughout treatment as clinically indicated. 
11 
ctDNA must be collected per Section 15.3.  First progression blood should be collected by the time of the next visit after documenting progression and 
prior to starting any non-protocol therapy. Note: Kits must be ordered and will take up to 3 days to arrive. 
12 
INR and PTT should be performed if clinically indicated, per Section 5.3i.  
13 
TSH and if abnormal, reflex to Free T4 and other work up per investigator, should be performed as clinically indicated at pre-study. While on treatment, 
monitor thyroid function every 3rd cycle. See Section 8.4 for ramucirumab dose modifications and Section 8.5 for pembrolizumab dose modifications. 
14 
See Section 5.1 for details. 
 


 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm 
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less. It is strongly 
recommended that CT slice of 0.5 cm be used.  If CT scans have slice 
thickness greater than 0.5 cm, the minimum size for a measurable lesion 
should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used, and the 
image acquisition protocol should be followed as closely as possible to 
prior scans. It is no longer necessary to distinguish between spiral and 
conventional CT. 
2. 
Body scans should be performed with breath-hold scanning techniques, if 
possible.  
3. 
PET-CT: At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements. However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with stand-alone CT. 
The slice thickness of 0.5 cm or less is highly recommended. If CT scans 
have slice thickness > 0.5 cm, the minimum size for a measurable lesion 
should be twice the slice thickness. 
4. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
5. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 


 
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6. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure. If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied. If the radiologist believes the 
lesion has gone, a default measurement of 0.0 cm should be recorded. 
 
10.2 
Objective Status at Each Disease Evaluation 
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ, 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions. Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease.  
 
For studies that use disease progression as an endpoint, all potential sites of metastases 
should be evaluated at each time point rather than following only sites of disease identified 
at baseline. It is acceptable to image only the areas of the body most likely to be involved 
with metastatic disease for the tumor type (chest, abdomen, pelvis, and/or bone scan are 
typical), with the addition of any areas with suspected involvement based upon clinical 
symptoms.  For study-specific imaging requirements, see the Study Calendar in Section 
9.0.  
 
a. 
Complete Response (CR): Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below). No new lesions. No 
disease related symptoms.  Any lymph nodes (whether target or non-target) must 
have reduction in short axis to < 1.0 cm. All disease must be assessed using the 
same technique as baseline. 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions. No unequivocal 
progression of non-measurable disease. No new lesions. All target measurable 
lesions must be assessed using the same techniques as baseline. 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration. 
All target measurable lesions must be assessed using the same techniques as 
baseline. 
d. 
Progression: One or more of the following must occur: 20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm. Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site. Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see 10.2e). 
Notes on progression and new lesions:  
1. 
For equivocal findings of progression (e.g. very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may 
continue until the next scheduled assessment.  If at the next scheduled 
assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
2. 
FDG-PET imaging can complement regular scans in identifying new 
lesions according to the following algorithm.  


 
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o 
Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of progression based on a new lesion. 
o 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as 
new site of disease to be considered progressive disease. In such 
a case, the date of progressive disease will be the date of the initial 
abnormal FDG-PET.   
 
3. 
A previous abnormal target lymph node that became normal and 
subsequently enlarged in size meeting the criteria for a pathologic and 
measurable lymph node (a short axis of ≥ 1.5 cm) should be added to the 
sum of diameters to determine if criteria for progression are met based on 
target lesions. 
 
2. 
A previously abnormal non-target lymph node that became normal and 
subsequently recurred must meet the criteria for progression based on 
non-target lesions to be considered progression.  
 
3. 
A normal lymph node at baseline (<1.0 cm) that subsequently becomes 
pathologic is considered a new lesion and should be considered 
progression.   
 
4. 
If a single pathologic lymph node is driving the progression event, 
continuation of treatment/follow-up and confirmation by a subsequent 
exam should be contemplated. If it becomes clear that the new lymph node 
has not resolved, or has increased in size, the date of progression would 
be the date the new lymph node was first documented. 
 
e. 
Symptomatic deterioration: Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression. Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment inadequate, objective status unknown: Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
Objective status notes: 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
 
2. 
An objective status of PR or stable cannot follow one of CR. Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression. 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 


 
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5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion.  
 
7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate.  
 
8. 
Lymph nodes are considered one organ.  Only two lymph nodes should 
be selected as target lesions.  Other involved lymph nodes should be 
assessed and followed as non-target lesions. 
 
9. 
“Paired” organs, i.e. lungs, kidneys and ovaries, are considered one organ.   
 
10. 
Pleural-based lung lesions are considered part of the lung in determining 
target lesions (a maximum of two lung lesions should be selected), 
whereas pleural effusions/thickening can be reported as a separate site. 
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b. 
PR:  Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above. 
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
 


 
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10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
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 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
10.5 
Time to Death 
 
From date of sub-study registration to date of death due to any cause.  Patients last known 
to be alive are censored at date of last contact. 
 
10.6 
Investigator-Assessed Progression-Free Survival 
 
From date of sub-study registration to date of first documentation of progression assessed 
by local review or symptomatic deterioration (as defined above), or death due to any cause.  
Patients last known to be alive without report of progression are censored at date of last 
disease assessment. For patients with a missing scan (or consecutive missing scans) 
whose subsequent scan determines progression, the expected date of the first missing 
scan (as defined by the disease assessment schedule) will be used as the date of 
progression.  
 
10.7 
Progression-Free Survival by Central Review 
 
From date of sub-study registration to date of first documentation of progression assessed 
by central review or symptomatic deterioration (as defined above), or death due to any 
cause.  Patients last known to be alive without report of progression are censored at date 
of last disease assessment. For patients with a missing scan (or consecutive missing 
scans) whose subsequent scan determines progression, the expected date of the first 
missing scan (as defined by the disease assessment schedule) will be used as the date of 
progression.  
 
10.8 
Duration of Response (DoR) 
 
From date of first documentation of response (CR or PR) to date of first documentation of 
progression assessed by local review or symptomatic deterioration (as defined above), or 
death due to any cause among patients who achieve a response (CR or PR).  Patients last 
known to be alive without report of progression are censored at date of last disease 
assessment. For patients with a missing scan (or consecutive missing scans) whose 
subsequent scan determines progression, the expected date of the first missing scan (as 
defined by the disease assessment schedule) will be used as the date of progression. 
 
 


 
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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design and Endpoint Justification 
Overall survival has been chosen as the key primary endpoint because neither response 
nor PFS have been demonstrated to be a robust and reliable endpoint in the 
immunotherapy relapsed setting. The study design includes randomization against a 
standard-of-care (SoC) arm as there is limited historical data on response, PFS, and OS 
in this setting to be able to specify benchmarks. While responses are not necessarily 
expected, the design includes an evaluation of response rate as a key secondary objective.  
The standard of care is chemotherapy (monotherapy) for these patients.  However, there 
is limited data on clinical outcomes for patients receiving chemotherapy after 
immunotherapy. To approximate the control arm event rates, we use published data on 
chemotherapy in the second-line setting.  
 
11.2 
Primary Objective 
The primary objective is to evaluate if there is sufficient evidence to pursue an independent 
Phase III study by comparing overall survival (OS) between patients previously treated with 
platinum-based chemotherapy and immunotherapy for Stage IV or recurrent non-small cell 
lung cancer randomized to ramucirumab and pembrolizumab (MK-3475) versus standard 
of care (SoC). 
 
11.3 
Sample Size, Accrual Duration, and Estimated Analysis Times 
 
The accrual goal is 65 eligible patients per arm. Assuming 10% of patients will be 
determined to be not eligible, the total accrual goal is 144 patients (72 patients per arm). 
The estimated accrual rate is 6-7 patients/month. The estimated duration of accrual is 21-
24 months.  It is assumed that the SoC arm will be a mixture of patients receiving docetaxel 
monotherapy or docetaxel combined with ramucirumab. The expected median OS for 
patients receiving docetaxel and ramucirumab is 10.5 months, based on the REVEL trial, 
and 8 months for single agent chemotherapy.  We estimate that around 50% of patients 
will receive docetaxel/ramucirumab. Given this, we estimate that the median OS for all 
patients will be around 9 months on the control arm. Given these assumptions, the 
estimated timing of the final analysis is 30-32 months after activation (10-12 months after 
completion of accrual).  
 
11.4 
Design, Sample Size Justification  
OS will be compared using the maximum of the standard and weighted log-rank test with 
weights equal to 1-S(t), where S(t) is the pooled survival estimate at time t (G(rho=0, 
gamma=1). See for example, Freidlin 1999 (Biometrics).  This analysis will be done using 
the 
svylogrank 
function 
in 
the 
survey 
package 
in 
R 
(https://cran.r-
project.org/web/packages/survey/survey.pdf).  Testing will be done at the 1-sided 0.10 
level.  
Because the proportional hazards assumption may not hold, sample size calculations were 
not done using the standard approaches. Simulations were performed to evaluate the 
properties of the design. The final analysis would take place when 90 OS events are 
observed.  The power to detect differences in OS, if the study reaches full accrual (N=130), 
using the combination test for various amounts of time delay in separation of curves is in 
Table 1. 
 
 


 
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Table 1. Power for Primary analysis of OS (90 events) 
Hazard Ratio after Separation 
Time Delay in Separation (months) 
0 
3 
4 
5 
1.5 
62% 
53% 
53% 
47% 
2.0 
94% 
90% 
84% 
80% 
2.5 
99% 
97% 
96% 
91% 
3.0 
100% 
100% 
99% 
97% 
 
11.5 
Interim Analysis Plan  
 
The study will include two interim analyses evaluating early stopping for futility. 
 
The first interim analysis evaluating early stopping for futility alone, will take place when at 
least 24 weeks have elapsed since the 18th eligible patient randomized to Arm B.  The 
analysis will likely take place approximately 12-14 months after study activation (~7-8 
months after the 18th eligible patient on Arm B has been enrolled to allow for required data 
to be submitted and reviewed).  It is estimated that by this time a total of 40 eligible patients 
will have been randomized to ramucirumab and pembrolizumab, 30 eligible patients will be 
evaluable for disease control at 12 weeks, and a total of 80 eligible patients will have been 
enrolled onto the study.  If the study reaches 80 total eligible patients prior to this time point, 
accrual to the study will be place on temporary hold until the decision of this analysis is 
determined.  
 
The objective of the interim futility analysis is to evaluate the response rate among patients 
with at least 24 weeks of follow-up and the disease control rate at 12 weeks (after 
randomization) among patients randomized to ramucirumab and pembrolizumab (MK-
3475) to determine if there is sufficient evidence to continue accrual to the study. 
 
For the evaluation of response, a patient will be coded as a responder if they have a CR 
or PR, confirmed or unconfirmed, per the definition in Section 10.  Patients not known to 
have a response will be coded as non-responder. 
 
For the evaluation of disease control at 12 weeks, a patient will be coded as having disease 
control at 12 weeks if they have a CR, PR, or stable disease at 12 weeks (+/- 2 week 
window), per the definition in Section 10.  Patients not known to have disease control at 12 
weeks who have at least 12 weeks of follow-up, will be coded as not having disease control 
at 12 weeks.  
 
The study will continue accrual (Section 11.3) if 1) 3 or more responses or, 2) DCR12 of 
50% or greater and at least 1 response. If neither of these criteria are met, then the study 
will be closed to further accrual. The probability of continuing based on the response rates 
and DCR12 are presented in the following table.  
 
 
 


 
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Table 2. Probability of Continuing Past Interim Analysis 
Probability of 
Response 
Additional Probability of Disease Control at 12 weeks  
+0.25 
+0.3 
+0.35 
+0.4 
+0.45 
+0.5 
0.025 
0.9 
1.3 
3.6 
8.1 
11.8 
20.2 
0.05 
6 
6.9 
9.9 
16.3 
23.4 
36.7 
0.1 
27.1 
28.5 
31.4 
41.6 
50.9 
64.2 
0.15 
52.9 
54.9 
59.3 
64.7 
72.2 
79.8 
0.2 
73.4 
74.3 
76.6 
82 
87.7 
92.5 
0.25 
87.8 
88.5 
89.4 
92.7 
94.1 
95.7 
 
For example, if the true response probability were 20% and the additional likelihood of 
DCR12 is 40%, or a 60% chance of DCR12, then the probability of continuing the study 
based on these criteria is 82%.   
 
It is estimated that this interim analysis will take place approximately 12-14 months after 
study activation.  
 
The second interim analysis evaluating futility will take place when at least 45 (50%) of the 
expected deaths have occurred, with the provision that this analysis will occur when at 
least two-thirds of these deaths were at least 3 months after randomization. This analysis 
will evaluate early stopping for futility testing the alternative hypothesis of a hazard ratio 
equal to 0.69 using a modified log-rank test for testing non-null hazard ratios at the 1-sided 
0.075 level.  The alternative was chosen given that we estimate the average hazard ratio 
to be 0.69 (46% improvement) at the interim analysis if there is a 3-month delay in 
treatment effect and the hazard ratio after 3 months is 0.5.  
 
This approach results in a 7.5% chance of falsely concluding futility under the alternative 
and a 45% chance of not concluding futility under the null. It is estimated that the earliest 
this analysis would take place is around 19 months (under the null).  The total estimated 
accrual duration is 21 months.  Therefore, with the 3-month stipulation, we estimate this 
analysis will occur around the time of completion of accrual to the study (with approximately 
55 events observed). 
 
a. 
Analysis Plans  
 
If the study continues to full accrual, the final analysis will take place upon the 
observation of 90 OS events, or a maximum of 15 months after completion of 
accrual.  At this time, it is estimated that 110 PFS events will have been reported.  
OS will be evaluated at the one-sided 10% level, as the interim futility analysis 
does not affect the type I error for OS testing.  
  
OS and PFS will be compared between the arms using the maximum of the 
standard log-rank test score statistic and a weighted log-rank test score statistic 
with weights equal to w(t) =1-S(t), the G(rho,gamma) weights with rho = 0 and 
gamma = 1 (Fleming and Harrington, 1996).  The threshold for this score statistic 
was determined based on simulation under the null to achieve a type I error rate 
of 10%.   
 
The primary analysis of OS is estimated to take place 10-12 months after 
completion of accrual (or at a maximum of 15 months after completion of accrual 
as noted above).   
 


 
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Survival distributions will be estimated using the method of Kaplan-Meier (OS, IA-
PFS, DoR).  Median and landmark time-point estimates will be based on the KM-
estimates.  The average hazard ratio will be estimated using a Cox Proportional 
hazards model. An assessment of the proportional hazards assumption will be 
performed, and an assessment of the time-dependent HR will be done. 
 
Secondary objectives include a comparison of response rates (RR), toxicity, and 
IA-PFS between the arms. Binary proportions will be summarized with associated 
confidence intervals. IA-PFS will be summarized as above and using the same test 
statistic. RR and toxicities will be compared using a chi-squared test at the 1-sided 
0.05 level. With 130 patients, this study has 92% power to detect a 20% 
improvement in RR between the arms (and 80% power to detect a 16% difference).  
An approximate 10% difference in proportions between the arms would be 
statistically significant at the 10% level. With 65 patients per arm, any toxicity with 
at least 5% prevalence is likely to be observed (96% chance).  Binary proportions 
can be estimated to within 12% with 95% confidence.  
 
If OS is not found to be significantly different between the two arms, but the RR is, 
then the investigational drug combination may be considered a candidate for 
definitive evaluation in a Phase III study if there is evidence to support a difference 
in other efficacy outcomes such as duration of response and/or IA-PFS. In this 
event, the study team and NCI will discuss the data in detail. If the decision is to 
pursue a follow-on Phase III within the Lung-MAP infrastructure, a follow-on Phase 
III study would be developed per SWOG/NCI procedures for new sub-studies.  
 
Subgroup analyses will be performed comparing OS, PFS, response between the 
arms within the stratification factors (PD-L1 and histology) and by TMB status. It is 
estimated that 70% of patients will be PD-L1 positive and 25% of patients will have 
squamous histology.  TMB will be evaluated both as a continuous factor at 
categorized as high and low/negative (>10 and <=10). There will be limited power 
to detect differences between the arms in the smaller of the subsets, but the 
analysis within the larger subgroups for these factors may have sufficient power to 
evaluate if there is a differential association within the entire study population 
versus the subgroup. 
 
To address the analysis of ctDNA (objective 1.3c), a proposal to use these 
specimens will be submitted as an amendment to CTEP for approval prior to 
commencing NGS assays. This proposal will include a scientific justification, clear 
statement of objectives, and a statistical analysis plan and justification.  
 
 
 
 


 
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b. 
Summary of Planned Analyses 
 
Table 3: Summary of Design and Planned Analyses 
 
Interim Analysis #1 
Interim 
Analysis # 2 
Final 
Analysis 
(OS) 
Analysis 
Description 
Futility evaluation  
Futility 
evaluation 
 
Primary 
objective 
Analysis 
Single arm evaluation 
Compare OS 
Compare 
OS 
Analysis 
population 
18 eligible patients on 
ramucirumab/pembrolizumab 
with at least 24 weeks of 
follow-up 
Estimated 30 evaluable for 
DCR12 
Full 
population 
accrued, at 
observation of 
45 OS events 
when at least 
30 of these 
deaths were 
at least 3 
months after 
randomization 
All eligible 
patients 
accrued 
Total 
Accrued 
Up to 80 eligible patients 
(40/arm) 
Up to 130 
eligible 
Up to 130 
eligible 
patients 
(65/arm) 
Decision 
Rule 
Continue: 
3+ responses or (DCR12 
50% and Response 1+) 
Stop: 
0 responses or (DCR12 < 
50% and 1-2 Responses) 
 
Test 
alternative, 
P<0.075 
P< 0.10 
 
Estimated 
Time of 
Analysis 
(months 
after study 
activation) 
12-14 months 
19 months  
30-32 
months 
(maximum 
15 months 
after 
completion 
of accrual) 
 
11.6 
Accrual Justification 
 
Accrual estimates are based on our observed experience with Lung-MAP. Eligibility to 
Lung-MAP has changed over the course of the study with a major modification from initially 
only allowing 2nd line squamous patients to allowing all previously-treated stage IV or 
recurrent patients. Given this, the accrual estimates included here are based on observed 
accrual to Lung-MAP between January 1, 2016 and December 31, 2017.  While squamous 
histology only accounts for 25% of NSCLC, we conservatively estimated that the expansion 
of eligibility to all histologic types of NSCLC, will double our accrual numbers.   Between 
January 1, 2016 and December 31, 2017, a total of 953 registered to be screened, 737 
received 
a 
sub-study 
assignment, 
and 
335 
registered 
to 
a 
sub-study 
of 
LUNGMAP.  However, in this time approximately 50% of patients not able to register to a 
sub-study was due to the lack of a study for non-match patients who had received 
immunotherapy previously, therefore we expect an additional 20-50% of sub-study 
registrations.   Given these numbers, we estimate 400-500 patients registering to a sub-
study. 
 


 
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We further estimate based on Lung-MAP experience, that approximately 60% of sub-study 
registrations will be to a non-match sub-study and 40% of the total registrations (2/3rds of 
non-match) will be previously-exposed to immunotherapy (IO).  Given that this sub-study 
population is restricted to patients who received IO either concurrently or following 
platinum-based chemotherapy (estimated to be approximately 70% of patients) and must 
not have progressed within 12 weeks of IO (estimated to be approximately 60-65% of 
patients), the estimated proportion patients registering to S1800A of all sub-study 
registrations is 17%, or 68-85 patients per year (6-7/month).   
 
11.7 
Data and Safety Monitoring  
 
The SWOG Data and Safety Monitoring Committee will oversee the conduct of the study.  
The Committee consists of four members from outside of SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet at 
the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. 
 
12.0 
DISCIPLINE REVIEW 
12.1 Radiology Review 
 
Central collection is required but review of scans will not be triggered if the study will not 
be submitted to the FDA for FDA approval of the investigational therapy. Central review of 
scans will be triggered only if deemed necessary for FDA evaluation.  A detailed description 
of the central radiology PFS review, including image acquisition parameters and image 
submission instructions, can be found in LUNGMAP Section 18.2f. 
 
a. 
To ensure the highest standards and consistency between different centers, all 
scans for disease assessment (baseline, interim and end of treatment scans) must 
be submitted to the National Cancer Institute’s National Clinical Trials Network 
(NCTN) Imaging and RT Quality Assurance Service Core (IROC) in Ohio for 
centralized review (see S1800A Section 15.0). 
 
b. 
Centralized review will be performed by 3 radiology experts.  The scans will be 
submitted to IROC.  IROC will transmit the scans to the reviewers who will transmit 
the results to the SWOG Statistics and Data Management Center. 
 
c. 
Details of submission of scans to IROC for centralized review and on the central 
review process are listed in S1800A Section 15.0 and LUNGMAP Section 15.6. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
See Section 13.0 of LUNGMAP for registration guidelines. 
 
In order to open Lung-MAP studies at the site, a separate Study Specific Worksheet (SSW) is 
required to be submitted to the CIRB for the LUNGMAP screening protocol and each sub-study.  
 
13.1 
Registration Timing 
 
Patients must plan to begin treatment within 10 calendar days after sub-study registration.  
 
Note: Some of the standard of care treatments have premedications required prior to start 
of treatment. See Section 7.2. 
 
13.2 
Investigator/Site Registration 
 


 
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For investigator/site registration, please refer to Section 13.2 of the LUNGMAP screening 
protocol. In addition, a Delegation Task Log is required for this sub-study.  
 
Delegation Tasks Log (DTL): 
Each site must complete a protocol-specific DTL using the DTL application in the 
Delegation Log section on the CTSU members’ website. The Clinical Investigator (CI) is 
required to review and electronically sign the DTL prior to the site receiving an approved 
site registration status and enrolling patients to the study.  To maintain an approved site 
registration status the CI must re-sign the DTL at least annually and when a new version 
of the DTL is released; and activate new task assignments requiring CI sign-off. Any 
individual at the enrolling site on a participating roster may initiate the site DTL. Once the 
DTL is submitted for CI approval, only the designated DTL Administrators or the CI may 
update the DTL. Instructions on completing the DTL are available in the Help Topics button 
in the DTL application and include a Master Task List, which describes DTL task 
assignments, CI signature, and CTEP registration requirements. 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol page on the CTSU website (www.ctsu.org) and 
(with the exception of the sample consent form and the Registration Worksheet) must be 
submitted on-line via the Web; see Section below for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Medidata Rave is a clinical data management 
system being used for data collection for this trial/study. Access to the trial in Rave 
is controlled through the CTEP-IAM system and role assignments.  
 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the relevant LPO or PO roster at the enrolling site of: 
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator. 
Rave role requirements:  
o 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of 
an Associate Plus (AP) registration type; 
o 
Rave Investigator role must be registered as a Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
o 
Rave Read Only role must hold an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
 
Individuals requiring write access to Rave must also be assigned the appropriate 
Rave tasks on the Delegation of Tasks Log (DTL). 
 


 
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Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 
a study invitation e-mail from iMedidata.  To accept the invitation, site staff must 
log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM username and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Site staff will not be able to access the study 
in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the iMedidata 
screen. If an eLearning is required and has not yet been taken, the link to the 
eLearning will appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been recorded, access 
to the study in Rave will be granted, and a Rave EDC link will display under the 
study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will receive a separate 
invitation from iMedidata to activate their account.  Account activation instructions 
are located on the CTSU website in the Data Management section under the Rave 
resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU 
members’ 
website 
in 
the 
Data 
Management 
> 
Rave 
section 
at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.comi’m having a .  
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (http://swog.org).  
 
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table. 
 
d. 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for delinquent form 
details and reports to be available on the DQP. Site staff should contact the LPO 
Data Manager for their protocol regarding questions about Rave Calendaring 
functionality.   
 
 


 
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14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 15 DAYS OF S1800A RANDOMIZATION, SUBMIT: 
 
S1800A Onstudy Form 
 
If needed, also submit: 
Radiation Therapy Form 
Brain Metastases Form 
 
 
S1800A Eligibility Criteria Form 
 
Smoking Status Assessment Form 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease at baseline*  
If needed, RT summary and/or planning document* 
 
 
 
 
If needed, radiology report from brain CT/MRI* 
 
*(NOTE: Upload reports via the Source Documentation: Baseline form in Rave) 
 
For patients screened under legacy S1400: PD-L1 testing (Dako 22C3 PharmDX 
assay) report. 
(NOTE: Upload report via the Source Documentation: Baseline form in Rave) 
 
Submit to IROC via TRIAD for Central Radiology Review:  Images from scans 
performed to assess disease at baseline as specified in Section 15.5. 
 
b. 
IF PATIENT CONSENTS, SUBMIT SPECIMENS: 
 
Specimens as specified in Section 15.0 of S1800A. 
 
c. 
WITHIN 15 DAYS AFTER EACH CYCLE (CYCLE = 21 DAYS) OF TREATMENT, 
SUBMIT: 
 
S1800A Treatment Form 
 
S1800A Adverse Event Form* 
 
S1800A Laboratory Values Form 
 
For Cycle 1 only: submit the S1800A Pre-Treatment Laboratory Values Form. 
 
*For the last cycle of treatment, include all adverse events occurring within 30 days 
after the last treatment. 
 
d. 
WITHIN 15 DAYS AFTER EVERY DISEASE ASSESSMENT (INCLUDING BOTH 
ON TREATMENT AND OFF PROTOCOL TREATMENT PRIOR TO DISEASE 
PROGRESSION [see S1800A Section 9.0 for Disease Assessment Schedule]), 
SUBMIT: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) documenting results of 
assessment 
 
Radiology reports from all scans performed to assess disease at follow-up (NOTE: 
Upload reports via the Source Documentation: Follow-up form in Rave) 
 
Submit to IROC via TRIAD for Central Radiology Review:  Images from scans 
performed to assess disease as specified in S1800A Section 15.5. 


 
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e. 
WITHIN 15 DAYS OF DISCONTINUATION OF TREATMENT SUBMIT: 
 
Off Protocol Treatment Notice documenting reasons for off protocol treatment 
 
 
Smoking Status Assessment Form  
 
Forms specified in Section 14.4.c. 
 
f. 
ONCE OFF PROTOCOL TREATMENT EVERY 6 MONTHS FOR THE FIRST 2 
YEARS FROM S1800A RANDOMIZATION, THEN AT THE END OF YEAR 3 
SUBMIT: 
 
Advanced NSCLC Follow-Up Form 
 
If needed, also submit: 
Radiation Therapy Form 
Brain Metastases Form 
 
 
Late Adverse Events (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] adverse event that is possibly, probably, or definitely related to protocol 
treatment, or a Serious Adverse Event [SAE] of any grade/attribution, that has not 
been previously reported). 
 
Note: Patients who enroll on a new sub-study following progression must continue 
follow-up on this sub-study, in addition to follow-up on the new sub-study. See 
Section 14.4i. 
 
g. 
WITHIN 15 DAYS OF PROGRESSION/RELAPSE, SUBMIT: 
 
Site(s) of Progression or Relapse Form 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease at follow-up (NOTE: 
Upload reports via the Source Documentation: Follow-up form in Rave) 
 
Submit to IROC via TRIAD for Central Radiology Review:  Images from scans 
performed to assess disease as specified in Section 15.5. 
 
h. 
WITHIN 28 DAYS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death documenting death information and S1800A End of 
Study form.  In addition, if the patient was still on protocol treatment, submit 
materials specified in Section 14.4e or if patient was no longer on treatment, submit 
a final Advanced NSCLC Follow-Up Form. 
 
i. 
DATA SUBMISSION FOR PATIENTS WHO HAVE PROGRESSED AND WISH 
TO REGISTER TO A NEW SUB-STUDY:  
 
WITHIN 15 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the Request for New Sub-Study Assignment Form under the patient’s 
screening protocol (LUNGMAP or S1400) in Rave®.  Continue follow-up on 
S1800A per Section 9.0.  See Section 14 of the screening protocol for additional 
data submission requirements following request for new sub-study assignment. 


 
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j. 
WITHIIN 30 DAYS OF MAXIMUM FOLLOW-UP OF 3 YEARS: 
 
S1800A End of Study Form 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
SWOG Specimen Tracking System (STS) 
 
See LUNGMAP Section 15.1 for SWOG Specimen Tracking System (STS) instructions. 
 
15.2  
Correlative Studies and Banking  (Optional for Patients) 
 
Specimens for correlative studies and banking (submitted to the SWOG Biospecimen Bank 
– Solid Tissue, Myeloma and Lymphoma Division, Lab #201) are considered optional for 
the patient: 
 
a. 
With patient’s consent, specimens must be collected and submitted as follows: 
 
1. 
Buffy Coat and Plasma: 
 
Specimens must be collected at the following times: 
 
• 
Pre-study (after consenting and prior to treatment initiation on sub-
study)  
Note: If a patient provided buffy coat and plasma for LUNGMAP (see 
Section 15.0 of LUNGMAP) and the blood collection was within 42 
days prior to the sub-study randomization, then no additional pre-
study blood specimen is required. 
• 
Weeks 4, 7, 10 - Patients that go off protocol treatment are not 
required to continue to submit specimens. 
• 
First Progression after study treatment - First progression blood 
should be collected by the time of the next visit after documenting 
progression and prior to starting any non-protocol therapy. 
 
Collect approximately 8-10 mL of blood in EDTA tubes. Blood should be 
processed within one hour after venipuncture. If immediate processing 
within this time frame is not possible, then refrigerate (4°C) blood in EDTA 
tubes. The approximate time from collection to processing should be 
recorded as part of the patient’s source documentation. EDTA tubes must 
be centrifuged at 800 x g for 10 minutes at 4°C for the collection of plasma. 
[Note: Sites that do not have a refrigerated centrifuge should spin at room 
temperature and ensure specimens are placed on ice (regular, not dry) 
immediately after being drawn and process rapidly.] Using a pipette, 
transfer the plasma to a 15-mL centrifuge tube. Remove the buffy coat 
layer (thin white or gray layer of cells between the plasma and red blood 
cells) and split between two appropriately labeled 2-mL cryovials.  
 
Spin the plasma in the 15-mL centrifuge tube at 800 x g for an additional 
10 minutes. Avoiding any pelleted material, pipette the plasma into labeled 
cryovials at 0.5 ml aliquots. Plasma must be clear before freezing; no cells 
or debris should be present.  
 
Plasma and buffy coat vials must be placed upright in a -80˚C freezer 
immediately after processing to ensure long-term viability.   
 
Frozen plasma and buffy coat specimens must be shipped to the SWOG 
Biospecimen Bank on dry ice. Frozen specimens may be shipped in 
batches – refer to Section 15b. 
 


 
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b. 
Specimen Submission and Labeling 
 
Samples for multiple patients may be shipped in batches to the SWOG 
Biospecimen Bank – Solid Tissue, Myeloma and Lymphoma Division, Lab #201, 
every 3 months, with a maximum of 5 patients recommended, if not more 
frequently. 
 
For additional information about labeling and shipping instructions for frozen 
plasma and buffy coat specimens, refer to the SWOG Specimen Submission 
webpage 
(https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures). 
 
1. Liquid specimens must be labeled with the following: 
• 
SWOG patient number 
• 
Patient initials 
• 
Collection date (date the specimen was collected from the patient) 
• 
Specimen type (e.g. blood, serum, etc.) 
 
c. 
Specimen collection kits are not being provided for this submission; sites must use 
institutional supplies. 
 
15.3 
LUNGMAP ctDNA Assay – Peripheral Whole Blood (REQUIRED FOR PATIENTS prior to 
treatment initiation) 
 
 
 
Blood specimens will be collected in order to isolate and investigate circulating tumor DNA 
(ctDNA) and blood tumor mutational burden (bTMB) – a form of fragmented DNA released 
into patient peripheral circulation specifically from the tumors. Analysis of ctDNA can reveal 
the presence of tumor-specific mutations and other abnormalities that can serve as 
biomarkers. The information collected will be limited to tumor-specific abnormalities known 
or suspected to play roles in tumor evolution.  Patient germ-line genetic information will not 
be collected. 
 
a. 
Kit Ordering 
 
Immediately after identifying a patient for trial and prior to treatment initiation, sites 
must contact Foundation Medicine Inc. – Blood Samples, Lab #232, to order kits 
as follows: 
 
• 
Email request to FMI Client Services at lung.map@FoundationMedicine.com 
• 
Site must identify itself as a participant in the S1800A SWOG Lung-MAP sub-
study and request the “Lung-MAP ctDNA Clinical Trial Kit.” 
• 
Reference the FMI Study ID: FoundationOneLiquidDx-AMC-PRO-20-1496 
• 
Provide the following information: 
o 
Treating physician's name 
o 
Treating physician's email address 
o 
Contact name 
o 
Contact email address 
o 
Contact phone 
o 
Address to which kits should be sent 
o 
Number of kits needed (one per patient per timepoint) 
 
Kits will arrive within 3 days after ordering (excluding weekends and holidays). 
 
Kits will read “Foundation Medicine Clinical Trials Kit,” and include two Roche Cell-
Free DNA blood collection tubes, collection instructions, FedEx return bags, and 
pre-printed FedEx airway bills. Blood collection tubes must be used before their 
expiration date. 
 
 


 
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b. 
Timepoints 
 
Collect blood:  
• 
After sub-study registration and prior to treatment initiation  
o 
Recommended to collect on Cycle 1 Day 1 (prior to treatment) 
during other labs to lessen patient visits 
 
Note: This is a separate requirement for a ctDNA whole blood 
specimen for all patients registered to S1800A, regardless of 
whether or not there was a ctDNA blood collection for 
LUNGMAP. 
 
• 
 At progression - First progression blood should be collected by the time 
of the next visit after documenting progression and prior to starting any 
non-protocol therapy 
 
c. 
Specimen Collection and Shipment Instructions 
 
Specimen must be logged via the SWOG Specimen Tracking System.  
 
Step 1: Check special tubes provided in kits to confirm liquid is clear and without 
cloudiness or crystals. 
 
Step 2: Label tubes with date of collection, patient identifiers as requested on the 
included labels (patient date of birth can be added as an extra identifier), 
and sub-study number. 
 
Step 3: Collect two tubes of whole blood (8.5 mL per tube) 
o 
Prevent backflow: tubes contain chemical additives and it is important to 
avoid backflow into patient 
o 
Collect specimen by venipuncture 
o 
Fill tubes completely (8.5 mL per tube) 
 
Step 4: Remove the tube from adapter and immediately mix by gentle inversion 8 
to 10 times. Inadequate or delayed mixing may result in inaccurate test 
results. One inversion is a complete turn of the wrist, 180̊ and back, per 
the figure below. 
 
 
 
Step 5: Place specimen into the specimen collection kit. 
o 
Confirm each tube is labeled with the supplied labels indicating the date 
of collection and two unique patient identifiers (label included in kit). 
 
Step 6: Select “Ship this Shipment and Generate Packing List” in the SWOG 
Specimen Tracking System to generate the Packing List. A copy of the 
SWOG Specimen Tracking Packing List must be included in the shipment. 
Confirm that the tubes are labeled as specified on the Packing List. 
 
Step 7: Preferably on the same day of collection, ship via FedEx overnight delivery 
at ambient temperature. Do not freeze or refrigerate blood samples. Keep 
at 43-99̊ F (6-37̊ C). 


 
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FMI accepts Saturday deliveries. If shipping on a Friday, please overnight 
shipment, and mark for Saturday delivery. 
 
d. 
Specimen Usage 
 
Cell-free, circulating DNA will be isolated from the plasma component of the whole 
blood. Using a hybrid-capture, next-generation sequencing technology (developed 
by Foundation Medicine), alterations in clinically significant cancer genes 
(oncogenes and tumor suppressor genes) will be identified and quantitated relative 
to wild-type sequences. Tumor-specific alterations will include point mutations, 
small insertions and deletions, chromosomal rearrangements and copy 
number/amplification events in (LUNGMAP ctDNA Assay) including an 
assessment of tumor mutation burden (TMB) will be conducted using ctDNA. A full 
proposal will be developed, reviewed, and approved by SWOG and CTEP once 
funding has been obtained. 
 
The ctDNA results are for research purposes and will not be shared with the 
investigator or patient.  
 
15.4 
Specimen Flow Diagram 
 
Please refer to Section 15 of LUNGMAP for the specimen flow diagram for the screening 
protocol. 
 
15.5 
Radiology Review (Required) 
 
CT, PET/CT, and/or MRI images must be locally read and interpreted by the local site 
radiology service.  Imaging exams must then be submitted to the Imaging and Radiation 
Oncology Core (IROC) at Ohio via TRIAD Imaging Submission procedures for central data 
collection and quality control (QC) check as well as retrospective central review. 
 
a. 
CT, PET/CT, and/or MRI images must be submitted to IROC Ohio for central 
review at the following timepoints: 
 
• 
Baseline 
• 
Every 6 weeks for the first year, then every 12 weeks until progression and 
discontinuation of treatment. 
 
All study participants must have a CT (or MR or PET/CT) exam prior to sub-study 
entry.  Participants must then undergo additional imaging every 6 weeks for the 
first year, then every 12 weeks until progression of disease and discontinuation of 
treatment.  The same imaging modality used for the pre-treatment exam must be 
used for the post-treatment exams (see Section 10.1c). Each exam should be 
performed per LUNGMAP Section 18.2f.  IROC will perform a QC of the imaging 
exams.   
 
Clinical management and treatment decisions will be made by the treating 
physician based on local site assessments and other clinically appropriate 
considerations. 
 
Central review of scans will not be triggered if the study will not be submitted to 
the FDA for FDA approval of the investigational therapy.  Central review of scans 
will be triggered only if deemed necessary for FDA evaluation. A detailed 
description of the central radiology PFS review, including image acquisition 
parameters and image submission instructions, can be found in LUNGMAP 
Section 18.2f. 
 
 


 
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b. 
TRIAD Digital Image Submission  
 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application.  TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
 
1. 
TRIAD Access Requirements: 
 
TRIAD will be the sole means of image transfer to the IROC Ohio. TRIAD 
should be installed prior to study participant enrollment to ensure prompt 
secure, electronic submission of imaging. 
 
• 
A valid CTEP-IAM account (see LUNGMAP Section 13.2). 
• 
Registration type of: Associate (A), Associate Plus (AP), Non-
Physician Investigator (NPIVR), or Investigator (IVR). Refer to the 
CTEP Registration Procedures section for instructions on how to 
request a CTEP-IAM account and complete registration in RCR. 
• 
TRIAD Site User role on the NCTN or ETCTN roster.  
 
All individuals on the Imaging and Radiation Oncology Core provider roster 
have access to TRIAD and may submit images for credentialing purposes, 
or for enrollments to which the provider is linked in OPEN. 
 
2. 
TRIAD Installations: 
 
To submit images, the individual holding the TRIAD Site User role will 
need to install the TRIAD application on their workstation. TRIAD 
installation documentation is available at:  
https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account 
and RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice. 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 82, No. 12, January 19, 2017) and the Office for Protection from Research Risks 
Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must be 
followed to comply with FDA regulations for the conduct and monitoring of clinical investigations.  
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Federal Register Vol. 82, No. 12, January 19, 2017) and the Office for 
Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
 


 
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Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312 and the CTEP Investigator’s Handbook. 
 
Publication and Industry Contact 
 
The agents supplied by CTEP, DCTD, NCI used in this protocol are provided to the NCI under 
Collaborative Agreements (CRADA, CTA, CSA) between the Pharmaceutical Companies 
(hereinafter referred to as "Collaborators") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agents in this study: 
 
1. 
Agents may not be used for any purpose outside the scope of this protocol, nor can Agents 
be transferred or licensed to any party not participating in the clinical study.  Collaborators 
data for Agents are confidential and proprietary to Collaborators and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of 
the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov.  
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations which would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborators, the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 


 
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5. 
Any data provided to the Collaborators for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborators for advisory review and 
comment prior to submission for publication.  Collaborators will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator's confidential and 
proprietary data, in addition to the Collaborator’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborators for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but 
in any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/media presentation should be sent 
to: 
 
E-mail:  ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to the Collaborators.  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Trial Master File 
  
This is an FDA registration study; therefore, all participating sites should be FDA "inspection ready". 
This entails maintaining a Trial Master File that includes essential documents that may be subject 
to FDA oversight. A list of essential documents is available on the SWOG website under QA/Audits, 
https://swog.org/Visitors/QA/Index.asp.  
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Serious Adverse Event Reporting Requirements  
 
a. 
Definition and Purpose 
 
Definition:  Adverse event means any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. (FDA, 
21 CFR 312.32). See Table 16.1 for definition of a Serious Adverse Event (SAE) 
and reporting requirements. 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 


 
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patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol. 
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported to SWOG 
Operations Office using the Cancer Therapy Evaluation Program Adverse Event 
Reporting System (CTEP-AERS).  CTEP's guidelines for CTEP-AERS can be 
found at http://ctep.cancer.gov.   
 
NOTE:  For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriate Treatment 
Cycle folder in Medidata Rave.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website. 
 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.   
 
In the rare event when internet connectivity is disrupted, a 24-hour notification is 
made to SWOG by telephone at 210-614-8808 or by email at adr@swog.org.  An 
electronic report MUST be submitted immediately upon re-establishment of 
internet connection. 
 
When the adverse event requires expedited reporting, submit the report via CTEP-
AERS within the number of calendar days of learning of the event specified in 
Table 16.1. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1.  The investigational agent(s) used in Arm B of this study are 
ramucirumab and pembrolizumab (MK-3475). If there is any question about the 
reportability of an adverse event or if internet connectivity is disrupted, please 
telephone or email the SAE Program Manager at the Operations Office, 210/614-
8808 or adr@swog.org, before preparing the report. 
 
NOTE: For this study, all adverse events requiring expedited reporting 
must initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is 
entered into RAVE, the Rules Engine will confirm whether or not the 
adverse event requires expedited reporting.  The CTEP-AERS report must 
then be initiated directly from the Adverse Event Form in Medidata Rave.  
Do not initiate the CTEP-AERS report via the CTEP-AERS website.  Sites 
are encouraged to confirm the Expedited Reporting Evaluation 
Recommendation with the reporting criteria outlined in Table 16.1 (or 
section 16.1f). 


 
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Table 16.1: 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a Non-CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 Arm B: Ramucirumab plus Pembrolizumab (MK-3475) 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are 
found in Section 16.1f. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
 
May 5, 2011 
 
 
f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under 
a non-CTEP-IND: 


 
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1. 
Group-specific instructions. 
 
Supporting Documentation Submission - Within 5 calendar days submit 
the documentation supporting the CTEP-AERS report to the SWOG 
Operations Office by fax 210-614-0006. Specific instructions will be sent 
by email to the reporting site by the SAE Program Manager. 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The 
commercial agent(s) used in Arm A of this study are docetaxel, gemcitabine, 
pemetrexed, or ramucirumab plus docetaxel. If there is any question about the 
reportability of an adverse event or if internet connectivity is disrupted please 
telephone or email the SAE Program Manager at the Operations Office, 
210/614-8808 or adr@swog.org, before preparing the report. 
 
NOTE: For this study, all adverse events requiring expedited reporting 
must initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is 
entered into RAVE, the Rules Engine will confirm whether or not the 
adverse event requires expedited reporting.  The CTEP-AERS report must 
then be initiated directly from the Adverse Event Form in Medidata Rave.  
Do not initiate the CTEP-AERS report via the CTEP-AERS website.  Sites 
are encouraged to confirm the Expedited Reporting Evaluation 
Recommendation with the reporting criteria outlined in Table 16.2. 
 
 
Table 16.2. Expedited reporting requirements for adverse events experienced by 
patients on study Arm A who have received the commercial drug(s) listed in 16.1g 
above within 30 days of the last administration of the commercial agent(s). 
 
 
Attribution 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via CTEP-AERS within 10 calendar days 
of learning of the eventb. 
a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), 
regardless of attribution.  Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent(s) and is attributed (possibly, probably, or definitely) to the 
agent(s) and is not due to cancer recurrence must be reported according to the instructions 
above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements. You may, however, be asked to submit supporting clinical 
data to the Operations Office in order to complete the evaluation of the event. If requested, the 
specified data should be sent within 5 calendar days by fax to 210-614-0006.  
 
 
h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 


 
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radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
SWOG requires all secondary malignancies that occur following treatment 
with an agent under a Non-NCI IND to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in 
each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy).  Second malignancies require ONLY routine reporting. 
 
For more information see: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applicati
ons/docs/aeguidelines.pdf 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system. Supporting 
documentation must also be submitted to SWOG Operations Office by fax 
to 210/614-0006 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
i. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss  Pregnancy loss is defined in CTCAE as “Death in 
utero.” Pregnancy loss should be reported expeditiously as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death. 
 
3. 
Death Neonatal  Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth  A neonatal death should be 


 
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reported expeditiously as Grade 4 “Death neonatal” under the General 
disorders and administration SOC. 
 
Neonatal death should NOT be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 210/614-0006.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at:   
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm   
 
 
 
 


 
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17.0 
BIBLIOGRAPHY
 
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Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, 
Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison 
CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous 
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Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer, Brahmer 
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Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer, Reck M, 
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Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, 
Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, 
Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. 
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Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer 
(CheckMate 012): results of an open-label, phase 1, multicohort study. Hellmann MD, Rizvi NA, 
Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens 
RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X, Antonia SJ.  Nivolumab plus 
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7  
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival 
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Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer 
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Ziogas AC, Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Terpos E, Rodolakis A, Vlahos G, 
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Rizvi NA, Antonia SJ, Shepherd FA, et al. Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) 
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18.0 
APPENDIX 
 
18.1 
New York Heart Association Classification 
 
18.2 
Instructions for the SWOG Biospecimen Bank 
 
18.3  
Child-Pugh Scoring 
 
18.4 
Live Vaccines Examples 
 
18.5 
PD-L1 22C3 IHC Assay 
 
 
 


 
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18.1 
New York Heart Association Classification 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by 
the physician. 
** 
At accustomed occupation or usual tasks. 
 
 
 
 


 
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18.2 
Instructions for the SWOG Biospecimen Bank 
 
Frozen Plasma and Buffy Coat 
The SWOG Biospecimen Bank will receive frozen plasma and buffy coat at up to 5 
timepoints per patient. Upon receipt, the Bank will accession, barcode, and bank 
specimens in a -80°C freezer. 
 
Formalin-fixed Paraffin-Embedded (FFPE) Tissue 
The SWOG Biospecimen Bank will receive FFPE specimens as either blocks or 
slides/sections at up to 1 timepoint per patient. Upon receipt, the Bank will accession, 
barcode, and bank specimens at ambient temperature.   
 
At the end of the study, the Bank will receive notification from the SWOG Statistics and 
Data Management Center to distribute specimens for testing, if applicable.   
 
 
 


 
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18.3 
Child-Pugh Scoring 
 
The score is used to assess the prognosis of chronic liver disease and employs five clinical 
measures of liver disease. Each measure is scored 1–3, with 3 indicating most severe 
derangement. 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, mmol/L 
(mg/dL) 
<34 (<2) 
34–50 (2–3) 
>50 (>3) 
Serum albumin, g/dL 
>3.5 
2.8–3.5 
<2.8 
Prothrombin time, 
prolongation in seconds  
(or INR) 
<4.0 (<1.7) 
4.0–6.0 (<1.7-2.2) 
> 6.0 (>2.2) 
Ascites  
None 
Mild (or suppressed with 
medication) 
Moderate to severe 
(or refractory) 
Hepatic encephalopathy  
None 
Grade I–II 
Grade III–IV 
 
 
Class A 
Class B 
Class C 
Total points 
5-6 
7-9 
10-15 
 
 
 
 


 
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18.4 
Live Vaccines Examples 
 
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.  
 
 


 
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18.5 
PD-L1 22C3 IHC Assay 
 
 
The FMI Dako PD-L1 (22C3) IHC assay was done as part of the Lung-MAP Screening Study to 
randomize patients for S1800A. PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying 
NSCLC patients for treatment. The results are based on PD-L1 protein expression determined by 
Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or 
complete membrane staining at any intensity. A specimen was considered to have PD-L1 
expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%. The clinical value for testing PD-
L1 expression is well documented.(1) 
 
 
Reference: 
 
 
 
1  Covert, M., Sheehan, C., Crouch, T., and Ramikissoon, S. Dako PD-L1 IHC 22C3 pharmDx 
Immunohistochemistry (IHC) Assay Verification Report. Foundation Medicine, Inc.PD-L1 
MBS-037, 2017. 

ICF_001.pdf: 
Readability Statistics: 
S1800A 
Flesch Reading Ease: 60.9 
Page 1 
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Version Date 8/4/2022 
 
 
 
 
Research Study Informed Consent Document 
 
Study Title for Participants: Targeted Treatment (ramucirumab plus pembrolizumab) for 
Advanced Non-Small Cell Lung Cancer 
 
LUNGMAP, “A Master Protocol to Evaluate Biomarker-Driven Therapies and 
Immunotherapies in Previously-Treated Non-Small Cell Lung Cancer (Lung-MAP 
Screening Study)” 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  
 
S1800A, “A Phase II Randomized Study of Ramucirumab Plus Pembrolizumab (MK-
3475) versus Standard of Care for Patients Previously Treated with Immunotherapy for 
Stage IV or Recurrent Non-Small Cell Lung Cancer (Lung-MAP Non-Matched Sub-
Study)” 
(NCT 03971474) 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study. This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services. We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this research study because you have non-small cell lung 
cancer that has spread outside your lungs, and your tumor sample did not have a biomarker that 
matches one of the treatment studies that are open or because you were not a candidate for a 
biomarker-matched treatment study.  
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 


 
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Why is this study being done? 
 
This study is being done to answer the following question:  
 
Can we lower the chance of your lung cancer growing or spreading by combining two drugs that 
work with your immune system to fight your cancer? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your lung cancer.  The usual approach is defined as care most people get for 
their lung cancer. 
 
What is the usual approach to my lung cancer? 
 
The usual approach for patients who are not in a study is treatment with chemotherapy or 
immunotherapy drugs.  If you have already received chemotherapy, other chemotherapy drugs or 
immunotherapy may be an option.  If you have already received immunotherapy, chemotherapy 
may be an option.  In addition, immunotherapy has been Food and Drug Administration (FDA) 
approved for patients whose disease has gotten worse. The approval was based on results of 
clinical trials where patients had improved overall survival with immunotherapy compared to 
standard chemotherapy. 
• For patients whose disease has gotten worse while receiving platinum-based 
chemotherapy (like cisplatin or carboplatin), immunotherapy options include 
pembrolizumab alone for tumors with a low tumor expression of PD-L1.   
• Other available immunotherapy options are nivolumab and atezolizumab, which do not 
need PD-L1 expression testing. 
 
What are my choices if I decide not to take part in this study? 
 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
• There are many other options that your physician can talk to you about. 
 
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will either get the current standard of care drug 
(docetaxel, gemcitabine, pemetrexed, or ramucirumab combined with docetaxel) or you will get 
the study drugs (ramucirumab combined with pembrolizumab), until your disease gets worse or 
the side effects become too severe. 


 
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After you finish your study treatment, your doctor will continue to follow your condition for up 
to three years from the time you went on study and watch you for side effects. If your disease has 
not gotten worse, follow up visits will occur every 3 months for the first year, then every 6 
months up to 3 years from the time you go on study. If your disease has gotten worse, follow up 
visits will occur every 6 months for 2 years, then at the end of the 3 years from the time you go 
on study. Your doctor may give you other tests or procedures if they think they are needed for 
the regular care of your disease.  
 
Should your disease worsen, you have the option to participate in a different sub-study. As 
before, the new sub-study that you will be offered will depend on a combination of the results of 
the previous testing done on your tumor sample and the sub-studies available. If the tests show 
that your tumor has more than one biomarker that qualifies you for a different sub-study, you 
will be assigned to one of these sub-studies randomly (by chance). A sub-study may be available 
if your tumor does not have any additional biomarkers being tested or you were not eligible to 
participate in other sub-studies. 
 
What are the risks and benefits of taking part in this study? 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer.   
 
There is also a risk that you could have side effects from the study drugs. These side effects may 
be worse and may be different than you would get with the usual approach for your cancer.   
 
Some of the most common side effects that the study doctors know about are: 
• Vomiting, diarrhea, nausea, constipation 
• Anemia which may require blood transfusions 
• Infection, especially when white blood cell count is low 
• Tiredness 
• Rash, itching 
 
There may be some risks that the study doctors do not yet know about.   
 


 
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Benefits 
 
There is evidence that the combination of ramucirumab plus pembrolizumab could shrink your 
type of cancer or prevent it from returning. It is unlikely that it will work in everyone with your 
cancer or help you live longer. This study will help the study doctors learn things that may help 
other people in the future. 
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study 
 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
• Your health changes and the study are no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• The study is stopped by the National Cancer Institute (NCI), Institutional Review Board 
(IRB), Food and Drug Administration (FDA), or study sponsor SWOG Cancer Research 
Network (SWOG).  The study sponsor is the organization who oversees the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
End of Overview and Key Information  
 
 
 


 
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What is the purpose of this study? 
 
There are several investigational treatments that are being tested in various sub-studies as part of 
this study. You will have already received the information on your biomarker testing. You have 
been assigned to this treatment study because your tumor sample did not have a biomarker that 
matches one of the treatment studies that are open or because you were not a candidate for a 
biomarker-matched treatment study. For this sub-study, you will be assigned to treatment with 
either the usual treatment, which is the current standard of care drug (docetaxel, gemcitabine, 
pemetrexed [for non-squamous cell NSCLC only], or ramucirumab combined with docetaxel) or 
to the investigational therapy (ramucirumab combined with pembrolizumab).  
 
The purpose of this study is to compare the usual treatment to using ramucirumab plus 
pembrolizumab.  The combination of ramucirumab plus pembrolizumab, drugs that work with 
your immune system to fight your cancer, could shrink your cancer, but it could also cause side 
effects, which are described in the risks section below.  
 
This study will help the study doctors find out if this different approach is better, the same, or 
worse than the usual approach.  The study doctors hope to learn if the study drug combination 
will enable patients to live longer compared to the usual approach.   
 
This immunotherapy drug combination, ramucirumab plus pembrolizumab, is not approved by 
the FDA for use in advanced lung cancer.  There will be up to 144 people taking part in this 
study. 
 
What are the study groups? 
 
This study has 2 study groups.   
 
• Group 1 – Standard of Care  
 
If you are in this group, you will get the usual drugs used to treat this type of cancer 
based on your previous treatment (docetaxel, gemcitabine, pemetrexed, or ramucirumab 
combined with docetaxel). Treatment will be given in cycles. Each cycle lasts 21 days. 
You will receive treatment until your disease gets worse or the side effects become too 
severe. 
 
Docetaxel: 
If you receive docetaxel, you will get docetaxel through a vein in the arm over about 30-
60 minutes on the first day of each cycle.   You will also receive dexamethasone tablets, 
an approved medication to help prevent allergic reactions to docetaxel. You will begin 
taking dexamethasone, twice a day, the day before you receive docetaxel and for two 
days after.  
 
 
 


 
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Gemcitabine: 
If you receive gemcitabine, you will get gemcitabine through a vein in the arm over 30 
minutes on days 1 and 8 of each cycle.   
 
Pemetrexed: 
Pemetrexed is not FDA-approved for squamous cell NSCLC. You will not receive 
pemetrexed if you have squamous cell NSCLC. 
 
If you receive pemetrexed, you will be given pemetrexed through a vein in the arm over 
10 minutes on day 1 of each cycle.  You will also receive dexamethasone tablets, an 
approved medication, Vitamin B12 injections to help reduce side effects of pemetrexed, 
and folic acid. Folic acid will be given 7 days before you receive pemetrexed on cycle 1 
and will continue every day until 4 weeks after the last dose of pemetrexed. Vitamin B12 
will be given 7 days before you receive pemetrexed every 3rd cycle. You will begin 
taking dexamethasone, twice a day, the day before you receive pemetrexed and for two 
days after.  
 
Ramucirumab in combination with Docetaxel: 
If you receive ramucirumab in combination with docetaxel, you will be given 
ramucirumab through your vein in the arm over 30-60 minutes before you are given 
docetaxel.  You will be given docetaxel through a vein in the arm over about 30-60 
minutes on the first day of each cycle.   You will also receive dexamethasone tablets, an 
approved medication to help prevent allergic reactions to docetaxel. You will begin 
taking dexamethasone, twice a day, the day before you receive docetaxel and for two 
days after.  
 
There will be up to 72 people in this group. 
 
• Group 2 – Investigational 
 
If you are in this group, you will get the study drugs called ramucirumab and 
pembrolizumab.  Ramucirumab will be given through your vein over 30-60 minutes 
followed by a 60-minute observation time before you are given pembrolizumab through 
your vein over 30 minutes.  You will receive ramucirumab and pembrolizumab for up to 
35 cycles (about two years) and then you will receive ramucirumab alone. If the infusion 
is well tolerated, the observation period may be reduced at the study doctor’s discretion.  
Each cycle lasts 21 days. Ramucirumab and pembrolizumab will be given on the first day 
of each cycle. You will receive treatment until your disease gets worse or the side effects 
become too severe. 
 
There will be up to 72 people in this group. 
 
We will use a computer to assign you to one of the study groups.  This process is called 
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group you are in.  You will be put into a group by chance. You will have an equal chance of 
being in Group 1 or Group 2. 
 
Another way to find out what will happen to you during this study is to read the chart below. 
Start reading at the left side and read across to the right, following the lines and arrows.  
 
 
 
  
What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study.  
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care.  We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 
effects.  
 
These exams, tests, and procedures to monitor your safety and health include:   
 
• A blood test to check thyroid function will be done every 3 cycles if you are receiving 
ramucirumab and/or pembrolizumab 
 
 
 
Randomize – 
The computer will 
randomly put you in a 
study group. 
Group 2 
Investigational 
(ramucirumab plus 
pembrolizumab) 
You agree to take 
part in the study 
and sign this 
consent form. 
Group 1 
Standard of Care 
(docetaxel, gemcitabine, 
pemetrexed or 
ramucirumab plus 
docetaxel) 
 


 
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Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
• Blood Test (circulating tumor DNA) before you begin the study and if your disease 
becomes worse 
 
You will be required to have about 1.5 tablespoons of your blood collected for the 
circulating tumor DNA testing.  An attempt will be made to do this blood draw at the 
same time as other blood draws. There is a chance that you will have another stick to 
obtain the blood. This blood will be tested for DNA not normally found in cells but that is 
present in your blood because it has been released from the tumors in your body.  The 
information collected will help the study doctors learn about tumor abnormalities that 
may play a role in tumor evolution. The results of this blood test are for research 
purposes. You and your doctor will not receive the results of this blood test. 
 
What risks can I expect from taking part in this study? 
 
General Risks 
 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer.   
 
You also may have the following discomforts: 
 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies.  
 
The drugs used in this study could be very harmful to an unborn or newborn baby.  There may be 
some risks that doctors do not yet know about.  It is very important that you check with your 
study doctor about what types of birth control or pregnancy prevention to use during the study 
and for 4 months after you have completed the study. 
 
Blood Draw Risks 
 
Common side effects of a blood draw are a small amount of bleeding at the time of the blood 
draw, brief pain, and maybe a bruise.  
  
 
 


 
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Side Effect Risks 
 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and let you know if changes 
occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study drugs. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
 
 


 
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Possible Side Effects of Docetaxel  
(Table Version Date: July 21, 2015) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving DOCETAXEL, more than 20 and up to 100 may have: 
• Swelling of the body 
• Hair loss 
• Change in nails 
• Rash, itching 
• Vomiting, diarrhea, nausea, constipation 
• Sores in mouth which may cause difficulty swallowing 
• Infection, especially when white blood cell count is low 
• Anemia which may require blood transfusions 
• Bruising, bleeding 
• Tiredness 
• Numbness and tingling of the arms and legs 
• Fever 
• Absence of menstrual period 
• Swelling and redness of the arms, leg or face 
• Pain 
• Watering, itchy eyes 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving DOCETAXEL, from 4 to 20 may have: 
• Severe skin rash with blisters and peeling which can involve inside of the mouth and 
other parts of the body. 
• Belly pain 
• Kidney damage which may require dialysis 
• Blood clot which may cause swelling, pain, shortness of breath 
• Abnormal heart rate 
• Shortness of breath, wheezing 
• Chest pain 
 
RARE, AND SERIOUS 
In 100 people receiving DOCETAXEL, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Cancer of bone marrow (leukemia) caused by chemotherapy 
 
 
 


 
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Possible Side Effects of Gemcitabine 
(Table Version Date: January 19, 2016) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving GEMCITABINE, more than 20 and up to 100 may have: 
• Flu-like symptoms of muscle pain, fever, headache, chills and fatigue 
• Nausea, vomiting 
• Rash 
• Hair loss 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Anemia which may require a blood transfusion 
• Muscle weakness 
• Blood in urine 
• Feeling of "pins and needles" in arms and legs 
• Numbness and tingling of the arms and legs 
• Tiredness 
• Difficulty sleeping 
• Swelling of arms, legs 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving GEMCITABINE, from 4 to 20 may have: 
• Swelling and redness of the area of radiation 
• Blisters on the skin 
• Diarrhea, constipation 
• Sores in mouth which may cause difficulty swallowing 
• Liver damage which may cause yellowing of eyes and skin, swelling 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Scarring of the lungs 
• Shortness of breath 
• Fluid in the organs which may cause low blood pressure, shortness of breath, swelling 
of ankles 
• Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may 
cause headache, seizure, blindness 
 
RARE, AND SERIOUS 
In 100 people receiving GEMCITABINE, 3 or fewer may have: 
• Severe blood Infection 
• Anemia, kidney problems which may require dialysis 
• Blood clot 
• Blockage of the airway which may cause cough 


 
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Possible Side Effects of Pemetrexed 
(Table Version Date: August 4, 2016) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving PEMETREXED, more than 20 and up to 100 may have: 
• Anemia which may cause tiredness, or may require blood transfusions 
• Constipation, nausea, vomiting, loss of appetite 
• Sores in mouth which may cause difficulty swallowing 
• Tiredness 
• Bruising, bleeding 
• Infection, especially when white blood cell count is low 
• Peeling of skin 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving PEMETREXED, from 4 to 20 may have: 
• Diarrhea 
• Swelling and redness of the area of radiation 
• Kidney damage which may cause swelling, may require dialysis 
• Liver damage which may cause yellowing of eyes and skin 
• Damage to the lungs which may cause shortness of breath 
• Scarring of the lungs 
• Itching 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of 
the body  
 
RARE, AND SERIOUS 
In 100 people receiving PEMETREXED, 3 or fewer may have: 
• Blockage of the bowels 
• Numbness and tingling of the arms and legs 
• Hair loss 
• Blood clot which may cause swelling, pain 
 
 
 


 
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Possible Side Effects of Dexamethasone 
(Table Version Date: September 22, 2017) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving DEXAMETHASONE, more than 20 and up to 100 may have: 
• High blood pressure which may cause headaches, dizziness 
• Pain in belly  
• Infection 
• Diabetes 
• Loss of bone tissue 
• Damage to the bone which may cause joint pain or loss of motion 
• Mood swings 
• In children and adolescents: decreased height 
• Swelling of the body, tiredness, bruising 
• Increased appetite and weight gain in belly, face, back and shoulders 
• Difficulty sleeping 
• Skin changes, rash, acne 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving DEXAMETHASONE, from 4 to 20 may have: 
• Blood clot which may cause swelling, pain, shortness of breath 
• Kidney stones 
• Glaucoma 
• Cloudiness of the eye, visual disturbances, blurred vision 
• A tear or a hole in the bowels which may cause pain or that may require surgery 
• Heartburn 
• Numbness and tingling of the arms, legs and upper body 
• Muscle weakness 
• Non-healing wound 
 
RARE, AND SERIOUS 
In 100 people receiving DEXAMETHASONE, 3 or fewer may have: 
• Bleeding from sores in stomach 
• Broken bones 
 
 
 


 
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Possible Side Effects of Ramucirumab  
(Table Version Date: April 2022) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving RAMUCIRUMAB, more than 20 and up to 100 may have: 
• Pain in belly 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving RAMUCIRUMAB, from 4 to 20 may have: 
• Anemia which may cause tiredness, or may require blood transfusion 
• An infection due to low white blood cells that may include fever, pain, redness, and/or 
difficulty breathing 
• High blood pressure 
• Diarrhea 
• Headache 
• Nosebleed 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving RAMUCIRUMAB, 3 or fewer may have: 
• Heart failure (heart stops beating) which may cause shortness of breath, chest pain, 
swelling of ankles, and tiredness 
• Stroke which may cause paralysis, weakness or headache 
• Blockage of the bowels which may cause pain, or vomiting 
• A tear or hole in the stomach and/or bowel which may cause pain and may require 
surgery 
 
Ramucirumab side effects have been observed in other clinical trials such as: 
• 
bleeding in the belly,  
• 
infusion related reaction which may cause fever, chills, rash, low blood pressure, 
• 
abnormal healing,  
• 
brain damage (possible headache, confusion, seizures, and/or vision loss),  
• 
and kidney damage which may cause swelling, and may require dialysis. 
 
Possible Side Effects of pembrolizumab (MK-3475): 
(CAEPR Version 2.6, July 15, 2021) 
 
Pembrolizumab (MK-3475) is an agent involved in the inhibition of “immune checkpoints,” and 
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and growth of immune cells (T-cells).  Immune-mediated side effects have been reported in 
patients receiving pembrolizumab (MK-3475).  In clinical trials, most immune-mediated side 
effects were reversible and managed by stopping pembrolizumab (MK-3475) temporarily, 
administration of corticosteroids and supportive care. 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving pembrolizumab (MK-3475), more than 20 and up to 100 may have: 
• Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving pembrolizumab (MK-3475), from 4 to 20 may have: 
• Nausea 
• Infection 
• Loss of appetite 
• Pain in back 
• Joint stiffness 
• Cough 
• Swelling and redness of the skin 
 
Pembrolizumab (MK-3475) may cause your immune system to attack normal organs and cause 
side effects in many parts of the body. These problems may include but are not limited to: 
 
• Anemia which may require blood transfusion 
• Pain in lymph nodes 
• Blood clot which may cause bleeding, confusion, paralysis, seizures and blindness 
• Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and 
pancreas). Signs and symptoms may include: headaches that will not go away or 
unusual headaches, extreme tiredness or changes in mood or behavior; decreased sex 
drive; weight loss or weight gain; excessive thirst or urine; dizziness or fainting 
• Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. Signs 
and symptoms of colitis may include: diarrhea or increase in bowel movements, blood 
in your stools or dark, tarry, sticky stools, severe belly pain or tenderness 
• Diarrhea 
• Sores in the mouth which may cause difficulty swallowing 
• Pain in belly 
• Sores in the bowels  
• Chills, fever 
• Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of 
hepatitis may include: yellowing of your skin or the whites of your eyes, severe nausea 
or vomiting; drowsiness; pain in the right upper belly 
• Pain or swelling of the joints 
• Problem of the muscle, including swelling, which can cause muscle pain and severe 
muscle weakness sometimes with dark urine 


 
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OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving pembrolizumab (MK-3475), from 4 to 20 may have: 
• Fluid in the joints  
• Pain in chest 
• Lung problems (pneumonitis and other conditions). Symptoms may include: new or 
worsening cough, chest pain, shortness of breath. 
• Skin: itching; acne; rash (can be severe); blisters and peeling on the skin, mouth; skin 
changes; hives 
 
 
RARE, AND SERIOUS 
In 100 people receiving pembrolizumab (MK-3475), 3 or fewer may have 
• A syndrome starting with flu-like symptoms and followed by swelling, tenderness 
which may cause flu-like symptoms, blurred vision, ringing in the ears, changes in hair 
or hair loss 
• Swelling of the gall bladder 
• Swelling of the spinal cord 
• Feeling of "pins and needles" in arms and legs 
• Redness, pain or peeling of palms and soles 
 
Pembrolizumab (MK-3475) may cause your immune system to attack normal organs and cause 
side effects in many parts of the body. These problems may include but are not limited to: 
 
• Heart problems including swelling and heart failure. Symptoms and signs of heart 
problems may include: Shortness of breath, swelling of the ankles and body 
• Swelling and redness of the eye 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Reaction during or following a drug infusion which may cause fever, chills, rash 
• Damage to organs in the body when donor cells attack host organs which may cause 
yellowing of eyes and skin, itchy dry skin  
• Damage to organs in the body when the body produces too many white cells 
• A condition with high blood sugar which leads to tiredness, frequent urination, 
excessive thirst, headache, nausea and vomiting, and can result in a coma 
• Problem of the nerves that can cause paralysis. Signs and symptoms may include: 
numbness, tingling of hands and feet; weakness of the arms, legs 
• Swelling of the brain (encephalitis/meningitis) which may cause headache, confusion, 
sleepiness, seizures, and stiff neck   
• Kidney problems, including nephritis and kidney failure requiring dialysis.  Signs of 
kidney problems may include: decrease in the amount of urine, blood in your urine, 
ankle swelling 
Swelling or tenderness of blood vessels 
 


 
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Pembrolizumab works by helping your immune system to fight your cancer. However, 
pembrolizumab can also cause your immune system to attack normal organs and tissues in your 
body and can affect the way they work, which can result in side effects. These side effects may 
be serious (i.e. causing hospitalization or be life-threatening), may result in death, and/or may 
occur after you stop taking pembrolizumab. These side effects can affect more than one of your 
normal organs and tissues at the same time. 
 
Additional Drug Risks 
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o and if you have been or are currently in another research study. 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  You must continue to use your approved 
method of birth control during the study and for 4 months after last dose. Tell your study doctor 
right away if you think that you or your partner have become pregnant during the study or within 
4 months after your last dose of study treatment. 
 
What are the costs of taking part in this study? 
 
You and/or your insurance plan will need to pay for the standard of care costs of medical care 
you get as part of the study, just as you would if you were getting the usual care for your cancer. 
This includes: 
 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
• the costs of getting the study agents (ramucirumab and pembrolizumab) ready and giving 
it to you. 
• the costs of the standard of care agents (docetaxel, gemcitabine, or pemetrexed) and 
getting it ready and giving it to you.  
• the costs of the supporting medications (dexamethasone, vitamin B12, and/or folic acid), 
and getting them ready and giving them to you 
• your insurance co-pays and deductibles. 
 


 
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Note: You or your insurance provider will not have to pay for the ramucirumab (for Study Group 
1 and Study Group 2) and pembrolizumab while you take part in this study.  
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
• The blood test for circulating tumor DNA at the beginning of the study and if your 
disease becomes worse. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment.   
 
What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court 
case.  However, some of your medical information may be given out if required by law.  If this 
should happen, the study doctors will do their best to make sure that any information that goes 
out to others will not identify who you are.  


 
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Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at your study records.  Your health information in the 
research database also may be shared with these organizations.  They must keep your 
information private, unless required by law to give it to another group.   
 
Some of these organizations are: 
 
• The study sponsor, SWOG and any company supporting the study now or in the future.  
• The NCI Central Institutional Review Board, (IRB), which is a group of people who 
review the research with the goal of protecting the people who take part in the study. 
• The Food and Drug Administration, (FDA), and the groups it works with to review 
research.   
• The National Cancer Institute, (NCI), and the groups it works with to review research. 
• The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research. 
• Transmission of Imaging and Data (TRIAD) and Imaging and Radiation Oncology Core 
(IROC) -Your medical images with clinical study data (e.g., the treatment Group you are 
assigned to, etc.) will be transferred using a computer program called TRIAD to IROC, a 
central imaging laboratory sponsored by the NCI and located at Ohio State University in 
Columbus, Ohio.  Your medical images will be reviewed by physicians at this 
organization as part of the study analysis for this trial.    
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information.  
 


 
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There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor. 
 
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
For questions about your rights while in this study, call the __________________ (insert name 
of organization or center) Institutional Review Board at __________________ (insert telephone 
number).  
 
Optional studies that you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 
with cancer in the future. The results will not be added to your medical records and you or your 
study doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies. There is no penalty for saying “no.” You and 
your insurance company will not be billed for these optional studies.  If you sign up for, but 
cannot complete any of these studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional sample collections for known laboratory studies and/or storage for possible 
future studies 
 


 
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Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Unknown future studies 
 
If you choose to take part in this optional study, your samples will be collected and stored. 
Storing samples for future studies is called “biobanking.”  The biobank is being run by SWOG 
and is supported by the NCI.  This is a publicly funded study. Samples from publicly funded 
studies are required to be shared as broadly as possible. However, we will protect your privacy. 
The goal of this is to make more research possible that may improve people’s health.  
 
The biobank is a public research resource. It has controlled access.  This means that researchers 
who want to get samples and data from it must submit a specific research request. The request 
identifies who they are and what their planned research project is. Before getting the samples and 
data, the researchers must agree to keep the data private, only use it for their planned research 
project, and never use it to try to identify you.  
   
Right now, we don’t know what research may be done in the future using your blood samples.  
This means that: 
 
• You will not be asked if you agree to take part in the future research studies.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
samples.  
 
Unknown future research studies may include sequencing of all or part of your DNA.  This is 
called genomic sequencing.  Sequencing allows researchers to identify your genetic code. 
Changes in your genetic code may be passed down through your family.  For example, these 
genetic changes may be passed down to your children in the same way that eye and hair color are 
passed down. These are called germline changes.   
 
 
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
 
1. About 2 teaspoons of blood will be collected from a vein in your arm (at the same time as 
other study blood tests) on Weeks 4, 7, 10, and again if your cancer gets worse.  


 
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2. Your samples will be stored in the biobank.  There is no limit on the length of time we 
will keep your samples and research information.  The samples will be kept until they are 
used for research or destroyed. 
3. Researchers can only get samples from the biobank after their research has been 
approved by experts.  Researchers will not be given your name or contact information.   
4. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information.   
 
What are the risks in this optional sample collection? 
 
1. The most common risks related to drawing blood from your arm are brief pain and maybe 
a bruise.   
2. Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
3. In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance.  There are laws against the misuse of genetic 
information, but they may not give full protection. For more information about the laws 
that protect you, ask your study doctor or visit:  https://www.genome.gov/10002328/  
 
How will information about me be kept private? 
 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
 
You will not benefit from taking part.  
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 


 
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There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, 
______________________ (insert name of study doctor for main trial) at __________________ 
(insert telephone number of study doctor for main trial), who will let the biobank know.  Then, 
any sample that remains in the biobank will be destroyed or returned to your study doctor.  This 
will not apply to any samples or related health information that have already been given to or 
used by researchers. 
 
What if I have questions about this optional sample collection? 
 
If you have questions about the use of your samples for research, contact the study doctor, 
______________________ (insert name of study doctor for main trial) at __________________ 
(insert telephone number of study doctor for main trial). 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for unknown future studies: 
 
1. 
My samples and related information may be kept in a Biobank for use in future 
health research. 
 
YES 
 
NO 
 
Contact for Future Research 
 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future.  
 
YES 
NO 
 
This is the end of the section about optional studies. 
 
 


 
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My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circled 
“yes.” 
 
 
Participant’s signature (or legally authorized representative)   
 
_____________________________________________________________________________  
 
Date of signature 
____________________________________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion 
 
______________________________________________________________________________
 
 
Date of signature 
____________________________________________________________