A Randomized Phase II Trial of Carboplatin-Paclitaxel With or Without Ramucirumab in Patients With Unresectable Locally Advanced, Recurrent, or Metastatic Thymic Carcinoma
Phase: PHASE2
Conditions: Locally Advanced Thymic Carcinoma, Metastatic Thymic Carcinoma, Recurrent Thymic Carcinoma, Unresectable Thymic Carcinoma
Sponsor: SWOG Cancer Research Network

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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
TITLE PAGE 
A RANDOMIZED PHASE II TRIAL OF CARBOPLATIN-PACLITAXEL WITH OR WITHOUT 
RAMUCIRUMAB IN PATIENTS WITH UNRESECTABLE LOCALLY ADVANCED, RECURRENT, OR 
METASTATIC THYMIC CARCINOMA. 
 
NCT#03694002 
 
 
STUDY CHAIRS: 
AGENTS: 
 
Anne Tsao, M.D. (Primary Chair: Medical Oncology) 
Commercially Available Agents:   
M.D. Anderson Cancer Center 
Carboplatin (CBDCA) (NSC-241240) 
1515 Holcombe Blvd. Unit 432 
Paclitaxel, Taxol® (NSC-673089) 
Houston, TX 77030 
 
Phone: 713/792-6363 
SWOG Held IND Agents: 
FAX: 713/792-1220 
Ramucirumab (NSC-749128) (IND 139595) 
E-mail: astsao@mdanderson.org  
 
Marianna Koczywas, M.D. (Medical Oncology) 
City of Hope National Medical Center 
1500 E Duarte Road 
Duarte, CA  91010 
Phone: 626/359-8111 ext: 69200  
 
FAX:  626/301-8898 
E-mail: mkoczywas@coh.org  
 
 
BIOSTATISTICIANS: 
 
Yingqi Zhao, Ph.D. 
Lu Qian, M.S. 
SWOG Statistics and Data Management Center 
1100 Fairview Ave N, M3-C102 
PO Box 190204 
Seattle, WA 98109-1024 
Phone: 206/667-4623 
FAX: 206/667-4408 
E-mail:  yqzhao@fredhutch.org  
E-mail: lqian@fredhutch.org  
 
 
ECOG-ACRIN Champion: 
 
Martin J. Edelman, M.D. 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone:  215/728-5682 
E-mail:  martin.edelman@fccc.edu  
 
 
 
 

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PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 
 

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TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................................................. 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective(s) ......................................................................................................................... 7 
1.2 
Secondary Objective(s) .................................................................................................................... 7 
1.3 
Additional Objective(s) ..................................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 7 
3.0 
DRUG INFORMATION .................................................................................................................. 11 
3.1 
Carboplatin (CBDCA) (NSC-241240) ............................................................................................ 11 
3.2 
Paclitaxel, Taxol® (NSC-673089) ................................................................................................... 13 
3.3 
Ramucirumab (Cyramza™, IMC-1121B, LY3009806) (NSC-749128, IND #139595) ................... 15 
4.0 
STAGING CRITERIA ..................................................................................................................... 19 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 19 
5.1 
Disease Related Criteria ................................................................................................................ 19 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 20 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 21 
5.4 
Specimen Submission Criteria ....................................................................................................... 22 
5.5 
Regulatory Criteria ......................................................................................................................... 22 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 22 
7.0 
TREATMENT PLAN ...................................................................................................................... 23 
7.1 
Pre-Medication ............................................................................................................................... 23 
7.2 
Treatment ....................................................................................................................................... 23 
7.3 
Criteria for Removal from Protocol Treatment ............................................................................... 24 
7.4 
Discontinuation of Treatment ......................................................................................................... 24 
7.5 
Follow-Up Period ............................................................................................................................ 24 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 24 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 24 
8.2 
General Dose Modification Guidelines ........................................................................................... 25 
8.3 
Dose Reductions for Carboplatin, Paclitaxel, and Ramucirumab .................................................. 25 
8.4 
Paclitaxel/Carboplatin Dose Modifications ..................................................................................... 25 
8.5 
Ramucirumab Discontinuations due to Toxicity ............................................................................. 29 
8.6 
Dose Modification Contacts ........................................................................................................... 31 
8.7 
Adverse Event Reporting ............................................................................................................... 31 
9.0 
STUDY CALENDAR ...................................................................................................................... 32 
9.1 
Arm A Carboplatin (CBDCA), Paclitaxel (Taxol®), and Ramucirumab (Cyramza™, IMC-1121B, 
LY3009806) .................................................................................................................................... 32 
9.2  
Arm B Carboplatin (CBDCA) and Paclitaxel (Taxol®) ................................................................... 35 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 38 
10.1 
Measurability of Lesions................................................................................................................. 38 
10.2 
Objective Status at Each Disease Evaluation ................................................................................ 39 
10.3 
Best Response ............................................................................................................................... 40 
10.4 
Performance Status ....................................................................................................................... 41 
10.5 
Time to Death ................................................................................................................................. 41 
10.6 
Progression-Free Survival ............................................................................................................. 41 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 42 
11.1 
Primary Objective and Power Justification ..................................................................................... 42 
11.2 
Secondary Objectives and Interim Analysis .................................................................................. 42 
11.3 
Accrual ........................................................................................................................................... 42 
11.4 
Data and Safety Monitoring Committee ......................................................................................... 42 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 43 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 43 
13.1 
Registration Timing ........................................................................................................................ 43 

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13.2 
Investigator/Site Registration ......................................................................................................... 43 
13.3 
OPEN Registration Requirements ................................................................................................. 46 
13.4 
Registration Procedures................................................................................................................. 47 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 48 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 48 
14.1 
Data Submission Requirement ...................................................................................................... 48 
14.2 
Master Forms ................................................................................................................................. 48 
14.3 
Data Submission Procedures ........................................................................................................ 48 
14.4 
Data Submission Overview and Time points ................................................................................. 49 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 50 
15.1 
Translational Medicine and Banking (OPTIONAL FOR PATIENT) ............................................... 50 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 52 
16.1 
ADVERSE EVENT REPORTING REQUIREMENTS .................................................................... 53 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 59 
18.0 
APPENDIX ..................................................................................................................................... 62 
18.1  
Child-Pugh Scoring ........................................................................................................................ 63 
18.2 
AUC CALCULATION ..................................................................................................................... 64 
18.3  
Carboplatin Dosing Worksheet ...................................................................................................... 65 
 

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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 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
at 866-651-2878 to receive 
further information and support.   
 
Contact the CTSU Regulatory 
Help Desk at 866-651-2878 for 
regulatory assistance. 
 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com.  
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see 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 
Workbench. Access this by 
using your active CTEP-IAM 
user ID and password at the 
following url: 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 on 
with CTEP-IAM username and password.  
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center by phone or email: 
206/652-2267 
lungquestion@crab.org  
 
For treatment or toxicity related questions contact the Study Chairs Anne Tsao, M.D. and Marianna 
Koczywas, M.D., at S1701Medical@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 – 1-888-823-5923, or ctsucontact@westat.com.   All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org.  
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
    No 
 
 
 
 
 
 
Patients with unresectable 
metastatic locally advanced, or 
recurrent thymic carcinoma 
Randomization 
ARM A 
Carboplatin 
Paclitaxel 
Ramucirumab  
Max. 6 cycles 
(Cycle length = 21 days) 
ARM B 
Carboplatin 
Paclitaxel 
Max. 6 cycle 
(Cycle length = 21 days) 
Off treatment 
Patient Progression? 
Off treatment 
Ramucirumab 
up to one year 
after 
randomization 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objective(s) 
 
a. 
The primary study objective is to compare progression-free survival between 
patients with incurable unresectable locally advanced, or recurrent, or metastatic 
thymic carcinoma randomized to carboplatin-paclitaxel with or without 
ramucirumab 
 
1.2 
Secondary Objective(s) 
 
a. 
To evaluate the frequency and severity of toxicity of carboplatin-paclitaxel with or 
without ramucirumab in this patient population 
 
b. 
To compare the response rate (complete response, partial response, confirmed 
and unconfirmed) between treatment arms in the subset of this patient population 
with measurable disease 
 
c. 
To compare disease control rate (complete response, partial response, confirmed 
or unconfirmed, stable disease) between treatment arms in the subset of this 
patient population with measurable disease 
 
d. 
To compare overall survival between treatment arms 
 
1.3 
Additional Objective(s) 
 
a. 
To bank specimens for future research 
 
2.0 
BACKGROUND 
 
Thymic carcinoma is a rare malignancy that arises from the thymus.  It is histologically classified 
as WHO type C thymoma and is a distinct entity from thymomas – they are composed of highly 
atypical cells similar in features to other carcinomas and lack any immature T-cell lymphocytes. 
Most thymic carcinomas are well-differentiated squamous cell carcinomas but other histologies 
such as mucoepidermoid carcinoma, basaloid carcinoma, clear cell carcinoma, sarcomatoid 
carcinoma, small cell carcinoma, and anaplastic/undifferentiated carcinoma can occur.   Unlike 
thymoma (WHO type A, AB, B), development of myasthenia gravis and other paraneoplastic 
syndromes are rare in thymic carcinoma. 
 
Thymic carcinoma has an incidence of 1.3 per 1000000 persons per year in the USA. (1) Patients 
with this disease are typically between 40 and 60 years old and are more likely to have locally 
invasive or distant metastasis than patients with thymoma WHO types A-B.  (2,3)  To date, there 
are few trials that have evaluated frontline chemotherapy regimens for thymic carcinoma.  The 
current literature, based on retrospective analyses and small Phase II non-randomized trials (see 
Table 1), indicates that carboplatin-paclitaxel is the preferred regimen for thymic carcinoma. 
(4,5,6,7,8)  It is the recommended regimen in the NCCN guidelines.    
 
In thymic carcinoma, carboplatin-paclitaxel yields response rates of 21.7% to 37.5%. 
(9,10,11,12,13) The median PFS ranges from 5 to 8.6 months, while median OS ranges from 20 
to 49.4 months.  Of note, 3 of the listed prospective trials, and the retrospective study are from 
Japan.  (14,15,16,17) However, the Lemma et al. (18) study was conducted in 4 centers in the 
United States.  It is clear, based on these clinical results, there is a critical need for developing 
novel therapies in thymic carcinoma. 
 
 

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Table 1: Single-arm clinical trials with carboplatin-paclitaxel in thymic carcinoma patients. 
Author 
Dose 
Thymic 
Carcinoma 
(n) 
ORR 
Median 
PFS 
(months) 
Median OS 
(months) 
Igawa et al.3 
Carbo AUC 6 
Paclitaxel 
200 mg/m2 
11 
36% 
7.9 
22.7 
Furugen et al.4   
Carbo AUC 6 
Paclitaxel 
200 mg/m2 
16 
37.5% 
8.6 
49.4 
Lemma et al.5 
Carbo AUC 6 
Paclitaxel 
225 mg/m2 
23 
21.7% 
5 
20 
Takeda et al.6  
Carbo AUC 6 
Paclitaxel 
200 mg/m2 
40 
36% 
7.5 
NR 
Maruyama et al.7* 
Carbo AUC 6 
Paclitaxel 
200 mg/m2 
5 
100% 
11** 
32 
* 
retrospective single institution analysis 
** reported as median duration of response 
 
Novel targets for thymic carcinoma have been challenging to identify.  Several publications have 
reported anecdotal C-KIT mutations (see Table 2) that have responded to targeted agents, but 
other case series suggest that the benefit of the angiogenic agents may be independent of KIT 
mutations.  Several biomarkers of the angiogenic pathway, such as VEGF-A, VEGFR-1, and 
VEGFR-2 are known to be overexpressed in thymic carcinomas, and their immunohistochemical 
(IHC) expression levels correlate with tumor invasiveness and clinical stage. (19,20)  In addition, 
serum VEGF is also highly upregulated in thymic carcinoma patients, suggesting an active pathway 
in carcinogenesis. (21)  
 
Anti-angiogenic agents have been assessed in combined trials enrolling both thymomas and thymic 
carcinomas in small early phase clinical trials.  However, many of these reports were derived from 
monotherapy agent studies, and none are in combination with chemotherapy, where a synergistic 
effect with anti-angiogenic agents may be found.  However, even as monotherapy, this class of 
agents does appear to have clinical benefit in both thymoma and thymic carcinomas.  For thymoma 
patients, a Phase I trial of SU14813 (VEGFRs, PDGFRs, KIT, and FLT-3), enrolled 4 thymoma 
patients with 2 patients achieving a PR with response durations of 15.3 and 9.0 months. (22)  
Motesanib diphosphate (AMG 706), and oral inhibitor of VEGFR-1,2,3, PDGFR and KIT, stabilized 
a metastatic thymoma patient for 1 year. (23)  Other thymoma case reports have noted benefit with 
sorafenib (inhibits VEGFR, PDGFR, Raf family kinases) as monotherapy and in combinations. (24)  
 
Specifically for thymic carcinoma, 5 separate case reports (see Table 2) showing durable partial 
responses to sorafenib in patients with refractory, previously treated thymic carcinoma. 

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(25,26,27,28,29) A case series of 4 chemo-refractory thymic carcinoma patients reported 
significant response durations over 1 year with sunitinib (inhibits all PDGFR, all VEGFR, KIT, 
CSF1R, FLT3, and glial cell line-derived neurotropic factor receptor). (30) A prospective Phase II 
trial administering sunitinib in platinum-refractory thymoma/thymic carcinoma reported in the thymic 
carcinoma cohort (n=23 evaluable) a 26% PR and 65% stable disease (SD). (31)  In this trial, there 
were no mutations in KIT detected in thirteen of the 25 patients.  4 of the 6 responders were 
assessed and did not carry actionable mutations; suggesting that the response to sunitinib was 
independent of a KIT mutation.  A Phase II trial of bevacizumab-erlotinib (NCT 00369889) in 
refractory thymoma and thymic cancers has completed enrollment, but results are still pending. 
 
Table 2: Clinical trials or case reports evaluating anti-angiogenic agents in thymic 
carcinoma patients.  
Author 
Agent 
Thymic 
Carcino-
ma (n) 
ORR 
Median 
PFS 
(months) 
Median OS 
(months) 
KIT Mutations 
and/or Protein 
expression 
Thomas et al.20 
Sunitinib 
25 
26% 
7.2 
Not reached 
1-yr OS 78% 
No mutations 
detected in 13 
patients (4 of 6 
responders had 
tumor evaluation) 
Strobel et al.19 
Sunitinib 
4 
3 PR 
1 
PR/SD 
2 not 
reported, 
18+ 
months, 
14+ months 
2 not reported, 
40+ months, 4 
months 
No mutations 
detected. High 
expression of C-
KIT IHC on all 4 
cases.   
Pagano et al. 
Sorafenib 
5 
2 PR 
2 SD 
1 PD 
28 weeks 
92 weeks 
1 C-KIT mutation 
exon 17 (D820E) 
in responder. 
Li et al.16 
Sorafenib 
1 
1 PR 
9+ months 
Not reported 
High expression of 
C-KIT IHC; 
mutations not 
assessed. 
Bisagni et al.14 
Sorafenib 
1 
1 PR 
15+ months 
Not reported 
C-KIT missense 
mutation exon 17 
(D820E) 
Disel et al.15 
Sorafenib 
1 
1 PR 
6+ months 
Not reported 
C-KIT deletion 
mutation exon 11, 
also amplified  
Catania et al.18 
Sorafenib 
1 
1 PR 
6 months 
3 years 
C-KIT missense 
mutation exon 13 
(K642E) 
Neuhaus et 
al.17 
Sorafenib 
1 
1 PR 
18 months 
21 months 
C-KIT mutations 
not assessed.  C-
KIT IHC negative.  
EGFR gene 
amplification 
noted.  
Anti-angiogenic Trials that include thymic carcinoma patients 
NCT00369889 
Bevacizu
mab 
Erlotinib 
refractory 
- 
- 
- 
- 
NCT01621568 
Sunitinib 
alternate 
dosing 
refractory 
- 
- 
- 
 

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Author 
Agent 
Thymic 
Carcino-
ma (n) 
ORR 
Median 
PFS 
(months) 
Median OS 
(months) 
KIT Mutations 
and/or Protein 
expression 
with 
3-week 
cycle 
NCT02623127 
Sunitinib 
refractory 
- 
- 
- 
- 
 
Note – several studies included other tumor types, such as thymoma or other solid tumors.  Table 
2 depicts only the thymic carcinoma patients. 
 
Currently, there is 2 active thymic malignancy trials in the world with anti-angiogenic agents in the 
chemo-refractory salvage setting.  The KOSMIC trial (NCT02623127), a Phase II study of sunitinib, 
is being conducted in South Korea with the primary endpoint of ORR.  A second trial that utilizes 
an alternative schedule of sunitinib (NCT01621568) is ongoing at Indiana University. 
 
Recently, ramucirumab, a fully humanized monoclonal antibody that targets VEGFR-2 has 
achieved regulatory approval in several tumor types. It has demonstrated activity as single agent 
and in combination with paclitaxel in 2 large, randomized trials for the treatment of refractory 
gastroesophageal cancer. (32)  Also, ramucirumab was FDA approved in the second line setting 
for NSCLC in combination with docetaxel (REVEL trial). (33) The addition of ramucirumab to 
docetaxel improved response rates (22.9% vs. 12.6%); median PFS (4.5 vs. 3 months); and median 
OS, the primary study end-point (10.5 vs. 9.1 months). (34,35) Based on its positive synergistic 
activity with chemotherapy and its reasonable preservation of quality of life, ramucirumab would be 
a potential agent to study in thymic carcinoma in combination with chemotherapy. 
 
The pre-clinical evidence of overexpression of VEGF receptors in thymic carcinoma together with 
the preliminary results of clinical activity of VEGFR inhibitors in refractory thymic carcinomas, 
suggest that anti-angiogenic therapy is a rationale therapeutic option and should be further 
evaluated in thymic carcinoma patients.  This benefit appears to be independent of any actionable 
mutation and should be investigated further. 
 
Given the positive results in gastroesophageal and NSCLC, there is significant rationale to believe 
that the combination of ramucirumab with chemotherapy will improve clinical outcomes of 
inoperable, advanced thymic carcinomas.  As there is currently no FDA approved targeted agent 
in thymic carcinoma, there is a significant opportunity for ramucirumab to become utilized in the 
front-line setting for this orphan disease.   We hypothesize that the triplet regimen of carboplatin-
paclitaxel-ramucirumab may have efficacy in thymic carcinoma.   Of note, the triplet regimen of 
carboplatin-paclitaxel with VEGF ligand inhibitor bevacizumab, is utilized in NSCLC and is a well-
tolerated frontline regimen.  We do not anticipate any safety issues or have any concerns with 
replacing bevacizumab with ramucirumab. 
 
 

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Inclusion of Women and Minorities 
 
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 
0 
0 
0 
0 
Asian 
3 
1 
0 
0 
4 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
 
0 
Black or African 
American 
3 
1 
0 
0 
4 
White 
39 
12 
5 
1 
57 
More Than One 
Race 
1 
0 
0 
0 
1 
Total 
46 
14 
5 
1 
66 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures  
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, carboplatin and paclitaxel are commercially available; therefore, Investigator 
Brochures are not applicable to these drugs.  Information about commercial drugs is publicly 
available in the prescribing information and other resources. 
 
For this study, ramucirumab is investigational and is being provided under an IND held by SWOG.  
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, further information may be requested by contacting 
the SWOG Operations Office at 210/614-8808. 
 
3.1 
Carboplatin (CBDCA) (NSC-241240) 
 
a. 
DESCRIPTION 
 
Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an 
analog of cisplatin, producing intrastrand DNA cross-links. 
 
b. 
TOXICOLOGY 
 
Human 
Toxicology: 
 
Side 
effects 
of 
carboplatin 
(CBDCA) 
include 
myelosuppression, nausea, vomiting, abdominal pain, diarrhea, and constipation.  
Other toxicities include allergic reaction (including hypersensitivity, i.e., rash, 
urticaria, erythema, pruritus, bronchospasm, and hypotension), peripheral 
neuropathy, paresthesia, loss of hair, hearing loss, visual disturbances and change 
in taste.  Serum creatinine elevations and blood urea elevations have occurred as 
well as abnormal liver function tests and decreased serum electrolyte values.  

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Although rare, pain, asthenia, cardiovascular, respiratory, genitourinary, and 
mucosal side effects have occurred in some patients.  Cancer-associated 
hemolytic uremic syndrome has been reported rarely.  The renal effects of 
nephrotoxic compounds may be potentiated by carboplatin.  Carboplatin is 
contraindicated in patients with a history of severe allergic reactions to cisplatin or 
other platinum-containing compounds or mannitol.  This drug should not be used 
in patients with severe bone marrow depression or significant bleeding.  The 
occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy.  
 
Pregnancy and Lactation:  Carboplatin may cause fetal harm; therefore, women of 
childbearing potential should be advised to avoid becoming pregnant. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  The differences in potencies of carboplatin and cisplatin are due to 
differences in aquation rates.  The initial half-life is 1.1 - 2.0 hours and the post-
distributional half-life is 2.6 - 5.9 hours.  65% of the dose is excreted in the urine 
within 12 hours.  Carboplatin is not bound to plasma proteins. 
 
Formulation:  Carboplatin is supplied as a sterile lyophilized powder available in 
single-dose vials containing 50 mg, 150 mg, and 450 mg of carboplatin for 
administration by intravenous injection.  Each vial contains equal parts by weight 
of carboplatin and mannitol.  Immediately before use, the content of each vial must 
be reconstituted with either Sterile Water for Injection, USP, 5% Dextrose in Water, 
or 0.9% Sodium Chloride Injection, USP, according to the following schedule: 
 
Vial Strength 
Diluent Volume 
 
 
50 mg 
5 ml 
150 mg 
15 ml 
450 mg 
45 ml 
 
 
These dilutions all produce a carboplatin concentration of 10 mg/mL.  Carboplatin 
can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in 
Water or 0.9% Sodium Chloride Injection, USP (NS). 
 
Carboplatin is also supplied as a solution for injection in vials containing 50 mg, 
150 mg, 450 mg, and 600 mg with a concentration of 10 mg/mL. 
 
Storage and Stability:  Unopened vials of carboplatin for injection are stable for the 
life indicated on the package when stored at controlled room temperature 15° - 
30°C and protected from light.  When reconstituted as directed, the solution of 
carboplatin exhibits no decomposition for 8 hours at room temperature (25°C).  
Like cisplatin, this drug should not be given through aluminum needles.  
CAUTION:  The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Therefore, it is advised that the reconstituted product be discarded 
8 hours after dilution. 
 
Administration:  Intravenous. 
 
Supplier:  Carboplatin is commercially available for purchase by the third party.  
This drug will not be supplied by the NCI. 
 

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Please refer to the Physician Desk Reference and package insert for complete 
information. 
 
3.2 
Paclitaxel, Taxol® (NSC-673089)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Paclitaxel is a diterpene plant product found in the 
needles and bark of the western yew, Taxus brevifolia.  The marketed 
formulation is prepared in a semi-synthetic process. Paclitaxel is a novel 
antimicrotubule agent that promotes the assembly of microtubules from 
tubulin 
dimers 
and 
stabilizes 
microtubules 
by 
preventing 
depolymerization.  This stabilization results in the inhibition of the normal 
dynamic reorganization of the microtubule network that is required for vital 
interphase and mitotic cellular functions.  In addition, paclitaxel induces 
abnormal arrays or “bundles” of microtubules throughout the cell cycle 
which interrupt mitosis.   
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Following intravenous administration of paclitaxel, the drug, 
plasma concentrations declined in a biphasic manner. The initial rapid 
decline represents distribution to the peripheral compartment and 
elimination of the drug. The later phase is a result, in part, of a relatively 
slow efflux of paclitaxel from the peripheral compartment. 
 
2. 
Distribution: In vitro studies of paclitaxel binding to human serum proteins 
using concentrations from 0.1 to 50 microgram/mL indicated that between 
89%-98% of paclitaxel is protein bound.  A Phase III study comparing 3- 
and 24-hour infusion showed that with a 24-hour infusion of paclitaxel, a 
30% increase in dose (135 mg/m2 vs 175 mg/m2) increased the maximum 
plasma concentration (Cmax) by 87%, whereas the area under the plasma 
concentration-time curve from time 0 to infinity [AUC(0-∞)] remained 
proportional. However, with a 3-hour infusion, for a 30% increase in dose, 
the Cmax and AUC(0-) were increased by 68% and 89%, respectively.  
The mean apparent volume of distribution at steady state, with the 24-hour 
infusion of paclitaxel, ranged from 227 to 688 L/m2, indicating extensive 
extravascular distribution and/or tissue binding of paclitaxel. 
 
3. 
Metabolism: Paclitaxel is metabolized via the cytochrome P450 
isoenzyme CYP2C8 to one major inactive metabolite (6-alpha-
hydroxypaclitaxel), and via the cytochrome P450 isoenzyme CYP3A4 to 2 
minor inactive metabolites (3-para-hydroxypaclitaxel and 6-alpha, 3-para-
dihydroxypaclitaxel).  There is limited evidence that the myelotoxicity of 
paclitaxel may be exacerbated in patients with serum total bilirubin >2 
times upper limit of normal and therefore, caution should be used when 
administering paclitaxel to patients with liver dysfunction. 
 
4. 
Elimination: Following the administration paclitaxel, the cumulative urinary 
recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, 
indicating extensive non-renal clearance.  Using radiolabeled paclitaxel 
infusion showed that unchanged paclitaxel in the feces accounted for 5% 
of the administered dose while total recovery of paclitaxel and its 
metabolites in the feces accounted for 56% to 101% of the administered 

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dose. The elimination half-life of paclitaxel ranged between 13.1 and 52.7 
hours. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Paclitaxel:  adverse effects reported in >20% of 
patients include anemia, infection, diarrhea, nausea, vomiting, mucositis, 
allergic reaction which may cause rash, hypotension, wheezing, shortness 
of breath, facial edema and swelling of the throat, asthenia, parathesia, 
and alopecia. 
 
Human Toxicity: 
Dose-limiting 
toxicity 
is 
myelosuppression 
with 
reversible 
granulocytopenia, anemia, and thrombocytopenia.  Allergic reactions 
occur in up to 8% of patients receiving paclitaxel as an intravenous 
infusion over 6 to 24 hours.  These can be acute anaphylactoid reactions 
to include flushing, hypotension, and bronchospasm; dermatitis and 
pruritus are also observed.  Hypertension has also been seen and may be 
related to concomitant medication with dexamethasone.  Premedication 
with diphenhydramine, cimetidine, and dexamethasone appears to 
diminish the incidence of these reactions.  Neurotoxicity can include distal 
painful paresthesias.  Rarely, this toxicity has required discontinuation of 
drug due to pain, impairment of fine motor skills, or difficulty ambulating.  
Experience to date suggests that this neuropathy is reversible.  Rarely, 
associated forms of neurotoxicity have included taste perversion, 
seizures, and mood changes.  Some patients have reported vision 
abnormalities such as blurred vision, "flashing lights" and scintillating 
scotomata.  Ischemic or infarcted colon, sometimes with involvement of 
other parts of the gastrointestinal tract, has also been seen.  Patients 
reporting abdominal discomfort should be monitored closely.  These 
events generally occurred while the patients were severely neutropenic.  
They may be most consistent with neutropenic enterocolitis (typhlitis).  
Although increased SGOT, SGPT, bilirubin and alkaline phosphatase, as 
well as hepatic failure and hepatic necrosis have been seen, one patient 
receiving this drug has also experienced hepatic encephalopathy, and two 
incidences of pancreatitis have been noted.  Neuroencephalopathy has 
also been reported.  Pulmonary toxicities that have occurred are 
pneumonitis and radiation pneumonitis (following concomitant paclitaxel 
and radiation). 
 
Other non-hematologic reactions include diarrhea, alopecia, myalgias and 
arthralgias, nausea or vomiting, mucositis (stomatitis and pharyngitis), 
light-headedness, myopathy, and fatigue.  Less commonly, cardiotoxicity 
has been associated with paclitaxel administration, to include arrhythmias 
(sinus bradycardia, ventricular tachycardia, atrial arrhythmia, and heart 
block), and myocardial infarction.  Skin reactions including erythema, 
induration, tenderness, ulceration, radiation recall, rash and nail changes 
have occurred including discoloration of fingernails and separation from 
nail bed. 
 
Post marketing experience with paclitaxel protein-bound particles for 
injectable suspension (Abraxane®) indicated reports of congestive heart 
failure, left ventricular dysfunction, and atrioventricular block with 
Abraxane.  Most of the affected individuals were previously exposed to 

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cardiotoxic drugs, such as anthracyclines, or had underlying cardiac 
history. 
When paclitaxel protein-bound particles for injectable suspension was 
administered in combination with gemcitabine, sepsis occurred in patients 
with or without neutropenia.  Risk factors for severe or fatal sepsis included 
biliary obstruction or presence of biliary stent. 
 
Refer to the current FDA-approved paclitaxel package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
I. 
Pregnancy and Lactation: Pregnancy Category D.  Paclitaxel may 
cause fetal harm when administered to a pregnant woman.  
Paclitaxel has been shown to be embryo- and fetotoxic in rats and 
rabbits and to decrease fertility in rats.  In these studies, paclitaxel 
was shown to result in abortions, decreased corpora lutea, a 
decrease in implanatations and live fetuses, and increased 
resorption and embryo-fetal deaths.  No information is available 
on the excretion of this drug in human milk.  Because many drugs 
are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants, it is recommended 
that nursing be discontinued. 
 
II. 
Drug Interactions: Paclitaxel metabolism is catalyzed by 
cytochrome P450 (CYP450) isoenzymes CYP2C8 and CYP3A4.  
Caution should be exercised when paclitaxel is co-administered 
with substrates, inhibitors, and inducers of CYP3A4 and CYP2C8.  
In addition, plasma levels of doxorubicin (and its active metabolite 
doxorubicinol) may be increased when paclitaxel and liposomal 
doxorubicin are used in combination. Although this interaction has 
not been reported with doxorubicin hydrochloride injection, the 
potential for the same reaction is possible.  In a Phase I trial, 
sequential infusions of escalating doses of paclitaxel and cisplatin 
showed that administration of paclitaxel after cisplatin may 
decrease the clearance of paclitaxel and cause profound 
myelosuppression. 
 
Due to potential drug interactions, a complete patient medication list, including 
paclitaxel, should be screened prior to initiation of and during treatment with 
paclitaxel. See Section 8.0 Toxicities to be Monitored and Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED  
 
Paclitaxel 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. 
 
3.3 
Ramucirumab (Cyramza™, IMC-1121B, LY3009806) (NSC-749128, IND #139595) 
 

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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 
 
1. 
Absorption: Ramucirumab is given via intravenous infusion. 
 
2. 
Distribution: In population pharmacokinetic models involving 2,820 
patients, the mean volume of distribution (Vd) of ramucirumab at steady 
state was 4.47 L.  
 
3. 
Metabolism: As a monoclonal antibody, ramucirumab is largely confined 
to the extracellular space, and elimination is primarily by catabolism. 
4. 
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. 
 
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 
 

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Adverse Events with 
Possible Relationship to Ramucirumab 
Likely (> 20%) 
Less Likely (4 – 
≤ 20%) 
Rare but Serious (≤ 3%) 
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 and 
gastrointestinal hemorrhage, infusion related reactions, impaired wound healing, 
Posterior Reversible Encephalopathy Syndrome (PRES), nephrotic syndrome, 
thyroid dysfunction, and worsening of pre-existing hepatic impairment.  
 
2. 
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 
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 3 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. 
It is not known whether ramucirumab is secreted in human milk. Women 
should not breastfeed during treatment with ramucirumab and for 2 
months after the last dose. 
 
3. 
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. 
 
 

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e. 
HOW SUPPLIED 
 
1. 
Ramucirumab will be supplied free of charge by Eli Lilly and distributed by 
McKesson. 
 
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. 
 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
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.   
 
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. 
 
 

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g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug ordering: Drug orders must be submitted by faxing the Drug Order 
Form – SWOG S1701 to McKesson at the number listed on the order form.  
This form can be found on the CTSU website (www.CTSU.org). 
 
2. 
Drug Handling and Accountability: Drug Accountability: The investigator, 
or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, disposition, and return or disposal of all drugs 
received from the supplier using the NCI Drug Accountability Record Form 
(DARF) available at http://ctep.cancer.gov. 
 
Electronic logs are allowed as long as a print version of the log process is 
the exact same appearance as the current NCI Oral DARF. 
 
3. 
Drug Returns: Unused drug supplies should NOT be returned. Unused 
drug should be disposed of per local institutional guidelines. 
 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to protocols@swog.org. 
 
4.0 
STAGING CRITERIA 
 
Not applicable for this study. 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met for a patient to be considered eligible for 
registration.  For each criterion requiring test results and dates, please record this information on 
the On study Form and submit via Medidata Rave® (see Section 14.0).  Any potential eligibility 
issues should be addressed to the Data Operations Center in Seattle at 206/652-2267 or 
lungquestion@crab.org prior to registration. 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 28 falls on a weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must be ≥ 18 years of age. 
 
b. 
Patients 
must 
have 
histologically 
or 
cytologically 
confirmed 
thymic 
carcinoma.  Thymic carcinoma may be defined as “thymic epithelial malignancy, 
consistent with thymic carcinoma”, or “WHO Type C thymic epithelial tumor”, or 
“thymic epithelial malignancy” with radiographic imaging consistent with thymic 
carcinoma.  
 
c. 
Patients must have unresectable thymic carcinoma, defined in Section 5.1.b., that 
is either locally advanced, recurrent, or metastatic. 
 
d. 
Patients must not be candidates for localized surgery. 
 
e. 
Patients must have measurable or non-measurable disease (See Section10.1) 
documented by CT or MRI.  Measurable disease must be assessed within 28 days 

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prior to randomization.  Non-measurable disease must be assessed within 42 days 
prior to randomization. The CT from a combined PET/CT may be used only if it is 
of diagnostic quality as defined in Section 10.1a. All known sites of disease must 
be assessed and documented on the Baseline Tumor Assessment Form (RECIST 
1.1). 
 
f. 
Patients must have a Zubrod performance status of 0 to 2 (See Section 10.4). 
 
g. 
Patients must not have undergone major surgery within 28 calendar days prior to 
randomization, or minor surgery/subcutaneous venous access device placement 
within 7 calendar days prior to randomization. The patient must not have elective 
or planned major surgery to be performed during the clinical trial. 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must not have had prior systemic anti-cancer therapy for locally advanced 
or metastatic unresectable thymic carcinoma. 
 
b. 
If patients have recurrent unresectable thymic carcinoma, patients may have had 
prior neoadjuvant or adjuvant chemotherapy if treatment concluded ≥ 6 months 
prior to randomization. 
 
c. 
Patients must have a CT or MRI scan of the brain to evaluate for CNS disease 
within 42 calendar days prior to registration.  Patient must not have brain 
metastases unless: (1) metastases have been treated and have remained 
controlled for at least 2 weeks following treatment, AND (2) patient has no residual 
neurological dysfunction off corticosteroids for at least 1 day. 
 
d. 
Patients must not be candidates for radiation therapy with curative intent.  Prior 
palliative radiation therapy is allowed if a period of 7 days has passed since the 
last dose was received and the patient has recovered from any associated toxicity 
at the time of randomization. 
 
 

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5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have adequate hematologic function, as evidenced by an absolute 
neutrophil count (ANC) ≥1500/mcL, hemoglobin ≥ 9 g/dL (5.58 mmol/L), and 
platelets ≥100,000/mcL documented within 28 calendar days prior to 
randomization. 
 
b. 
Patients must have adequate coagulation function as defined by International 
Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds 
above the institutional upper limit of normal (IULN) (unless receiving 
anticoagulation therapy) documented within 28 calendar days prior to 
randomization.   
 
Patients receiving warfarin must be switched to low molecular weight heparin and 
have achieved stable coagulation profile 14 days prior to randomization.  
 
c. 
Patients must not have experienced any Grade 3 or above GI bleeding within 84 
calendar days prior to randomization 
  
d. 
Patients must not have a history of deep vein thrombosis (DVT), pulmonary 
embolism (PE), or any other significant thromboembolism (venous port or catheter 
thrombosis or superficial venous thrombosis are not considered “significant”) 
during the 84 calendar days prior to randomization. 
 
e. 
Patients must have adequate hepatic function as defined by a total bilirubin ≤1.5 x 
the institutional upper limit normal (IULN), and aspartate transaminase (AST) and 
alanine transaminase (ALT) ≤ 3.0 x IULN. For patients with liver metastases, total 
bilirubin and AST or ALT must be ≤ 5.0 x IULN These tests must be documented 
within 28 calendar days prior to randomization. 
 
f. 
Patients must not have any of following:  
• 
cirrhosis at a level of Child-Pugh B (or worse) (See Appendix 18.1) 
• 
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.  
 
g. 
Patients must have adequate renal function as defined by a serum creatinine ≤ 1.5 
x IULN, or creatinine clearance (measured via 24-hour urine collection) ≥ 40 
mL/minute (that is, if serum creatinine is >1.5 x IULN, a 24-hour urine collection to 
calculate creatinine clearance must be performed) documented within 28 calendar 
days prior to randomization.  
 
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
 
72 x creatinine (mg/dl) 
 
h. 
Patient urinary protein must be ≤ 1+ on dipstick or routine urinalysis (UA); if urine 
dipstick or routine analysis is ≥ 2+, a 24-hour urine collection for protein must 
demonstrate <1000 mg of protein in 24 hours). These tests must be documented 
within 28 calendar days prior to randomization. 
 
i. 
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 6 months prior to randomization. 
  

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j. 
Patients must not have a history of uncontrolled or poorly controlled hypertension 
(defined as >160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite 
standard medical management. 
 
k. 
Patients must not be pregnant or nursing due to the risk of harming fetus or infant. 
Women/men of reproductive potential must have agreed to use an effective 
contraceptive method (hormonal or barrier method of birth control; abstinence) 
prior to randomization, during the study participation and for 4 months after the last 
dose of protocol treatment. A woman is 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 period for use of contraceptive 
measures outlined in the protocol, he/she is responsible for beginning 
contraceptive measures. 
 
l. 
Patients must not have experienced hemoptysis (defined as bright red blood or ≥ 
1/2 teaspoon) within 2 months prior to randomization or with radiographic evidence 
of intratumor cavitation or has radiologically documented evidence of major blood 
vessel invasion or encasement by cancer. 
 
m. 
Patients must not have a prior history of gastrointestinal perforation/fistula (within 
6 months of randomization) or risk factors for perforation.  
 
n. 
Patients must not have a serious or nonhealing wound, ulcer, or bone fracture 
within 28 calendar days prior to randomization.  
 
o. 
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. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must be offered the opportunity to participate in banking of specimens for 
future research as described in Section 15.1. 
 
5.5 
Regulatory Criteria 
 
a. 
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. 
 
b. 
As a part of the OPEN registration process (see Section 13.3 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. 
 
6.0 
STRATIFICATION FACTORS 
 
Not applicable for this study. 
 
 

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7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Study Chairs Anne Tsao, M.D. and 
Marianna Koczywas, M.D., at S1701Medical@swog.org. For dosing principles or questions, please 
consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at www.swog.org 
(then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 
 
7.1 
Pre-Medication 
Premedication associated with standard drug administration and supportive care (including 
anti-diarrheals, antibiotics, diuretics, or other medications) may be given as indicated by 
the current American Society of Clinical Oncology (ASCO) guidelines. 
 
Premedication prior to carboplatin and paclitaxel infusions are recommended per 
institutional standards. Recommended premedication agents include histamine H1 
antagonists such as diphenhydramine hydrochloride 50 mg I.V. (or equivalent). Additional 
premedication may be provided at treating investigator discretion. 
 
7.2 
Treatment 
 
Note that women of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to Cycle 1 Day 1. 
 
a. 
Arm A 
 
Agent 
Dose 
Route 
Day 
Schedule 
Ramucirumab 
10 mg/kg 
IV 
over 60min 
1 
Every 21 days 
Carboplatin 
AUC 6 * 
IV 
1 
Every 21 days 
Paclitaxel 
200 mg/m2 
IV 
1 
Every 21 days 
Note: 1 cycle = 21 days 
* See Sections 18.2 and 18.3 
 
Carboplatin, Paclitaxel, and Ramucirumab will be administered on Day 1 of Cycles 
1-6. Note that Ramucirumab will be administered first over 60 minutes. The 
chemotherapy combination (carboplatin and paclitaxel) will be administered per 
institutional guidelines. 
 
After 6 cycles of the chemotherapy combination, patients who have not progressed 
will receive maintenance ramucirumab alone on Day 1 of Cycle 7 and subsequent 
cycles for up to 1 year after randomization.   
 
Vital signs (temperature, blood pressure, heart rate, oxygen saturation, and 
respiratory rate) are to be performed before dose administration per institutional 
guidelines.   
 
b. 
Arm B 
 
Agent 
Dose 
Route 
Day 
Schedule 
Carboplatin 
AUC 6 * 
IV 
1 
Every 21 days 
Paclitaxel 
200 mg/m2 
IV 
1 
Every 21 days 
* Note:  1 cycle = 21 days 
* See Sections 18.2 and 18.3 
 

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Carboplatin and Paclitaxel may be administered according to institutional 
guidelines.  Completion of treatment is up to a maximum of 6 cycles. 
 
Vital signs (temperature, blood pressure, heart rate, oxygen saturation, and 
respiratory rate) are to be performed before dose administration per institutional 
guidelines. 
 
7.3 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2) 
 
b. 
Unacceptable toxicity 
 
c. 
Treatment delay for any reason > 21 days (or as noted in Section 8.0)  
 
d. 
Completion of treatment  
 
Arm A: 6 cycles of chemotherapy combination + 1 year of ramucirumab after 
randomization 
 
Arm B: Maximum of 6 cycles of chemotherapy combination 
 
e. 
Patients may withdraw from the study at any time for any reason 
 
7.4 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off-Treatment 
Notice. 
 
7.5 
Follow-Up Period 
 
All patients will be followed until death or 2 years after randomization, whichever occurs 
first.   
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for Serious Adverse Event reporting only.  A copy of the 
CTCAE Version 5.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 5.0 
 
b. 
Routine toxicity reporting 
 
This study will use the CTCAE Version 4.0 for routine toxicity reporting.  A copy of 
the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0. 
 
 

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Version Date 07/27/2022 
 
 
 
8.2 
General Dose Modification Guidelines  
 
a. 
Missed doses are to be omitted rather than made up. 
 
b. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
c. 
The treating physician can reduce the dose of only one of the 3 drugs if the toxicity 
is felt to be related to only one of the drugs. 
 
d. 
Once dose is reduced, patients will continue at the new dose. No dose re-
escalations are allowed. 
 
e. 
If all drugs are held > 21 days, patient must be removed from protocol treatment. 
If one drug is held for > 21 days, then that drug should be permanently 
discontinued and the other drug could be continued as long as the treating 
physician believes the patient is deriving clinical benefit. 
 
f. 
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.   
 
8.3 
Dose Reductions for Carboplatin, Paclitaxel, and Ramucirumab 
 
Dose Level 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
Ramucirumab 
(mg/kg) 
0 (Starting Dose) 
6 
200 
10 
-1 
5 
175 
8 
-2 
4 
150 
6 
-3 * 
Discontinue 
Discontinue 
Discontinue 
* Dose reductions beyond this level are not permitted. 
 
8.4 
Paclitaxel/Carboplatin Dose Modifications  
 
a. 
Hematologic Toxicity  
 
Toxicity 
Paclitaxel  
Carboplatin  
Neutropenia 
 
 
Grade < 2 
No dose modification 
No dose modification 
Grade 3 
Hold therapy and repeat 
labs weekly until 
resolution to < Grade 2. 
Depending on symptom 
resolution, treatment 
may resume at the next 
lower dose or remain 
the same. 1 
Hold therapy and repeat 
labs weekly until 
resolution to < Grade 2. 
Grade 4 
Hold therapy and repeat 
labs weekly until 
Hold therapy and repeat 
labs weekly until 

S1701 
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Version Date 07/27/2022 
 
 
 
Toxicity 
Paclitaxel  
Carboplatin  
resolution to < Grade 2. 
Treatment may resume 
at the next lower dose. 1 
resolution to < Grade 2. 
Neutropenic fever 
 
 
Grade > 4 
Hold therapy and repeat 
labs weekly until 
resolution to < Grade 2. 
Growth factor support is 
recommended. 
Treatment may resume 
at the same dose with 
growth factor support or 
can resume at the next 
lower dose. 1 
Hold therapy and repeat 
labs weekly until 
resolution to < Grade 2. 
1 Patients with ANC < 500/mcl or febrile neutropenia despite two dose level 
reductions of paclitaxel, should have one dose level reduction of carboplatin, in 
addition to a third dose level reduction of paclitaxel. 
Thrombocytopenia 
 
 
Grade 1 
No dose modification 
No dose modification 
Grade > 2 
Hold therapy and repeat 
labs weekly until 
resolution to < Grade 1. 
Hold therapy and repeat 
labs weekly until 
resolution to < Grade1. 
Treatment may resume 
at the next lower dose. 2 
2 For example, if current AUC is 6, reduce dose to AUC 5. Patients with platelets 
< 50,000/mcl despite two dose level reductions of carboplatin, should have one 
dose level reduction of paclitaxel, in addition to a third dose level reduction of 
carboplatin. 
 
b. 
Non-Hematologic Toxicity  
 
Toxicity 
Paclitaxel  
Carboplatin  
Neuropathy 
 
 
Grade ≤ 1 
No dose modification 
No dose modification 
Grade 2 
Hold protocol therapy 
until resolution to 
Grade ≤ 1.  
Hold protocol therapy 
until resolution to 
Grade ≤ 1.  
Grade > 3 
Discontinue therapy 
Hold therapy, until ≤ 
Grade 2 
Other non-hematologic 
toxicities 
 
 
Grade ≤ 2 
No dose modification 
No dose modification 
Grade 3 or 4 
Hold therapy until ≤ 
Grade 2 
Hold therapy until ≤ 
Grade 2 
 
 
 

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c. 
Arthralgia/Myalgia  
 
The following dose adjustments are based on the worst grade experienced of 
arthralgia/myalgia of any preceding treatment course.  
 
Arthralgia/Myalgia 
Paclitaxel 
Carboplatin 
Grade 0-1 
No dose modification 
No dose modification 
Grade 2 
Hold treatment until 
resolution to ≤ Grade 1. 
If post-medication 
dexamethasone (4 mg orally 
BID for 3-5 days) was 
incorporated in regimen, 
reduce by 1 dose level.  
If no dexamethasone was 
used, then prior to making 
any dose level reductions 
add regimen to subsequent 
courses.  
No dose modification 
Grade 3 
Hold treatment until 
resolution to ≤ Grade 1. 
If post-medication 
dexamethasone (4 mg orally 
BID for 3-5 days) was 
incorporated in regimen, 
reduce by 1 dose level.  
If no dexamethasone was 
used, then prior to making 
any dose level reductions 
add regimen to subsequent 
courses. 
 No dose modification 
 
d. 
Hepatic Toxicity (Paclitaxel dose modification only) 
 
The following dose adjustments for paclitaxel are based on ALT, AST, and bilirubin 
serum levels and should be obtained within 7 days of treatment.  
ALT and/or AST 
 
Bilirubin 
Paclitaxel 
≤ Grade 1 
and/or 
≤ Grade 2 
No dose modification 
≥ Grade 2 
and/or 
≥ Grade 3 
HOLD* 
* Hold until ALT and/or AST resolution to ≤ Grade 1 and Bilirubin is ≤ Grade 2. If 
recovery of toxicity exceeds 2 weeks, discontinue from all protocol therapy, and 
remove patient from study.  
 
If recovery of toxicity occurs within 2 weeks, reduce dose by 1 level above for 
both agents (paclitaxel and ramucirumab). No dose reduction will be done for 
carboplatin. 
 
 

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e. 
Gastrointestinal Toxicity  
 
Nausea and/or vomiting should be controlled with adequate antiemetic therapy. 
Prophylactic anti-emetic therapy can be used at the discretion of the treating 
physician. Patients are encouraged to take plenty of oral fluids. If symptoms persist 
despite maximal anti-emetic therapy, contact provider.  
 
Diarrhea should be managed with appropriate anti-diarrheal therapy. Patients 
should be encouraged to take plenty of oral fluids. If symptoms do not decrease to 
Grade 1 or less with adequate anti-diarrheal therapy, contact provider. 
 
f. 
Hypersensitivity Reactions to Paclitaxel 
 
Caution: Patients who had a mild to moderate hypersensitivity reaction have been 
successfully rechallenged, but careful attention to prophylaxis and bedside 
monitoring of vital signs is recommended.  
 
1. 
Mild symptoms (e.g., mild flushing, rash, pruritus) -Complete infusion. 
Supervise at bedside. No treatment required.  
 
2. 
Moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest 
discomfort) -Stop infusion. Give intravenous diphenhydramine 25 mg and 
intravenous dexamethasone 10 mg. Resume infusion after recovery of 
symptoms at a low rate (20 mg/hr.) for 15 minutes. If no further symptoms, 
resume infusion at full dose rate until infusion is complete. If symptoms 
recur, stop infusion. The patient should receive no additional paclitaxel for 
that cycle but may be retreated after discussion with the principal 
investigator. Record toxicity on flow sheets.  
 
3. 
Severe life-threatening symptoms (e.g., hypotension requiring pressor 
therapy, angioedema, respiratory distress requiring bronchodilation 
therapy, generalized urticaria) -Stop infusion. Give intravenous 
diphenhydramine and dexamethasone as above. Add epinephrine or 
bronchodilators if indicated. If wheezing is present and is not responsive 
to administration of 0.35 cc of nebulized salbutamol solution (or 
equivalent), epinephrine is recommended. Patient should discontinue all 
protocol therapy and be removed from study. Report as serious adverse 
event.  
 
g. 
Other Toxicities  
 
For any Grade 2, 3 or 4 toxicities not mentioned above, excluding hemoglobin, 
lymphocytes, alopecia or Grade 2 nausea, the treatment should be withheld until 
the patient recovers to < Grade 1.  If an abnormal laboratory value is reported, the 
toxicity should be possibly related to paclitaxel and carboplatin treatment to result 
in dose reduction. The paclitaxel and carboplatin treatment should then be 
resumed at dose level (-1) (permanent dose reduction). Dose reduction will be 
done for the drug that is most likely to have caused the toxicity. For Grade 1 
toxicities, no dose reduction should be made. 
 
In case patients develop nausea/vomiting/diarrhea or myelosuppression, 
supportive medications will be prescribed as per Clinical Center and ASCO 
guidelines. 
 
 

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8.5 
Ramucirumab Discontinuations due to Toxicity 
  
Table 1: Dose Interruptions for Ramucirumab 
Toxicity 
Grade 
Dose Interruptions 
Toxicity Management 
Infusion-
Related 
Reactions 
Any Grade 
No dose modifications. 
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 1 
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. 
 
-Steroids should not be used for routine 
premedication of ≤ Grade 2 infusion 
reactions. 
> Grade 3 
Permanently 
discontinue protocol 
therapy. 
-Manage 
severe 
infusion-related 
reactions per institutional standards 
(e.g., IM epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid). 
 
Table 2: Dose Modifications for Ramucirumab 
Toxicity 
Grade 
Dose Modifications 
Hypertensio
n 
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 protocol therapy. 
Grade 2 Symptomatic 
Hold protocol therapy until symptoms resolve. Start or 
adjust anti-hypertensive medication. 
Grade 3 
Hold protocol therapy until resolution of symptoms and 
returns to Grade 2. 
Grade 4 
Permanently discontinue protocol therapy. 
 
Impaired 
Wound 
Healing 
Prior to planned 
surgery 
Withhold ramucirumab for at least 28 days prior to 
surgery. 
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. 

S1701 
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Version Date 07/27/2022 
 
 
 
Toxicity 
Grade 
Dose Modifications 
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 protocol therapy until 
resolution to < 2 gram/24 hours.  Restart 
ramucirumab at the next lower dose. 
• 
If the protein level ≥2 g/24 hours reoccur, 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 protocol therapy. If patient 
experiences 
nephrotic 
syndrome, 
permanently 
discontinue protocol therapy. 
 
Other 
Adverse 
Events 
Grade 4 
Permanently 
discontinue 
treatment 
immediately, 
except for 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 within21 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 3: Dose Discontinuations for Ramucirumab 
Toxicity 
Grade 
Dose Discontinuation 
Arterial Thromboembolic Events, 
Gastrointestinal Perforation, and 
Hemorrhage/Bleeding 
≥ Grade 3 
Permanently discontinue ramucirumab. 
 
Reversible posterior 
leukoencephalopathy syndrome 
Any Grade 
Permanently discontinue ramucirumab. 
 
Congestive heart failure 
≥ Grade 3 
Permanently discontinue ramucirumab. 
 
Liver injury/liver failure or Hepatic 
encephalopathy and/or 
hepatorenal syndrome resulting 
from liver cirrhosis 
Any Grade 
Permanently discontinue ramucirumab. 

S1701 
Page 31 
Version Date 07/27/2022 
 
 
 
 
8.6 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Study Chairs Anne Tsao, 
M.D. and Marianna Koczywas, M.D., at S1701Medical@swog.org. 
 
8.7 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.1 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 

S1701 
Page 32 
Version Date 07/27/2022 
 
 
 
 
9.0 
STUDY CALENDAR 
 
9.1 
Arm A Carboplatin (CBDCA), Paclitaxel (Taxol®), and Ramucirumab (Cyramza™, IMC-1121B, LY3009806) 
  
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Maintenance ¥ 
Off 
Tx  
Off 
Tx   
REQUIRED 
STUDIES 
PRE-
STUDY  
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15  
Wk 
16 
Wk 
17 
Wk 
18 
C 
7 
C 
8 
Subseq 
C Ω  
Prior 
to 
Prog 
* 
After 
Prog 
α 
PHYSICAL 
  
History & Physical 
Exam 
X 
X  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
  
Weight & 
Performance 
Status 
X 
X  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X 
  
Disease 
Assessment Ø  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
X Ø 
X Ø 
  
Toxicity Notation 
X 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X € 
X € 
Vital Signs ∑ 
X  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
  
  
LABORATORY 
  
CBC/Hgb/Platelets 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X € 
X € 
INR and PTT £ 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X £ 
X € 
X € 
Bilirubin 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X € 
X € 
AST and ALT 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X € 
X € 
Serum 
Creatinine/Calc 
CrCl 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
X € 
X € 
Urine Protein 
Check £ 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X £ 
X € 
X € 
Serum Pregnancy 
Test 
 
X© 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCANS 
  

S1701 
Page 33 
Version Date 07/27/2022 
 
 
 
  
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Maintenance ¥ 
Off 
Tx  
Off 
Tx   
REQUIRED 
STUDIES 
PRE-
STUDY  
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15  
Wk 
16 
Wk 
17 
Wk 
18 
C 
7 
C 
8 
Subseq 
C Ω  
Prior 
to 
Prog 
* 
After 
Prog 
α 
CT or MRI for 
Disease 
Assessment Ø 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
X Ø 
X Ø 
  
SPECIMEN 
SUBMISSION 
  
Tumor Tissue 
(See Section 15.1) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Peripheral Blood 
(See Section 15.1) 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X ß 
X ß 
TREATMENT 
(21 day cycle) 
  
Carboplatin 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Paclitaxel 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
  
  
Ramucirumab 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
X 
  
  
 
Click here for Footnotes 
 
NOTE: Forms are found on the CTSU website (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 the Best Practices document located at https://www.swog.org/clinical-trials/protocol-workbench. 
 
 

S1701 
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Version Date 07/27/2022 
 
 
 
Footnotes for Arm A Calendar 
 
¥ After 6 cycles of the chemotherapy combination, patients who have not progressed will receive maintenance ramucirumab alone on Day 1 of 
Cycle 7 and subsequent cycles for up to 1 year after randomization (See Section 10.2d). 
 
Ω During continued treatment, items marked under physical and laboratory should be performed at every subsequent maintenance treatment (every 
3 weeks). Disease assessments are to take place every 9 weeks until disease progression. 
 
* After off treatment prior to progression, patients should be followed by repeating indicated laboratory tests every 3 months for first year, and then 
every 6 months until 2 years from date of randomization. 
 
α After off treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 3 
months for first year, and then every 6 months until 2 years from date of randomization. 
 
Ø CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.0) must be repeated every 6 weeks for the first 18 weeks 
and, then every 9 weeks, until disease progression. 
 
€ Assessment should continue until resolution of all acute adverse events. 
 
∑ Vital signs (blood pressure, heart rate, oxygen saturation, temperature, and respiratory rate) are to be performed before dose administration per 
institutional guidelines.   
 
≠ If the pre-study tests are obtained within 14 days prior to treatment, the tests need not to be repeated on Cycle 1 Day 1. 
 
£ Urine Protein, PTT, and INR should be performed prior to every subsequent cycle throughout treatment, then as clinically required. 
 
©  Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to  Cycle 1 Day 1. 
 
ß With patient’s consent, peripheral blood must be collected upon removal from protocol treatment for any reason. (See Section 15.1). 
 
 

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Version Date 07/27/2022 
 
 
 
9.2  
Arm B Carboplatin (CBDCA) and Paclitaxel (Taxol®) 
  
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Off 
Tx  
Off 
Tx  
REQUIRED 
STUDIES 
PRE-
STUDY  
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15  
Wk 
16 
Wk 
17 
Wk 
18 
Prior 
to 
Prog*  
After 
Prog 
α 
PHYSICAL 
  
History & Physical 
Exam 
X 
 X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Weight & 
Performance 
Status 
X 
X  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Disease 
Assessment Ø  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X Ø 
  
Toxicity Notation 
X 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X € 
X € 
Vital Signs ∑ 
 X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
LABORATORY 
  
CBC/Hgb/Platelets 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X € 
X € 
INR and PTT 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bilirubin 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X € 
X € 
AST and ALT 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X € 
X € 
Serum 
Creatinine/Calc 
CrCl 
X 
X ≠ 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X € 
X € 
Urine Protein 
Check 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum Pregnancy 
Test 
 
X© 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCANS 
  
CT or MRI for 
Disease 
Assessment Ø 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X Ø 
  
SPECIMEN 
SUBMISSION 
  

S1701 
Page 36 
Version Date 07/27/2022 
 
 
 
  
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Off 
Tx  
Off 
Tx  
REQUIRED 
STUDIES 
PRE-
STUDY  
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15  
Wk 
16 
Wk 
17 
Wk 
18 
Prior 
to 
Prog*  
After 
Prog 
α 
Tumor Tissue 
(See Section 15.1) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Peripheral Blood 
(See Section 15.1) 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
X ß 
X ß 
TREATMENT 
(21 day cycle) 
  
Carboplatin 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
Paclitaxel 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
  
  
 
Click here for Footnotes 
 
NOTE: Forms are found on the CTSU website (https://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 the Best Practices document located at https://www.swog.org/clinical-trials/protocol-workbench. 
 
 

S1701 
Page 37 
Version Date 07/27/2022 
 
 
 
Footnotes for Calendar 9.2 
 
Footnotes for Arm B Calendar 
 
* After off treatment prior to progression, patients should be followed by repeating indicated laboratory tests every 3 months for first year, and then 
every 6 months until 2 years from date of randomization. 
 
α After off treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 3 
months for first year, and then every 6 months until 2 years from date of randomization. 
 
Ø CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.0) must be repeated every 6 weeks for the first 18 weeks 
and, then every 9 weeks, until disease progression. 
 
€ Assessment should continue until resolution of all acute adverse events. 
 
∑ Vital signs (blood pressure, heart rate, oxygen saturation, temperature, and respiratory rate) are to be performed before dose administration per 
institutional guidelines.   
 
≠ If the pre-study tests are obtained within 14 days prior to treatment, the tests need not to be repeated on Cycle 1 Day 1. 
 
©  Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1. 
 
ß With patient’s consent, peripheral blood must be collected upon removal from protocol treatment for any reason. (See Section 15.1) 

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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 1 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.  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. 
A malignant lymph node is 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 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.  Body scans should by performed with breath-hold scanning 
techniques, if possible.  
 
2. 
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 conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
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. 
 
5. 
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 0.0cm should be recorded. 
 

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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, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. 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 1 measurable lesion. 
Greater than or equal to 30% decrease under baseline of the sum of appropriate 
diameters of all targets 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 Section 10.2e). 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm. 
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
 
2. 
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. 
 
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. 

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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. 
 
g. 
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. 
 
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. 
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  2 or more objective statuses of CR a minimum of 4 weeks apart documented 
before progression or symptomatic deterioration. 
 
b. 
PR:  2 or more objective statuses of PR or better a minimum of 4 weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
c. 
Unconfirmed CR:  1 objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 

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d. 
Unconfirmed PR:  1 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 1 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. 
 
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 registration to date of death due to any cause.  Patients last known to be alive 
are censored at date of last contact. 
 
10.6 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression 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. 
 
 

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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Objective and Power Justification 
 
The primary study objective is to compare progression-free survival between patients with 
unresectable locally advanced, recurrent, or metastatic Thymic Carcinoma (TC) 
randomized to carboplatin-paclitaxel with or without ramucirumab. Patients will be 
randomized with equal probability between carboplatin/paclitaxel with or without 
ramucirumab. 
 
A design with 90% power to detect a hazard ratio of 0.5 (2-fold increase in medians under 
exponential survival) using a 1-sided 0.10 level log-rank test would require 54 PFS events.  
Assuming a uniform accrual rate of 2 patients per month, 18 months of follow-up, PFS is 
exponentially distributed, and the median PFS within the carboplatin/paclitaxel arm is 6 
months, then 60 eligible patients are needed.  Accounting for an ineligible rate of 10%, 
the total target accrual is 66 patients accrued over 33 months. 
 
11.2 
Secondary Objectives and Interim Analysis 
 
With 30 eligible patients per arm, toxicity rates and other binary proportions can be 
estimated to be within 18% with 95% confidence.  Assuming 90% of the patients will have 
measurable disease, response rates and disease control rates can be estimated to be 
within 19% with 95% confidence.  Any toxicity with at least 10% prevalence is likely to be 
observed (with 96% probability).  Binary proportions will be compared between the arms 
using either a Fisher’s exact or Chi-squared test at the 1-sided 0.10 level. With 30 patients 
per arm, this design has at least 90% power to detect a 35% difference in proportions 
between the arms.  
 
Overall survival will be compared between the arms also using a 1-sided 0.10 level test. 
However, the power to detect differences in OS will be very limited with this sample size. 
 
An interim analysis evaluating early stopping for futility alone will be done upon the 
observation of 27 PFS events (50% of expected).  For futility testing, the alternative 
hypothesis of at least 2-fold improvement in PFS for the experimental arm will be tested at 
one-sided level 0.025, using an extension of the log-rank test that allows for testing a 
relative risk not equal to 1. It is estimated that this analysis will take place approximately 
27 months after initiation of accrual, when approximately 50 eligible patients have been 
enrolled.  The approximate hazard ratio associated the boundary based on the fixed-
sample p-value scale is 0.96. 
 
11.3 
Accrual  
 
SWOG has no experience accruing to this patient population and thymic carcinoma is of 
definite interest in terms of rare populations to be studied in SWOG.  Given our lack of 
experience, accrual estimates are not as well supported as our estimates in other settings. 
 
11.4 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of 4 members from outside of the 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. 
 
 

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12.0 
DISCIPLINE REVIEW 
 
A discipline review is not required for this study. 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Initiation of treatment must be planned to start no more than 7 calendar days after 
registration. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, 
or TRIAD or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository 
(RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
 
 

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• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks 
Log (DTL). 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< https://ctep.cancer.gov/investigatorResources/default.htm >.   
 
For 
questions, 
please 
contact 
the 
RCR 
Help 
Desk 
by 
email 
at 
< RCRHelpDesk@nih.gov >. 
 
b. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to the following: 
 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the 
following criteria: 
 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form 
FDA 1572 
• 
An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation 
to the CTSU Regulatory Office. For sites using the CIRB, IRB approval 
information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
 

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2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1701 protocol page 
located on the CTSU members’ website.   
 
• 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the 
protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the SWOG link to expand, then select trial protocol 
#S1701 
• 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided.   
 
3. 
Requirements for S1701 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via 
the Regulatory Submission Portal, where they will be entered and tracked 
in the CTSU RSS.  
 
Regulatory Submission Portal:  www.ctsu.org (members’ area) → 
Regulatory Tab → Regulatory Submission 
 
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should 
alert the CTSU Regulatory Office immediately at 866-651-2878 in order to 
receive further instruction and support. 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website.   
 
 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 

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outlined by the Lead Network. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam)  and a ‘Registrar’ role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.  If a DTL 
is required for the study, the registrar(s) must also be assigned the OPEN Registrar task 
on the DTL. 
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database.  OPEN can be accessed at https://open.ctsu.org or from the 
OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.   To assign 
an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 
1572 in RCR the IRB number used on the site’s IRB approval.  If a DTL is required for the 
study, the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 

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• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self-Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
Authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org.  
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
 

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13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
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 abstract page on the CTSU website 
(https://www.ctsu.org) and (apart from the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see 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. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an active CTEP-IAM account (check at  
https://eapps-ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization 
roster at the enrolling site.  To hold the Rave CRA role or CRA Lab Admin role, the 
user must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  If the study has a DTL, individuals 
requiring write access to Rave must also be assigned the appropriate Rave tasks 
on the DTL.  
 
Upon initial site registration approval for the study in 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 users 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. Please note, site users 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. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 

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information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 
888/823-5923 or by e-mail at ctsucontact@westat.com.  
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG web 
site (www.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. 
 
14.4 
Data Submission Overview and Time points  
 
a. 
WITHIN 7 DAYS OF REGISTRATION 
 
Submit the following: 
 
S1701 On study Form 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
  
Pathology Report documenting histologic confirmation of thymic carcinoma* 
 
Submit radiology reports from all scans performed to assess disease at baseline.* 
 
*NOTE: Upload these reports via the Source Documentation: Baseline form in 
Rave®. 
 
b. 
WITHIN 70 DAYS AFTER REGISTRATION, IF PATIENT CONSENTS: 
 
Submit baseline tissue, baseline blood and Cycle 3 blood specimens as outlined 
in Section 15.0. 
 
c. 
WITHIN 14 DAYS AFTER EACH CYCLE (1 CYCLE = 21 DAYS) OF 
TREATMENT: 
 
Submit the following: 
 
S1701 Treatment Form 
 
S1701 Adverse Event Form 
 
d. 
WITHIN 14 DAYS AFTER EACH DISEASE ASSESSMENT (see study calendar) 
UNTIL PROGRESSION OF DISEASE: 
 
Submit the following: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports (Upload these reports via the Source Documentation: Follow- 
Up form in Rave®.) 
 
 

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e. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice 
 
S1701 Treatment Form 
 
S1701 Adverse Event Form 
 
If patient consents, also submit blood specimen as outlined in Section 15.0. 
 
f. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the following: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
All radiology reports used to document progression (Upload via the Source 
Documentation: Follow-Up form in Rave®) 
 
If the patient was off protocol treatment, also submit the  
 
Follow-Up Form  
 
g. 
AFTER OFF TREATMENT, SUBMIT EVERY 3 MONTHS FOR FIRST YEAR, AND 
THEN EVERY 6 MONTHS UNTIL 2 YEARS FROM RANDOMIZATION. 
 
Follow-Up Form 
 
Late Effects Form (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] long term toxicity that has not been previously reported 
 
h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death. If the patient was still on protocol treatment, also 
submit the forms listed in Section 14.4e. If the patient was off protocol treatment, 
also submit the Follow-Up Form. 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Translational Medicine and Banking (OPTIONAL FOR PATIENT)  
 
Patients must be offered the opportunity to participate in banking of specimens for future 
research. Collection of specimens is critical to the interpretation of this study and should 
be acquired if at all possible. If the patient consents, specimens must be submitted as 
described in this section.  
 
a. 
Archived Tumor Tissue 
 
Within 60 calendar days after registration, submit the following: 
 
1 or 2 paraffin-embedded tissue blocks containing formalin fixed tumor FFPE or 
needle aspirate slides from time of diagnosis (or subsequent, but prior to protocol 
therapy). If blocks are unavailable, 6-8 unstained slides, 4 to 5 microns are 

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acceptable alternatives. It is not necessary to perform an additional biopsy for this 
purpose. Paraffin blocks may be processed according to standard institutional 
protocols. Cytology (i.e., fine-needle aspirations) can be accepted only if they are 
paraffin embedded as cell blocks. 
 
b. 
Buffy Coat and Plasma  
 
Draw approximately 10 mL blood in 1-2 lavender (EDTA) tubes (depending on tube 
size) at the following 3 time points:  
 
• 
After registration, prior to treatment on Cycle 1 Day 1 
• 
Cycle 3 Day 1 
• 
Upon removal from protocol treatment for any reason 
 
Blood should be placed on wet ice immediately after collection and processed as 
soon as possible (preferably within 2 hours). Centrifuge vacutainer tubes at 
approximately 800 x g for 10 minutes (preferably in a refrigerated centrifuge, if 
available).  Immediately after centrifugation, carefully transfer plasma to a new 15 
mL conical tube using a pipette, being careful not to aspirate the interface between 
the plasma and the platelets (buffy coat layer).  Set aside original purple top tubes 
for later processing.  Then centrifuge plasma a second time at 1200 x g for 10 
minutes.  After the second centrifugation, aliquot plasma in 500 ul aliquots into 6-
10 labeled 1.8-2.0 ml cryovials, being careful not to disturb the pellet in the bottom 
of the tube.  The buffy coat, a whitish layer of cells between the plasma and red 
blood cell layers, should be collected from the original purple top tube(s) and 
transferred into 2 labeled 1.8-2.0 ml cryovials (contamination with RBC not a 
concern).  Freeze cryovials immediately and store at or below -70° until shipping. 
 
Blood products may be batch shipped every 3 months on dry ice.   
 
c. 
Specimen Collection and Submission Instructions 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. Complete specimen collection and 
submission instructions can be accessed on the SWOG Specimen Submission 
webpage  
 (https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures)  Specimen must be shipped by overnight 
delivery, excluding Fridays. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies.   
 
e. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site (www.swog.org) and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at  

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https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  
SpecTrack start-up instructions (both written and demo) are available after 
signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The Specimen 
Submission Form is NOT required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page 
(https://spectrack.crab.org/Instructions); or contact the Data Operations 
Center at 206/652-2267 to be routed to the Data Coordinator for further 
assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of tissue, buffy coat, and plasma samples for SWOG 
Repository Submission biobanking is identified as follows: 
 
Lab #201:  
SWOG Specimen Repository – Solid Tissue, Myeloma 
and Lymphoma Division, Lab #201 
Phone: 614/722-2865 
Contact:  SWOG Repository Coordinator 
Email: bpcbank@nationwidechildrens.org  
 
2. 
Federal guidelines for the shipment of blood products: 
 
a. 
The tube must be wrapped in an absorbent material. 
 
b. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 
c. 
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d. 
Pack the Styrofoam shipping container in a cardboard box. 
 
e. 
Mark the box "Biohazard". 
 
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. 46, No. 17, January 27, 1981, part 50) 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. 

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Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
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.  
 
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. 
 
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 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
a. 
Purpose 
 
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 
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 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. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm. The company, Eli Lilly and Company, will also receive a copy of 
the report electronically via the CTEP-AERS Web-based application.  
 
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. When Internet connectivity is disrupted, a 24-hour notification is to be made 
to the SWOG Operations Office by telephone at 210-614-8808 or by email at 
adr@swog.org.  Once Internet connectivity is restored, a 24-hour notification that 
was made by phone or using adr@swog.org must be entered electronically into 
CTEP-AERS by the original submitter at the site. 

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When the adverse event requires expedited reporting, submit the report 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 A of this study are 
ramucirumab plus carboplatin and paclitaxel.  If there is any question about the 
reportability of an adverse event or if on-line CTEP-AERS cannot be used, please 
telephone, or email the SAE Specialist at the Operations Office, 210-614-8808 or 
adr@swog.org, before preparing the report. 
 
 
 

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Table 16.1: 
Late Phase II and Phase III 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 Ramucirumab plus carboplatin and paclitaxel, Arm A 
 
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 
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 

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f. 
Expedited reporting for commercial 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 16.2. The commercial agents used in both arms of this study are carboplatin 
and paclitaxel. If there is any question about the reportability of an adverse event 
or if on-line CTEP-AERS cannot be used, please telephone, or email the SAE 
Specialist at the Operations Office, 210/614-8808 or adr@swog.org, before 
preparing the report. 
 
Table 16.2 Expedited reporting requirements for adverse events experienced 
by patients on both study arms within 30 days of the last administration of 
the commercial agents. 
 
 
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 
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. 
 
 
g. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase II and Phase III Studies Utilizing an Agent under 
a Non-CTEP IND: 
 
1) 
Group-specific instructions. 
 
Supporting Documentation Submission - Within 5 calendar days submit 
the following to the SWOG Operations Office by fax to 210/614-0006 or 
mail to the address below: 
• 
Printed copy of the first page of the CTEP-AERS report 
• 
Copies of clinical source documentation of the event 
• 
If applicable, and they have not yet been submitted to the SWOG 
Statistics and Data Management Center, copies of Off Treatment 
Notice and/or Notice of Death. 
 
 

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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, 
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.  3 
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 via 
CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
A copy of the report and the following supporting documentation must also 
be submitted to SWOG Operations Office within 30 calendar days by fax 
to 210/614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
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, Fetal Death, 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, 

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accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium, and 
perinatal conditions – Other (pregnancy loss)” under the Pregnancy, 
puerperium, and perinatal conditions SOC.   
 
3. 
Death Neonatal Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
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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Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus 
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34  
Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus 
docetaxel for second-line treatment of Stage IV non-small-cell lung cancer after disease 
progression on platinum-based therapy (REVEL): a multicenter, double-blind, randomized Phase 
III trial. Lancet 384:665-73, 2014. 
 
35  
Perol M, Ciuleanu TE, Arrieta O, et al. Quality of life results from the Phase III REVEL randomized 
clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-docetaxel in advanced/metastatic 
non-small cell lung cancer patients with progression after platinum-based chemotherapy. Lung 
cancer 93:95-103, 2016. 

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18.0 
APPENDIX 
 
18.1 
Child-Pugh Scoring 
18.2 
AUC Calculation 
18.3 
Carboplatin Dosing Worksheet 
 
 

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18.1  
Child-Pugh Scoring 
 
The score is used to assess the prognosis of chronic liver disease and employs 5 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 (s) 
<4.0 
4.0–6.0 
> 6.0 
Ascites 
None 
Mild (or suppressed with 
medication) 
Moderate to severe 
(or refractory) 
Hepatic encephalopathy 
None 
Grade 1-2 
Grade 3-4 
 
 
 

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18.2 
AUC CALCULATION 
 
The area under the plasma drug concentration-time curve (AUC) reflects the actual body 
exposure to drug after administration of a dose of the drug and is expressed in mg*h/L. 
 
After an I.V. bolus injection, the AUC can be calculated by the following equation:  
 
Trapezoidal rule: It consists in dividing the plasma concentration-time profile into several 
trapezoids and calculating the AUC by adding the area of these trapezoids.  
 
AUC= Area under the concentration-time curve  
 
F = bioavailability  
 
D = dose  
 
CL= clearance  
 
C(0) = extrapolated plasma concentration at time 0   
 
λ = elimination rate constant = CL/Vd 
 
 
 

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18.3  
Carboplatin Dosing Worksheet 
 
 
TO CALCULATE Creatinine Clearance (CrCl) from SERUM CREATININE: 
 
 
CrCl =                       (140 - age)      X     wt. in kg.*        X     0.85 (if female)    
                                    72 X serum creatinine ** 
 
 
CrCl =                       (140 -       )      X      (            )         X     0.85 (if female) 
                                    72 X                                       
 
 
TO CALCULATE CARBOPLATIN DOSE WITH CALVERT FORMULA: 
 
 
USE CALCULATED CREATININE CLEARANCE (AS ABOVE) TO SUBSTITUTE FOR 
GFR. 
 
(AUC) (GFR + 25) = CARBOPLATIN DOSE PER CYCLE IN 
mg 
 
(6) (                   +25) =                                  mg of carboplatin 
 
 
This is the TOTAL DOSE of carboplatin (not mg/m2). 
 
Please note that: GFR should NOT exceed 125 ml/min. Hence, the maximum total  
carboplatin dose should NOT exceed 900 mg for this study. 
 
*      Use current (actual) weight. This should be actual weight but not exceed 
140% of IBW.  
**     Carboplatin dose should be calculated using a serum creatinine value 
obtained within 3 days prior to each course therapy.  In patients whose 
serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the 
Cockroft-Gault formula to calculate the estimated creatinine clearance for 
carboplatin dosing.