Clinical trial NCT02426658
Conditions: Stage IV Non-Small Cell Lung Cancer
Sponsor: Wake Forest University Health Sciences
Start date: 2015-05-01; Completion date: 2022-10-07
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial studies how well pemetrexed disodium works in treating patients with stage IV non-small cell lung cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 3. Performance status means how well patients are able to perform daily activities and care for themselves. Patients with a performance status of 3 have a limited ability to move around. Currently, only patients who are able to perform most of their daily activities may receive chemotherapy, due to the side effects it may cause. Pemetrexed disodium causes fewer side effects than many chemotherapy drugs and may help treat patients with stage IV non-small cell lung cancer and a lower performance status.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the effect of single agent pemetrexed (pemetrexed disodium) on tumor progression in ECOG performance status 3 patients with stage IV non-squamous histology non-small cell lung cancer in a single arm pilot study.

II. To evaluate the effect of single agent pemetrexed on quality of life in ECOG performance status 3 patients with stage IV non-squamous histology non-small cell lung cancer in a single arm pilot study.

SECONDARY OBJECTIVES:

I. To evaluate toxicity associated with single agent pemetrexed on tumor progression in ECOG performance status 3 patients with stage IV non-squamous histology non-small cell lung cancer in a single arm pilot study.

OUTLINE:

Patients receive pemetrexed disodium intravenously (IV) over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days and then every 6 weeks thereafter.

Arms: arm 1: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Quality-of-Life Assessment and Laboratory Biomarker Analysis.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pemetrexed Disodium intervention 3: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV intervention 3: QOL studies

Protocol documents:
Prot_SAP_000.pdf: 
A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
 
 
Principal Investigator: 
 
Stefan C. Grant, MD, JD, MBA 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
 
 
 
  
 
 
Co-Investigators: 
 
 
William J. Petty, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
Jimmy Ruiz, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
Marcelo Bonomi, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
Maria Matsangou, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
ClinicalTrials.gov NCT02426658 
 
 
Participating Institution(s):  
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Version Date: 
 
 
04-28-15 
Amended: 
 
 
 
04-13-17 
 
 
Confidential


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 2 of 45 
 
Table of Contents 
SCHEMA ................................................................................................................................... 4 
1.0 
Introduction and Background .......................................................................................... 5 
2.0 
Objectives ...................................................................................................................... 6 
2.1 
Primary Objectives ..................................................................................................... 6 
2.2 
Secondary Objective................................................................................................... 7 
3.0 
Patient Selection ............................................................................................................ 7 
3.1 
Inclusion Criteria ......................................................................................................... 7 
3.2 
Exclusion Criteria ........................................................................................................ 7 
3.3 
Inclusion of Women and Minorities ............................................................................. 8 
4.0 
Registration Procedures ................................................................................................. 8 
5.0 
Study Outcomes and Study Measures............................................................................ 9 
5.1 
Primary Outcomes ...................................................................................................... 9 
5.2 
Secondary Outcomes ................................................................................................. 9 
6.0 
Treatment Plan ..............................................................................................................11 
6.1 
Study-Related Interventions .......................................................................................11 
6.2 
Treatment Administration ...........................................................................................12 
6.2.1 
Premedication regimen and concurrent medications ............................................12 
6.2.2 
Laboratory monitoring ..........................................................................................12 
6.3 
General Concomitant Medication and Supportive Care Guidelines ............................13 
6.4 
Duration of Therapy ...................................................................................................13 
6.5 
Duration of Follow Up ................................................................................................14 
7.0 
Dosing Delays/Dose Modifications ................................................................................14 
8.0 
Measurement of Effect ..................................................................................................15 
8.1 
Antitumor Effect .........................................................................................................15 
8.1.1 
Definitions ............................................................................................................15 
8.1.2 
Methods for Evaluation of Measurable Disease ...................................................17 
8.1.3 
Response Criteria ................................................................................................18 
8.1.4 
Evaluation of Non-Target Lesions ........................................................................18 
8.1.6 
Duration of Response ................................................................................................19 
8.1.7 
Survival Outcomes ....................................................................................................20 
9.0 
Adverse Events List and Reporting Requirements .........................................................20 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 3 of 45 
 
9.1 
Adverse Event List for Pemetrexed ............................................................................20 
9.2 
Adverse Event Characteristics ...................................................................................20 
9.3 
STRC SAE Reporting Requirements .........................................................................21 
9.4  
WFUHS IRB AE Reporting Requirements .................................................................21 
10.0 
Pharmaceutical Information ...........................................................................................22 
10.1 
Pharmaceutical Accountability ...................................................................................22 
10.2 
ALIMTA (Pemetrexed) ...............................................................................................22 
11.0 
Data Management .........................................................................................................24 
12.0 
Statistical Considerations ..............................................................................................24 
12.1 
Analysis of Primary Objectives ..................................................................................24 
12.2 
Analysis of Secondary Objectives ..............................................................................25 
12.3 
Power and Sample Size ............................................................................................26 
12.4 
Estimated Accrual Rate .............................................................................................26 
12.5 
Estimated Study Length .............................................................................................27 
12.6 
Interim Analysis Plan .................................................................................................27 
References ...............................................................................................................................28 
Appendix A – Protocol Registration Form ..................................................................................30 
Appendix B – Subject Eligibility Checklist ..................................................................................31 
Appendix C – Mandatory STRC SAE Reporting Guidelines ......................................................33 
Appendix D – Adverse Event Log .............................................................................................36 
Appendix E: Pre-Study ..............................................................................................................38 
Appendix F: Pre-Treatment .......................................................................................................39 
Appendix G: Day of Treatment ..................................................................................................40 
Appendix H: Post-Treatment .....................................................................................................41 
Appendix I: Tumor Measurement Form .....................................................................................44 
Appendix J: Response Criteria ..................................................................................................45 
Appendix K – Survival Data.......................................................................................................48 
 
 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 4 of 45 
 
 
 
SCHEMA 
 
 
 
 
 
 
Consent and pre-study data collection 
Corticosteroid administration 
Prior to each treatment 
Labwork 
Pemetrexed 500 mg/m2 
administration every 21 days 
Study follow-up 
Vitamin supplementation 
QoL assessment 
every cycle (21 days), 
Tumor measurements 
every 2 cycles 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 5 of 45 
 
1.0 
Introduction and Background 
 
Lung cancer is the third most common cancer in both men and women and the leading 
cause of cancer death.1 Only approximately 15% of lung cancer cases are diagnosed at 
the local stage, and 5-year relative survival rates for regional and distant metastases are 
a dismal 26.5% and 4%, respectively.1 Systemic therapy is the predominant treatment 
for patients with advanced non-small cell lung cancer (NSCLC), based on clinical trials 
conducted over several decades that demonstrated improved survival and quality of 
life.2-4 However, current National Comprehensive Cancer Network (NCCN) guidelines for 
patients with Stage IV non-squamous NSCLC and a performance status (PS) of 3 or 4 is 
best supportive care. Restricting treatment based on performance status is largely based 
on toxicity data from historic chemotherapy trials,5-8 and previous studies have limited 
use of the chemotherapy pemetrexed to patients with PS 0 to 2. Given the relatively mild 
toxicity profile of pemetrexed,9, 10 the ability to mitigate side effects with folic acid and 
vitamin B12 supplementation,11 and the reported benefit of single agent pemetrexed in 
elderly patients with good performance status,12, 13 further study of its effectiveness and 
tolerability is warranted in patients with a PS of 3. 
 
PS is considered an important prognostic factor for patients with advanced NSCLC.5-8 
The ECOG 1594 trial randomly assigned patients to one of four platinum-based double-
agent chemotherapy regimens: 1) paclitaxel (135 mg/m2) over 24 hours with cisplatin (75 
mg/m2) on a 21-day cycle; 2) cisplatin (100 mg/m2) with gemcitabine (1 g/m2) on Days 1, 
8, and 15 on a 28-day cycle; 3) cisplatin (75 mg/m2) with docetaxel (75 mg/m2) on a 21-
day cycle; and 4) paclitaxel (225 mg/m2) over 3 hours with carboplatin (area under the 
curve, 6).14 The Data Monitoring Committee observed an excessive rate of adverse 
events among the patients with a PS of 2 and recommended discontinuation of 
enrollment of patients with a PS of 2. This observation contributed to many cooperative 
groups excluding patients with a PS of 2 from trials that included platinum-based 
therapy. A subsequent analysis of this trial revealed that patients with a PS of 2 had a 
poor prognosis, but the overall rate of treatment-related toxicity was similar among 
patients with a PS of 2 compared with patients with a PS of 0 or 1. Patients with a PS of 
2 compared with patients with a PS of 0 or 1 experienced a higher rate of adverse 
events, but this was because of a higher rate of disease-related adverse events. 
 
Pemetrexed is a multitargeted antifolate agent that has been approved for use in locally 
advanced or metastatic non-squamous non-small cell lung cancer as initial treatment in 
combination with cisplatin, as maintenance treatment of patients whose disease has not 
progressed after four cycles of platinum-based first-line chemotherapy, and after prior 
chemotherapy as a single-agent.10 The primary adverse effect of pemetrexed, 
myelosuppression, presents as neutropenia and thrombocytopenia and is the dose-
limiting toxicity of the drug. Elevated pretreatment levels of plasma homocysteine (a 
marker of folate deficiency) has been shown to be predictive of severe 
myelosuppression, while a high pretreatment level of methylmalonic acid (a marker of 
vitamin B12 deficiency) is an independent predictor of severe diarrhea and mucositis.11 It 
has been reported that supplementation with folic acid and vitamin B12 substantially 
reduces pemetrexed-related toxicity without reducing efficacy.11 In Scagliotti et al’s 
Phase III, the key hematologic grade 3 or 4 drug-related toxicities for 
cisplatin/pemetrexed were significantly lower than those in cisplatin/gemcitabine 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 6 of 45 
 
(neutropenia: 15% versus 27%, anemia: 6% versus 10%, and thrombocytopenia: 4% 
versus 13%, respectively; P<0.001).15 Drug-related grade 3 or 4 febrile neutropenia (1% 
versus 4%, respectively; P<0.002) and alopecia (all grades, 12% versus 21%, 
respectively; P<0.001) were also significantly lower.15 
 
Clinical trials evaluating use of pemetrexed in patients with NSCLC and a PS ≥2 are 
limited to a study by Jung et al. that retrospectively examined pemetrexed use in 56 
Korean patients with NSCLC and PS ≥2 who had relapsed or progressed after prior 
chemotherapy treatment.16 Anemia was the most frequent adverse event (28.4%), 
followed by nausea (23%). Grade 3-4 hematologic toxicity occurred in 8.8% of cases. 
None of the patients required dose modifications due to toxicity. Non-squamous cell 
carcinoma histology was significantly associated with a superior response rate (P=0.045) 
and disease control rate (P=0.008). The median survival time and the median 
progression free survival (PFS) time were 6.11 months and 2.17 months, respectively. 
Studies considering advanced age are available, such as the randomized phase II trial 
by Gridelli et al. evaluating single-agent pemetrexed versus sequential 
pemetrexed/gemcitabine in patients with NSCLC and PS of 0 to 2 who were ineligible for 
platinum-based chemotherapy. This study found that single-agent pemetrexed 
demonstrated moderate activity and was well tolerated, regardless of advanced age.13 
Similarly, in a single-arm phase II study of pemetrexed in elderly (≥70 years old) 
Japanese patients with advanced non-squamous NSCLC demonstrated favorable 
antitumor activity and mild toxicity.17  In an analysis of two randomized phase III trials 
evaluating the survival and safety of pemetrexed in elderly patients (<65 years and ≥65 
years, and <70 years and ≥70 years) with nonsquamous NSCLC and PS 0-1, Gridelli et 
al found minimal variation in the hematologic toxicities between the age groups, and the 
majority of hematologic toxicity rates were low.12  
 
The primary endpoint of this single arm pilot study is to evaluate the effect of single 
agent pemetrexed chemotherapy in ECOG Performance Status 3 patients with stage IV 
non-squamous histology non-small cell lung cancer. We hypothesize that patients with 
non-squamous histology NSCLC and ECOG PS 3 receiving single agent pemetrexed 
chemotherapy will have a prolonged time to progression compared to best supportive 
care alone and will have improved quality of life (QOL) as measured by the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
version 3.0 (EORTC QLQ-C30) and the corresponding lung cancer-specific module 
(QLQ-LC13).18 
2.0 
Objectives 
2.1 
Primary Objectives 
2.1.1 To evaluate the effect of single agent pemetrexed on tumor progression 
in ECOG Performance Status 3 patients with Stage IV non-squamous 
histology non-small cell lung cancer in a single arm pilot study. 
2.1.2 To evaluate the effect of single agent pemetrexed on quality of life in 
ECOG Performance Status 3 patients with Stage IV non-squamous 
histology non-small cell lung cancer in a single arm pilot study. 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 7 of 45 
 
2.2 
Secondary Objective 
2.2.1 To evaluate toxicity associated with single agent pemetrexed on tumor 
progression in ECOG Performance Status 3 patients with Stage IV non-
squamous histology non-small cell lung cancer in a single arm pilot study. 
3.0 
Patient Selection 
 
3.1 
Inclusion Criteria  
 
3.1.1 Patients must have histologically confirmed Stage IV non-squamous 
histology non-small cell lung cancer 
 
3.1.2 ECOG performance status of 3 
 
3.1.3 Sensitizing EGFR, ALK and ROS-1 mutations are either negative or 
unknown 
 
3.1.4 Patients must have normal organ and marrow function as defined below: 
 
- 
absolute neutrophil count  
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
creatinine clearance  
 
>45 mL/min 
 
3.1.5 The effects of pemetrexed on the developing human fetus are unknown.  
For this reason and because Pregnancy Category D agents are known to 
be teratogenic, women of child-bearing potential and men must agree to 
use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician 
immediately. 
 
3.1.6 Ability to understand and the willingness to sign an IRB-approved 
informed consent document  
 
3.1.7 Ability to understand and complete the EORTC QOL instruments 
 
3.1.8 ≥18 years of age 
 
3.2 
Exclusion Criteria  
 
3.2.1 Patients who have previously received chemotherapy for non-small cell 
lung cancer, or have received radiotherapy within 2 weeks prior to 
entering the study, or who have not recovered from adverse events due 
to treatment more than 2 weeks earlier. 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 8 of 45 
 
 
3.2.2 Patients whose tumors are positive for the sensitizing EGFR mutation. 
 
3.2.3 Patients whose tumors are positive for the sensitizing ALK fusion 
 
3.2.4 Patients whose tumors are positive for the sensitizing ROS-1 fusion 
 
3.2.5 Patients may not be receiving any other investigational agents. 
 
3.2.6 Patients with symptomatic or recurrent brain metastases should be 
excluded from this clinical trial because of their poor prognosis and 
because they often develop progressive neurologic dysfunction that 
would confound the evaluation of neurologic and other adverse events. 
 
3.2.7  Patients whose pathology has squamous cell features unless there is an 
unequivocal determination of non-squamous pathology. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pemetrexed. 
 
3.2.9 Pregnant women are excluded from this study because pemetrexed is a 
Category D agent with the potential for teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with pemetrexed, 
breastfeeding should be discontinued. 
 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnicities who meet the above-described 
eligibility criteria are eligible to participate in this study.  
 
The study consent form will also be provided in Spanish for Spanish-speaking 
participants. Based on CCCWFU population estimates for lung cancer patients, 
we expect approximately 40% of participants to be women. Translating this to our 
sample size estimate of 30 patients, we anticipate enrolling at least 12 women. 
Similarly, we expect approximately 4% of study participants to be Hispanic/Latino 
(N=1). We anticipate enrolling 18% Black or African American (N=5) patients.  
For other minority groups (American Indian, Asian) we anticipate enrolling 
approximately 4% (N=1) patient.  Should we not meet or exceed these estimates, 
the PI will engage the Cancer Center Health Equity Advisory Group to discuss 
strategies to enhance recruitment in these target populations. 
4.0 
Registration Procedures 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control 
trial, must be registered with the CCCWFU Protocol Registrar or entered into ORIS Screening 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 9 of 45 
 
Log within 24 hours of Informed Consent. Patients must be registered prior to the initiation of 
treatment.   
 
You must perform the following steps in order to ensure prompt registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix A) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed 
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, 
either by fax or e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will:   
 
 
assign a patient study number 
 
register the patient on the study 
5.0 
Study Outcomes and Study Measures 
 
5.1 
Primary Outcomes 
5.1.1 Time to tumor progression in ECOG Performance Status 3 patients with 
Stage IV non-squamous histology non-small cell lung cancer receiving 
single agent pemetrexed 
5.1.2 Quality of life metrics in accordance with the EORTC QLQ-C30 and QLQ-
LC13 instruments and PS in ECOG Performance Status 3 patients with 
Stage IV non-squamous histology non-small cell lung cancer receiving 
single agent pemetrexed 
5.2 
Secondary Outcomes 
5.2.1 Hematologic toxicity associated with single agent pemetrexed on tumor 
progression in ECOG Performance Status 3 patients with Stage IV non-
squamous histology non-small cell lung cancer 
5.2.2 Response rate in ECOG Performance Status 3 patients with Stage IV 
non-squamous histology non-small cell lung cancer receiving single agent 
pemetrexed 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 10 of 45 
 
5.2.3 Overall survival in ECOG Performance Status 3 patients with Stage IV 
non-squamous histology non-small cell lung cancer receiving single agent 
pemetrexed 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 11 of 45 
 
6.0 
Treatment Plan 
6.1 
Study-Related Interventions  
 
 
Pre- 
Studya 
Prior to each 
treatmentb 
At Each 
Treatmentc 
After 
treatmentd 
Follow-up 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concurrent meds 
X 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
Vital signs (HR, BP, RR, 
Temp) 
X 
 
X 
 
 
 
Height, Weight, BSA 
X 
 
X 
 
 
 
 
PS and QOL 
X 
 
X 
 
 
 
Tumor measurementse 
X 
 
 
Xl 
 
 
CBC w/diff, platelets 
X 
Xk 
 
Xm 
 
 
Serum chemistryf 
X 
X 
 
 
 
 
B-HCGg 
X 
 
 
 
 
 
Folic acid supplementationh 
 
X 
 
 
 
 
 
Vitamin B12 administrationi 
 
X 
 
Xn 
 
 
Corticosteroid administrationj 
 
X 
X 
X 
 
 
Adverse event evaluation 
X 
 
 
X 
 
 
X 
a Pre-study requirements listed in table must be completed within 21 days prior to registration. See Appendix E. 
b See Appendix F. To be completed prior to each treatment administration. 
c See Appendix G. To be completed for each treatment. 
d See Appendix H. 
e See Appendix I. 
f BUN, creatinine, bilirubin, SGOT [AST], SGPT [ALT]; within 7 days prior to treatment. 
g Serum pregnancy test (women of childbearing potential). 
h Begin folic acid once daily at least 7 days before the first dose of pemetrexed. Continue folic acid during the full 
course of therapy and for 21 days after the last dose of pemetrexed. 
i Administer vitamin B12 1 mg intramuscularly at least 7 days prior to the first dose of pemetrexed and at least every 
3 cycles thereafter. 
j Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after pemetrexed 
administration 
k Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is 
≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min within 7 days prior to treatment. 
l Patients should be reevaluated for response every 6 weeks (+/- 2 weeks). In addition to a baseline scan, 
confirmatory scans should also be obtained 6 weeks following initial documentation of objective response. See 
Appendix I. 
m 7-10 days after the first treatment administration 
n Every 3 cycles 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 12 of 45 
 
6.2 
Treatment Administration 
 
Treatment can be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 9.0. Appropriate dose modifications are 
described in Section 7.0. No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Regimen Description 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
 
 
 
Pemetrexed 
500 mg/m2 in 
100 mL of 0.9% 
Sodium 
Chloride 
Injection 
(preservative 
free) 
 
 
 
IV over 10 
minutes 
 
 
 
Day 1 
 
21 days 
 
6.2.1 Premedication regimen and concurrent medications 
 
 
 
 
 
 
 
Vitamin Supplementation: 
Administer folic acid 400 mcg to 1000 mcg orally once daily beginning at 
least 7 days before the first dose of pemetrexed. Continue folic acid 
during the full course of therapy and for 21 days after the last dose of 
pemetrexed. 
 
Administer vitamin B12 1 mg intramuscularly at least 1 week prior to the 
first dose of pemetrexed and at least every 3 cycles thereafter. 
Subsequent vitamin B12 injections may be given the same day as 
treatment with pemetrexed. 
 
Corticosteroids: 
Administer dexamethasone 4 mg by mouth twice daily the day before, the 
day of, and the day after pemetrexed administration. As an alternative, 
the day of treatment dexamethasone may be administered as a single 
dose of 10 mg intravenously prior to administration of the chemotherapy. 
6.2.2 Laboratory monitoring 
 
A CBC should be performed 7-10 days after the first dose for the first 
cycle of pemetrexed treatment. Patients should be monitored for nadir 
and recovery. Patients should not begin a new cycle of treatment unless 
the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, 
and creatinine clearance is ≥45 mL/min. Chemistry tests will be 
performed to evaluate renal and hepatic function prior to each treatment. 
 
 
 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 13 of 45 
 
6.2.3 Performance status and QOL 
 
 
ECOG performance status and QOL will be assessed at the start of every 
cycle (i.e. every 3 weeks). QOL will be assessed by the EORTC QLQ-
C30 and QLQ-LC13.18 
 
The EORTC QLQ-C30 is reportedly the most frequently used QOL 
instrument in lung cancer clinical trials.19 The QLQ-30 is a 30-item multi-
dimensional questionnaire designed for use in cancer populations.18 It 
contains nine multi-item scales: five functional scales (physical, role, 
cognitive, emotional, and social); three symptom scales (fatigue, pain, 
and nausea and vomiting); and a global health and quality-of-life scale, 
requested by 4-point Likert or visual analogue scales. Several single-item 
symptom measures are also included. The QLQ-LC13 is a lung cancer-
specific module to be used in conjunction with the QLQ-30 and is 13 
additional items. These questionnaires have been shown to be reliable 
and valid in over 60 languages, can be self- or interviewer-administered 
and take approximately 11 minutes to complete.18, 19 
6.3 
General Concomitant Medication and Supportive Care 
Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and 
blood products, erythropoietin, antibiotics, antiemetics, etc., as clinically 
indicated. Medications considered necessary for the patient's well-being may be 
given at the discretion of the investigator, i.e., chronic treatments for concomitant 
medical conditions, as well as agents required for life-threatening medical 
problems, etc. The reason(s) for treatment, dosage, and dates of treatment 
should be recorded on the flow sheets. 
 
6.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may 
continue until one of the following criteria applies: 
 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), including hematologic or nonhematologic 
Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 
neurotoxicity is observed 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
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6.5 
Duration of Follow Up 
 
Patients will be followed for adverse events monitoring for a minimum of 30 days 
after the last study drug is administered or until death, whichever occurs first. 
Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event.  
 
Patients will be followed every 6 weeks until death for monitoring survival study 
endpoints. 
7.0 
Dosing Delays/Dose Modifications 
 
Dose adjustments at the start of a subsequent cycle should be based on nadir 
hematologic counts or maximum nonhematologic toxicity from the preceding cycle of 
therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, 
patients should be retreated using the guidelines in Tables 1-3. Patients should be 
removed from study if they have not fully recovered with respect to treatment related 
toxicity more than 6 weeks after the last treatment, i.e. a >3 week delay. 
 
Table 1: Dose reduction – Hematologic Toxicities 
Nadir ANC<500 mm3 and nadir platelets ≥50,000/mm3 
75% of previous dose 
Nadir platelets <50,000/mm3 without bleeding 
regardless of nadir ANC  
75% of previous dose 
Nadir platelets <50,000/mm3 with bleedinga regardless 
of nadir ANC 
50% of previous dose 
aThese criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding 
 
If patients develop non-hematologic toxicities (excluding neurotoxicity) ≥Grade 3, 
treatment should be withheld until resolution to less than or equal to the patient’s pre-
therapy value. Treatment should be resumed according to guidelines in Table 2. Patients 
should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. 
 
Table 2: Dose reduction – Nonhematologic toxicitiesa,b 
Any Grade 3 or 4 toxicities except mucositis 
75% of previous dose 
Any diarrhea requiring hospitalization (irrespective of 
Grade) or Grade 3 or 4 diarrhea 
75% of previous dose 
Grade 3 or 4 mucositis 
50% of previous dose 
aNCI Common Toxicity Criteria 
bExcluding neurotoxicity (see Table 3) 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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8.0 
Measurement of Effect 
8.1 
Antitumor Effect  
 
As part of normal medical care, patients should be reevaluated for response 
every 6 weeks. In addition to a baseline scan, confirmatory scans should also be 
obtained after approximately 6 weeks to monitor for disease progression. Scans 
will be done independently of the study, however data acquired from the scans 
will be used for research purpose to evaluate the effects of the product under 
investigation. For the purposes of this study, patients should be reevaluated for 
response every 6 weeks (+/- 2 weeks). In addition to a baseline scan, 
confirmatory scans should also be obtained 6 weeks (+/- 2 weeks) following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.20 
8.1.1 Definitions  
 
 
 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the 
time of their first treatment with pemetrexed 
 
Inevaluable for objective response: When no imaging/measurement is 
done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. 
o If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time 
point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would most likely happen 
in the case of PD. 
 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
o 10 mm by CT scan (CT scan slice thickness no greater than 5 
mm; when CT scans have slice thickness >5 mm, the minimum 
size should be twice the slice thickness);  
o 10 mm caliper measurement by clinical exam (lesions which 
cannot be accurately measured with calipers should be recorded 
as non-measurable). 
o 20 mm by chest X-ray. 
 
Measurable lesions: 
o Malignant lymph nodes: To be considered pathologically enlarged 
and measurable, a lymph node must be ≥15 mm in short axis 
when assessed by CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. 
o Lytic bone lesions or mixed lytic-blastic lesions with identifiable 
soft tissue components that can be evaluated by crosssectional 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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imaging techniques such as CT or MRI can be considered 
measurable if the soft tissue component meets the definition of 
measurability described above. 
o ‘Cystic lesions’ thought to represent cystic metastases can be 
considered measurable if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
 
Non-measurable lesions: Non-measurable lesions are all other lesions, 
including small lesions (longest diameter <10 mm or pathological lymph 
nodes with 10 to <15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
o Lesions with prior local treatment, such as those situated in a 
previously irradiated area or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion.  
 
Target lesions: All measurable lesions up to a maximum of two lesions 
per organ and five lesions in total, representative of all involved organs, 
should be identified as target lesions and recorded and measured at 
baseline. 
o Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and be representative of all 
involved organs, as well as their suitability for reproducible 
repeated measurements. 
o All measurements should be recorded in metric notation using 
calipers if clinically assessed. 
o A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters, which will be used as 
reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. If lymph nodes are to 
be included in the sum, only the short axis will contribute. 
o Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded even if the nodes regress 
to below 10 mm on study. When lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met since a normal lymph node is 
defined as having a short axis of <10 mm. 
o Target lesions that become ‘too small to measure’: While on 
study, all lesions (nodal and non-nodal) recorded at baseline 
should have their actual measurements recorded at each 
subsequent evaluation, even when very small. However, 
sometimes lesions or lymph nodes become so faint on a CT scan 
that the radiologist may not feel comfortable assigning an exact 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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measure and may report them as being ‘too small to measure’, in 
which case a default value of 5 mm should be assigned. 
o Lesions that split or coalesce on treatment: When non-nodal 
lesions ‘fragment’, the longest diameters of the fragmented 
portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of 
the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
 
Non-target lesions: All lesions (or sites of disease) not identified as target 
lesions, including pathological lymph nodes and all non-measurable 
lesions, should be identified as non-target lesions and be recorded at 
baseline. Measurements of these lesions are not required and they 
should be followed as ‘present’, ‘absent’ or in rare cases, ‘unequivocal 
progression’. 
8.1.2 Methods for Evaluation of Measurable Disease 
 
 
The same method of assessment and the same technique should be 
used to characterize each identified and reported lesion at baseline and 
during follow-up. 
 
 
CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. MRI is also acceptable in 
certain situations (e.g., for body scans but not for lung). 
 
Lesions on a chest X-ray may be considered measurable lesions if they 
are clearly defined and surrounded by aerated lung. However, CT is 
preferable. 
 
Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm in diameter as assessed using calipers. For the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Ultrasound (US) should not be used to measure tumor lesions. 
 
Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to 
be considered in complete response. 
 
Cytology and histology can be used in rare cases (e.g., for evaluation of 
residual masses to differentiate between Partial Response and Complete 
Response or evaluation of new or enlarging effusions to differentiate 
between Progressive Disease and Response/Stable Disease). 
 
Use of endoscopy and laparoscopy is not advised. However, they can be 
used to confirm complete pathological response. 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
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8.1.3 Response Criteria 
 
 
Complete Response (CR):  Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm 
 
Partial Response (PR):  At least a 30% decrease in the sum of diameters 
of target lesions, taking as reference the baseline sum of diameters 
 
Progressive Disease (PD):  At least a 20% increase in the sum of 
diameters of target lesions, taking as reference the smallest sum on study 
(this may include the baseline sum). The sum must also demonstrate an 
absolute increase of at least 5 mm. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD. 
8.1.4 Evaluation of Non-Target Lesions 
 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker levels. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Non-CR / Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker levels above normal limits. 
 
Progressive Disease (PD):  Unequivocal progression of existing non-target 
lesions. 
o When patient has measurable disease: To achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, 
even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. 
o When patient has only non-measurable disease: There is no 
measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified, a useful test that can 
be applied is to consider if the increase in overall disease burden 
based on change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for 
measurable disease. Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’ or an increase in lymphangitic disease 
from localized to widespread. 
 
New lesions: The appearance of new malignant lesions denotes disease 
progression. 
o The finding of a new lesion should be unequivocal (i.e., not 
attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor, 
especially when the patient’s baseline lesions show partial or 
complete response). 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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o If a new lesion is equivocal, for example because of its small size, 
continued therapy and follow-up evaluation will clarify if it represents 
truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the 
initial scan. 
o A lesion identified on a follow-up study in an anatomical location that 
was not scanned at baseline is considered a new lesion and disease 
progression. 
o It is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT in assessment of progression 
(particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following 
algorithm: 
 
Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is PD based on a new lesion. 
 
No FDG-PET at baseline and a positive FDG-PET at follow-
up: 
 
If the positive FDG-PET at follow-up corresponds to a 
new site of disease confirmed by CT, this is PD. 
 
If the positive FDG-PET at follow-up is not confirmed 
as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). 
 
If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this 
is not PD. 
 
8.1.5 Evaluation of Best Overall Response 
 
Appendix I provides a summary of the overall response status calculation at each 
time point for patients who have measurable and non-measurable (therefore non-
target) disease at baseline. 
 
8.1.6 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are first met for CR/PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
 
The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease 
is objectively documented. 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
8.1.7 Survival Outcomes 
 
Progression-Free Survival is defined as the duration of time from the start of 
treatment to the time of progression, death, or date of last contact 
 
Overall Survival is defined as the duration of time from the start of treatment to 
date of death or date of last contact. 
9.0 
Adverse Events List and Reporting Requirements 
9.1 
Adverse Event List for Pemetrexed 
 
 
 
In clinical trials, the most common adverse reactions (incidence ≥20%) during 
therapy with pemetrexed as a single agent were fatigue, nausea, and anorexia. 
 
 
 
Grade 3 or 4 adverse reactions: 
 
Incidence 1% to 5% 
Hematologic – anemia, leukopenia, neutropenia, thrombocytopenia 
Hepatic – increased ALT 
Gastrointestinal – nausea, anorexia, vomiting 
General – fatigue 
 
Incidence Less than 1% 
Hepatic – increased AST 
Gastrointestinal  - stomatitis/pharyngitis 
9.2 
Adverse Event Characteristics 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.   
 
 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
9.3 
STRC SAE Reporting Requirements 
 
The Safety and Toxicity Reporting Committee (STRC) is responsible for reviewing SAEs 
for CCCWFU Institutional studies as outlined in Appendix B. STRC currently requires 
that all unexpected 4 and all grade 5 SAEs on these trials be reported to them for 
review. All CCCWFU Clinical Research Management (CRM) staff members assisting a 
Principal Investigator in investigating, documenting and reporting an SAE qualifying for 
STRC reporting are responsible for informing a clinical member of the STRC as well as 
the entire committee via the email notification procedure of the occurrence of an SAE.  
9.4  
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events 
shall be promptly reported to the IRB, according to institutional policy. Reporting to the 
IRB is required regardless of the funding source, study sponsor, or whether the event 
involves an investigational or marketed drug, biologic or device. Reportable events are 
not limited to physical injury, but include psychological, economic and social harm. 
Reportable events may arise as a result of drugs, biological agents, devices, procedures 
or other interventions, or as a result of questionnaires, surveys, observations or other 
interactions with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the 
IRB and other applicable parties of unanticipated problems involving risk to subjects or 
others. The Principal Investigator, however, is ultimately responsible for ensuring the 
prompt reporting of unanticipated problems involving risk to subjects or others to the 
IRB. The Principal Investigator is also responsible for ensuring that all reported 
unanticipated risks to subjects and others which they receive are reviewed to determine 
whether the report represents a change in the risks and/or benefits to study participants, 
and whether any changes in the informed consent, protocol or other study-related 
documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site 
where the study has been approved by the WFUHS IRB (internal events) must be 
reported to the WFUHS IRB within 7 calendar days of the investigator or other members 
of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external 
events) must be reported to the WFUHS IRB within 7 calendar days of the investigator 
or other members of the study team becoming aware of the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit 
of the research and as a result warrants a substantive change in the research protocol or 


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Non-Squamous Non-Small Cell Lung Cancer 
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CCCWFU # 62115 
 
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informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
10.0 Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the pharmaceutical agent 
administered in this study can be found in Section 9.1. 
10.1 Pharmaceutical Accountability 
 
This drug is commercially available. 
10.2 ALIMTA (Pemetrexed)  
 
 
Product description:  Pemetrexed disodium heptahydrate has the chemical 
name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-
d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is marketed by 
Lilly USA, LLC. ALIMTA is supplied as a sterile lyophilized powder for 
intravenous infusion available in single-dose vials. The product is a white to 
either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial 
of ALIMTA contains pemetrexed disodium equivalent to 100 mg pemetrexed and 
106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. 
Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. 
 
Solution preparation: Reconstitute each 500-mg vial with 20 mL of 0.9% 
Sodium Chloride Injection (preservative free). Reconstitution gives a solution 
containing 25 mg/mL ALIMTA. Gently swirl each vial until the powder is 
completely dissolved. The resulting solution is clear and ranges in color from 
colorless to yellow or green-yellow without adversely affecting product quality. 
The pH of the reconstituted ALIMTA solution is between 6.6 and 7.8. 
FURTHER DILUTION IS REQUIRED. Reconstituted ALIMTA solution must be 
further diluted into a solution of 0.9% Sodium Chloride Injection (preservative 
free), so that the total volume of solution is 100 ml. Reconstitution and further 
dilution prior to intravenous infusion is only recommended with 0.9% Sodium 
Chloride Injection (preservative free). ALIMTA is physically incompatible with 
diluents containing calcium, including Lactated Ringer’s Injection, USP and 
Ringer’s Injection, USP and therefore these should not be used. 
Coadministration of ALIMTA with other drugs and diluents has not been studied, 
and therefore is not recommended. 
 
Storage requirements and Stability: Chemical and physical stability of 
reconstituted and infusion solutions of ALIMTA have been demonstrated for up to 
24 hours following initial reconstitution, when stored refrigerated. When prepared 
as directed, reconstitution and infusion solutions of ALIMTA contain no 
antimicrobial preservatives. Store at 25°C (77°F); excursions permitted to 15-
30°C (59-86°F). Discard any unused portion.  
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
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CCCWFU # 62115 
 
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Route of administration:  ALIMTA is administered as an intravenous infusion 
over 10 minutes. .As with other potentially toxic anticancer agents, care should 
be exercised in the handling and preparation of infusion solutions of ALIMTA. 
The use of gloves is recommended. If a solution of ALIMTA contacts the skin, 
wash the skin immediately and thoroughly with soap and water. If ALIMTA 
contacts the mucous membranes, flush thoroughly with water. ALIMTA is 
compatible with standard polyvinyl chloride (PVC) administration sets and 
intravenous solution bags. ALIMTA is not a vesicant. There is no specific antidote 
for extravasation of ALIMTA. To date, there have been few reported cases of 
ALIMTA extravasation, which were not assessed as serious by the investigator. 
ALIMTA extravasation should be managed with local standard practice for 
extravasation as with other non-vesicants. 
 
Drug interactions:  
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 
Although ibuprofen (400 mg four times a day) can decrease the clearance of 
pemetrexed, it can be administered with ALIMTA in patients with normal renal 
function (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is 
needed with concomitant NSAIDs in patients with normal renal function. Caution 
should be used when administering NSAIDs concurrently with ALIMTA to 
patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 
79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, 
indomethacin) should be avoided for a period of 2 days before, the day of, and 2 
days following administration of ALIMTA. In the absence of data regarding 
potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., 
meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing 
for at least 5 days before, the day of, and 2 days following ALIMTA 
administration. If concomitant administration of NSAIDs is necessary, patients 
should be monitored closely for toxicity, especially myelosuppression, renal, and 
gastrointestinal toxicity. 
 
Nephrotoxic Drugs 
ALIMTA is primarily eliminated unchanged renally as a result of glomerular 
filtration and tubular secretion. Concomitant administration of nephrotoxic drugs 
could result in delayed clearance of ALIMTA. Concomitant administration of 
substances that are also tubularly secreted (e.g., probenecid) could potentially 
result in delayed clearance of ALIMTA. 
 
Disposal:  Unused portions of agent should be disposed of in accordance with 
general anticancer agent guidelines 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
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11.0 Data Management 
 
Informed consent document 
ORIS 
Protocol registration form 
ORIS 
Pre-study data collection form 
REDCap 
Pre-treatment data collection form 
REDCap 
Treatment data collection form 
REDCap 
Follow-up data collection form 
REDCap 
Tumor Measurement form 
REDCap 
Treatment Response form 
REDCap 
12.0 Statistical Considerations 
12.1 Analysis of Primary Objectives 
 
There are two primary objectives in this study: 1) To evaluate the effect of single 
agent pemetrexed on tumor progression in ECOG Performance Status 3 patients 
with Stage IV non-squamous histology non-small cell lung cancer  and 2) To 
evaluate the effect of single agent pemetrexed on quality of life in ECOG 
Performance Status 3 patients with Stage IV non-squamous histology non-small 
cell lung cancer. 
 
Both of these objectives will be examined using a pilot study of 30 patients.  We 
now will describe the analytic strategy to address each aim. 
 
Based on historic data, the median progression free survival time for comparable 
patients has ranged from 2.8 to 4.9 months.17, 21-23  However, the patients in this 
protocol are likely to have a worse prognosis since their ECOG performance status 
is 3 whereas the patients in the references had better ECOG performance status.  
Therefore, one goal of this trial is to see whether there is evidence that the median 
progression free survival time in this group of treated patients could be  12 weeks 
(i.e., 2.8 months).   In order to do this we will determine whether each patient has a 
progression (or dies) before or after 12 weeks.  We will then construct a 95% exact 
(Clopper Pearson) confidence interval around the proportion with PFS greater than 
or equal to 12 weeks.  If this confidence interval includes 50% then that would 
provide evidence that the therapy is potentially promising.  However, if the upper 
bound of the confidence interval does not include 50% then this would indicate that 
the treatment may not be promising for patients since we could rule out the 
possibility that the median PFS is 12 weeks or longer.   We have designed this 
study to enroll 30 patients.  If 9 out of 30 do not have a progression (or dies) at 12 
weeks (30%) then the upper bound of a 2-sided 95% confidence interval would not 
include 50%, however if 10 or more patients (out of 30) do not have progression (or 
dies) at 12 weeks then the upper bound would include 50% suggesting that the 
treatment is promising.   
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
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In addition to estimating this confidence interval  we will construct a Kaplan Meier 
survival curve to describe the time to progression data. 
 
For the quality of life outcome we wish to compare the pre-treatment with the post-
treatment values over time.  Quality of life will be assessed every 3-weeks during 
the trial and we anticipate examining each of these assessments.  For the purposes 
of identifying a primary time point for comparison we will compare the 12 week QOL 
value with the baseline QOL value.   Since some patients may not have a 12 week 
measure, but we will assess QOL at each treatment time (i.e. every three weeks) 
we can use a longitudinal mixed models analysis to look at QOL over the time 
course.   This approach would handle missing data if the data is missing at random, 
which means that measured covariates can be used to predict whether missing 
data will occur.   We believe that it is possible that patients who have worse 
baseline co-morbid conditions may be more likely to have a 12-week QOL missing, 
and thus we will use these characteristics in the longitudinal mixed model analysis 
to examine change in QOL over time adjusting for baseline covariates. Based on 
historic data, most patients eligible for this study would have worsening QOL over a 
12 week period, thus we wish to determine whether QOL can remain stable or 
possibly improve.   To do this we will calculate a paired t-test to see if the average 
change is more than 0 (worsening) versus a two-sided alternative that the 
difference is 0 or better. 
 
It should be noted that since this is a pilot study, there is a possibility that one of the 
two primary comparisons (confidence interval calculation and QOL change) may 
not meet the criteria for success, however if there is evidence that the effects are 
trending in the correct direction (i..e, if the average change in 12 week QOL is 0 or 
positive (implying some improvement)) then this would provide evidence that the 
treatment regimen is possibly working and could possibly warrant further studies.   
12.2 Analysis of Secondary Objectives 
 
There are three secondary objectives in this protocol 1) to evaluate the toxicities 
associated with single agent pemetrexed on tumor progression in ECOG 
Performance Status 3 patients with Stage IV non-squamous histology non-small 
cell lung cancer (in particular we will examine neutropenia, thrombocytopenia 
and fatigue (although fatigue will also be captured as part of quality of life 
assessment), 2) to estimate the response rate in ECOG Performance Status 3 
patients with Stage IV non-squamous histology non-small cell lung cancer 
receiving single agent pemetrexed and 3) to estimate the overall survival in 
ECOG Performance Status 3 patients with Stage IV non-squamous histology 
non-small cell lung cancer receiving single agent pemetrexed 
 
For toxicities we will estimate the number and type of toxicities observed during 
this protocol focusing on unexpected grade 3 or higher toxicities.  No formal 
statistical tests will be done on these estimates. 
 
Response rate will be estimate every 6 weeks for patients and these estimates 
will be presented with confidence intervals as well. 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 26 of 45 
 
Overall survival will be examined by estimating a Kaplan-Meier survival curve 
using all patients enrolled. 
 
 
 
12.3 Power and Sample Size 
 
Since this is an aggressive disease and patients enrolled will be at ECOG 
Performance Status 3, it is an expected that all patients will progress or die prior 
to the end of the follow-up therefore we anticipate that all 30 patients will provide 
data for the time until progression endpoint analysis. .  Quality of life will be 
measured at each visit when treatment is administered so it is expected that all 
patients will have some follow-up assessments to be used in analyses. 
 
As described above, the first analysis will consist of determining what proportion 
of patients are progression-free (and alive) at 12 weeks (yes/no).   With a total of 
30 patients, a two-sided 95% confidence interval (using the Clopper-Pearson 
exact calculation) will have a maximum width of 0.374 (i.e., +/- 0.187).  Thus, if 
the observed proportion of patients who are progression free at 12 weeks is 50% 
then the lower bound of this interval will rule out 31.3% (or lower).   Likewise, if 
30% or fewer patients are progression free at 12 weeks then the upper bound of 
this confidence interval will rule out 50% and thus suggest that the median 
progression free survival for this treatment is less than 12 weeks. 
 
We have a planned interim analysis to take place after the first 15 patients are 
enrolled and have had more than 12 weeks of follow-up.  If 2 or fewer of these 
first 15 patients have a response (i..e progress by 12 weeks) then we will stop 
the trial since the upper bound of a 2-sided 99% exact confidence interval would 
rule out 50%. 
 
Likewise, with 30 patients enrolled, we have 80% power to detect a change in 
QOL equal to 0.53 standard deviations using a paired t-test with alpha=0.05 (2-
sided test). 
 
As stated above, since this is a pilot study, it is possible that we may not observe 
statistical significance for these two aims, however if the point estimates for these 
aims are in the correct direction this will provide evidence that the therapy may 
be a promising alternative for patients and thus warrant further investigation.  If 
this were to occur, the data from this trial would be used to provide preliminary 
estimates of what PFS rates may be expected and what change in QOL may be 
expected in a larger efficacy study. 
12.4 Estimated Accrual Rate 
 
We anticipate that there will be many patients eligible for this trial since this 
population does not have many treatment options, thus we expect 2-3 patients a 
month and accrual would be finished between 10-15 months. 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 27 of 45 
 
12.5 Estimated Study Length 
 
Since this is an aggressive disease we anticipate that within 1-year of follow-up 
of the last enrolled patient we will have sufficient data to perform all analyses.  
Thus, we anticipate that the length of this study will be between 22 and 27 
months. 
12.6 Interim Analysis Plan 
 
As described above an interim analysis will take place after 15 patients have 
been enrolled and have sufficient follow-up to determine whether their 
progression free survival time is above 2.8 months or not. 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 28 of 45 
 
References 
 
1. SEER Cancer Statistics Review, 1975-2011. In: Howlader N NA, Krapcho M, Garshell J, 
Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, 
Chen HS, Feuer EJ, Cronin KA, editor. Bethesda, MD: National Cancer Institute, 2014. 
2. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on 
individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative 
Group. Bmj. 1995;311: 899-909. 
3. Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy vs supportive 
care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest. 
1994;106: 861-865. 
4. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with 
advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin 
Oncol. 1988;6: 633-641. 
5. Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl 
Cancer Inst. 1980;65: 25-32. 
6. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al. A randomized trial of the four most active 
regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986;4: 14-22. 
7. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage 
non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol. 1991;9: 
1618-1626. 
8. Paesmans M, Sculier JP, Libert P, et al. Prognostic factors for survival in advanced non-
small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and 
amalgamation algorithms in 1,052 patients. The European Lung Cancer Working Party. J Clin 
Oncol. 1995;13: 1221-1230. 
9. Fuld AD, Dragnev KH, Rigas JR. Pemetrexed in advanced non-small-cell lung cancer. Expert 
Opin Pharmacother. 2010;11: 1387-1402. 
10. Li X, Wei S, Chen J. Critical appraisal of pemetrexed in the treatment of NSCLC and 
metastatic pulmonary nodules. Onco Targets Ther. 2014;7: 937-945. 
11. Niyikiza C, Baker SD, Seitz DE, et al. Homocysteine and methylmalonic acid: markers to 
predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther. 2002;1: 545-552. 
12. Gridelli C, Brodowicz T, Langer CJ, et al. Pemetrexed therapy in elderly patients with good 
performance status: analysis of two phase III trials of patients with nonsquamous non-small-cell 
lung cancer. Clin Lung Cancer. 2012;13: 340-346. 
13. Gridelli C, Kaukel E, Gregorc V, et al. Single-agent pemetrexed or sequential 
pemetrexed/gemcitabine as front-line treatment of advanced non-small cell lung cancer in 
elderly patients or patients ineligible for platinum-based chemotherapy: a multicenter, 
randomized, phase II trial. J Thorac Oncol. 2007;2: 221-229. 
14. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 
in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic 
nonsmall cell lung carcinoma. Cancer. 2001;92: 2639-2647. 
15. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-
stage non-small-cell lung cancer. J Clin Oncol. 2008;26: 3543-3551. 
16. Jung SY, Yoo SJ, Shin JY, et al. Pemetrexed in previously treated non-small cell lung 
cancer patients with poor performance status. Zhongguo Fei Ai Za Zhi. 2011;14: 33-38. 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 29 of 45 
 
17. Kim YH, Hirabayashi M, Kosaka S, et al. Phase II study of pemetrexed as first-line treatment 
in elderly (>/=75) non-squamous non-small-cell lung cancer: Kyoto Thoracic Oncology 
Research Group Trial 0901. Cancer Chemother Pharmacol. 2013;71: 1445-1451. 
18. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85: 365-376. 
19. Damm K, Roeske N, Jacob C. Health-related quality of life questionnaires in lung cancer 
trials: a systematic literature review. Health Econ Rev. 2013;3: 15. 
20. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45: 228-247. 
21. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J 
Clin Oncol. 2004;22: 1589-1597. 
22. Zukin M, Barrios CH, Pereira JR, et al. Randomized phase III trial of single-agent 
pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung 
cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 
2013;31: 2849-2853. 
23. Hattori Y, Iwasaku M, Satouchi M, et al. A phase II study of pemetrexed in chemotherapy-
naive elderly patients aged >/= 75 years with advanced non-squamous non-small-cell lung 
cancer (HANSHIN Oncology Group 003). Jpn J Clin Oncol. 2013;43: 1184-1189. 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 30 of 45 
 
Appendix A – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  ___ ___ ___ ___ ___ 
 
 
SEX:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
Stage at Diagnosis: ____________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
ECOG Performance Status: ___ ___ ___    
 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to 
the registrar at 336-7136772 or registra@wakehealth.edu. 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 31 of 45 
 
 
Appendix B – Subject Eligibility Checklist 
 
IRB Protocol No.  
CCCWFU Protocol No. 
Study Title: A Phase II Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV Non-
Squamous Non-Small Cell Lung Cancer 
Principal Investigator:  Stefan Grant, MD 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm *  
(Please document dates and lab results) 
Histologically confirmed Stage IV non-squamous 
histology non-small cell lung cancer 
□ 
□ 
 
ECOG performance status of 3 
□ 
□ 
 
Sensitizing EGFR, ALK and ROS-1 mutations are 
either negative or unknown 
□ 
□ 
 
Absolute neutrophil count ≥1,500/mcL 
□ 
□ 
 
Platelets ≥100,000/mcL 
□ 
□ 
 
Creatinine clearance ≥45 mL/min 
□ 
□ 
 
The effects of pemetrexed on the developing 
human fetus are unknown.  For this reason and 
because Pregnancy Category D agents are 
known to be teratogenic, women of child-bearing 
potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for 
the duration of study participation. Should a 
woman become pregnant or suspect she is 
pregnant while participating in this study, she 
should inform her treating physician immediately 
□ 
□ 
 
Ability to understand and the willingness to sign 
an IRB-approved informed consent document 
□ 
□ 
 
Ability to understand and complete the EORTC 
QOL instruments 
□ 
□ 
 
>18 years of age 
□ 
□ 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 32 of 45 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Chemotherapy for Stage IV non-small cell lung 
cancer or radiotherapy within 2 weeks prior to 
entering the study or those who have not 
recovered from adverse events due to agents 
administered more than 2 weeks earlier 
□ 
□ 
 
Tumors known to be positive for the sensitizing 
EGFR mutation, the sensitizing ALK fusion or the 
sensitizing ROS-1 fusion 
□ 
□ 
 
Receiving any other investigational agents 
□ 
□ 
 
Symptomatic or recurrent brain metastases 
□ 
□ 
 
Patients whose pathology has squamous cell 
features unless there is an unequivocal 
determination of non-squamous pathology 
□ 
□ 
 
History of allergic reactions attributed to 
compounds of similar chemical or biologic 
composition to pemetrexed 
□ 
□ 
 
Pregnancy 
□ 
□ 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
ORIS Assigned PID: __________________  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility:_______________________ Date: _______________ 
 
Signature of Treating Physician**:  _____________________________________ Date:  _______________ 
 
**Principal Investigator signature can be obtained following registration if needed 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 33 of 45 
 
Appendix C – Mandatory STRC SAE Reporting Guidelines 
 
Mandatory Safety and Toxicity Review Committee (STRC; Previously CROC) 
Serious Adverse Event (SAE) Notification Procedure 
 
Mandatory STRC SAE Reporting Requirements – Revised 6/05/2012 
 
This document describes STRC reporting and use of the electronic submission form that is 
submitted for unexpected grade 4 and any grade 5 (death during protocol intervention) 
SAEs on CCCWFU Institutional interventional trial patients. There are multiple entities that 
require reporting of SAEs. Each entity has different rules for what is reported, and how it is 
reported.  
 
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) 
should NOT be used to evaluate whether an event should be reported to STRC. Only the rules 
for reporting described in this document should be considered. 
 
As defined in the NCI summary IV reporting guidelines, CCCWFU Institutional studies 
covered by these reporting requirements are defined as: In-house, internally reviewed 
trials, including those collaborative studies conducted with industry sponsorship in 
which the center is a primary contributor to the design, implementation, and monitoring 
of the trial, or participation in a multi-site trial initiated by an institutional investigator at 
another center.  Institutional trials are almost always authored by a researcher here at 
CCCWFU. Institutional protocols are labeled NCI Code=”I” for Institutional on the protocol 
screen in ORIS. Cooperative group protocols are not considered Institutional, but Research 
Base trials are classified as Institutional. 
 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional studies, as defined 
above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs on these trials 
be reported to them for review. All Clinical Research Management (CRM) staff members 
assisting a PI in documenting and reporting an SAE that qualifies for STRC reporting are 
responsible for informing a clinical member of the STRC by phone, followed by informing the 
entire committee via the required email notification. 
 
THESE REPORTING REQUIREMENTS APPLY TO EVERYONE WORKING WITH CANCER 
CENTER INSTITUTIONAL PROTOCOLS. 
 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event not including routinely experienced events per protocol (e.g. 
myelosuppression) and all grade 5 events (death during protocol intervention) should be 
reported. The patient is considered “on-treatment” as defined in the protocol, which can extend 
days/weeks/months past the last date of actual protocol intervention.  
 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 34 of 45 
 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, Phase 2 and 
Phase 3 Interventional Trials 
 
 
ADVERSE EVENT 
Grade 1, Grade 2, Grade 3 
 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT 
TO STRC 
Unlikely 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT 
TO STRC 
Possible 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT 
TO STRC 
Probable 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT 
TO STRC 
Definite 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT 
TO STRC 
 
STRC reporting may not be appropriate for specific expected adverse events for protocols. In those 
situations the adverse events that will not require STRC reporting must be specified in the text of 
the approved protocol. 
 
STRC notification responsibilities of the person handling the reporting/documenting of the 
SAE: 
 
1. Make a phone call to the appropriate clinical member of the STRC as listed below (page if 
necessary)—see note 2 below 
2. Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. This 
form is found at either the ORIS main menu page or by going to 
http://ccc.wfubmc.edu/oris/strc.aspx. 
This will ensure that all persons that the event applies to will be notified; remember to file a 
copy of your confirmation. (Form instructions will walk you through the required fields, 
consult the help page for further instructions.) 
3. Ensure that you document that the appropriate persons on the STRC has been contacted. 
4. Follow up with/update the clinical member of STRC regarding any new developments or 
information obtained during the course of the SAE investigation and reporting process. 
 
Elements needed to complete the electronic STRC form: 
1. ORIS Patient ID (PID) 
2. Name of STRC Clinician notified/Date/Time/Comments. 
3. Grade of event. 
4. Is this related to protocol intervention or treatment? 
5. Is suspension of the protocol needed? 
6. Is any change to consent or protocol needed? 
7. Was the nature or severity of the event unexpected? 
8. Date of the event. 
9. Brief description of the event using approved CTC version terminology. 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 35 of 45 
 
10.  Date of last study dose before event. 
11. Relevant tests/labs. 
12. Most importantly make sure that the Investigator assigns attribution to the reported 
event (grade) using the appropriate CTCAE version for the protocol. 
 
The Clinical Members of STRC to Notify by Phone or Page: 
 
 Bayard Powell, MD – Director-at-Large, CCCWFU; Chair, PRC; Section Head, 
Hematology/Oncology.  6-7970 / 6-2701 / Pager 806-9308 
 Glenn Lesser, MD – Hematology Oncology 6-9527 / 6-0256 / Pager 806-8397 
 Kathryn Greven, MD – Vice Chair – Radiation Oncology. 3-3600 / Pager 806-8314 
 Marissa Howard-McNatt, MD – General Surgery 6-0545 / 806-6438 
 
Definition of Unavailable: As a general guideline if the first clinician that is contacted does not 
respond to the phone call or page within a reasonable amount of time, then initiate contact with their 
backup.  Give the back-up a reasonable amount of time to respond to a phone call or page before 
contacting another member. This is a general guideline.  You must use your best judgment as a 
clinical research professional given the time of day, severity of the SAE, and other circumstances as 
to when it is appropriate to contact backup clinicians.  If the event occurs near the end of day, then 
leave messages (voice or email) as appropriate and proceed with submitting your STRC notification 
form.  The important criteria is that have taken reasonable steps to notify and document that you 
have initiated some type of contact to one or more of the clinical members of STRC. 
 
STRC CLINICAN RESPONSIBILITY:  It is the responsibility of the STRC clinician to review all 
reported events, evaluate the events as they are reported; and communicate a response to the 
Investigator, event reporter and the members of STRC. The review will include but not be limited to 
the information reported; there may be times when additional information is needed in order for an 
assessment to be made further communication directly with the investigator may be warranted. 
STRC reserves the right to agree with the investigator’s assessment if STRC does not agree with the 
investigator STRC reserves the right to suspend the trial pending further investigation. 
 
AMENDMENTS TO PREVIOUS REPORTS:  If you are not able to supply all pertinent information 
with the initial submission, once the additional information is available do not submit a new report. 
Go to the original email that was received by STRC and others “reply to all” and entitle your email 
“Amendment for (list date of event and patient ID) this will avoid duplications of the same event. List 
the additional information which you are reporting. 
 
 
 
 
 
 
 
 
 
 
 
 


A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 Patients with Stage IV  
Non-Squamous Non-Small Cell Lung Cancer 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62115 
 
Protocol version date 04-13-17 
 
Page 36 of 45 
 
Appendix D – Adverse Event Log 
 
 
 
 
 
Adverse 
Event 
Description 
Cycle of 
Toxicity 
OnsetA 
Start 
Date 
 
Stop 
Date 
 
AE Type 
Grade (1-5) 
per CTC v. 
4.0 
Attribution 
Dose 
Limiting  
ToxicityA 
Serious 
Action Taken 
Treating 
Physician 
Initials/ 
Date 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy 
Withheld 
Therapy D/C 
Therapy 
Adjusted 
Other: _______ 
N/A 
 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy 
Withheld 
Therapy D/C 
Therapy 
Adjusted 
Other: _______ 
N/A 
 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-threatening 
Death 
Other: _______ 
None 
Therapy 
Withheld 
Therapy D/C 
Therapy 
Adjusted 
Other: _______ 
N/A 
 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
Page 38 of 45 
 
 
Appendix E: Pre-Study 
 
 
1. Medical history:______________________________________________________ 
___________________________________________________________________ 
___________________________________________________________________ 
___________________________________________________________________ 
 
2. Concurrent medications:________________________________________________ 
____________________________________________________________________ 
____________________________________________________________________ 
___________________________________________________________________ 
 
3. Physical exam:________________________________________________________ 
____________________________________________________________________ 
___________________________________________________________________ 
 
4. Vital signs: 
a. HR______ 
b. BP___/___ 
c. RR____ 
d. Temp____ 
 
5. CBC results: 
Date __ __ /__ __ / __ __ 
 
a. WBC____ 
b. RBC____ 
c. Hemoglobin____ 
d. Hematocrit____ 
e. MCV____ 
f. MCH____ 
g. MCHC____ 
 
h. RDW____ 
i. 
Neutrophils____ 
j. 
Lymphocytes____ 
k. Monocytes____ 
l. 
Eosinophils____ 
m. Basophils____ 
n. Platelets____ 
 
6. Serum chemistry results: 
Date __ __ /__ __ / __ __ 
 
a. BUN____ 
b. Creatinine____ 
c. bilirubin____ 
d. SGOT[AST] ____ 
e. SGPT[ALT] ____ 
 
 
7. Documentation of negative pregnancy test for women of child-bearing potential? 
Yes 
  
No 
  
N/A  
 
If N/A – Please give specific reason with dates:________________________________ 
 
 
8. QOL questionnaire administered 
a. EORTC QLQ-C30  
Yes 
  
No 
    
Date: __ __ / __ __ / __ __ 
b. EORTC QLQ-LC13  Yes 
  
No 
  
Date: __ __ / __ __ / __ __


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
 
 
 
 
 
Page 39 of 45 
Cycle #:_________ 
Appendix F: Pre-Treatment 
 
1. CBC results: 
Date __ __ /__ __ / __ __ 
 
a. WBC____ 
b. RBC____ 
c. Hemoglobin____ 
d. Hematocrit____ 
e. MCV____ 
f. MCH____ 
g. MCHC____ 
h. RDW____ 
i. 
Neutrophils____ 
j. 
Lymphocytes____ 
k. Monocytes____ 
l. 
Eosinophils____ 
m. Basophils____ 
n. Platelets____ 
 
2. Serum chemistry results: 
Date __ __ /__ __ / __ __ 
 
a. BUN____ 
b. Creatinine____ 
c. bilirubin____ 
d. SGOT[AST] ____ 
e. SGPT[ALT] ____ 
 
3. (For 1st treatment only): Documentation of Folic Acid supplementation started at least 7 
days before first dose of pemetrexed? 
Yes 
  
No 
   NA (Not 1st cycle) 
    
Date started: __ __ / __ __ / __ __ 
 
4. (For 1st treatment only): Documentation of Vitamin B12 administration at least 7 days 
before first dose of pemetrexed? 
Yes 
  
No 
   NA (Not 1st cycle) 
    
Date administered: __ __ / __ __ / __ __ 
 
5. Documentation of Corticosteroid administration the day before each dose of 
pemetrexed? 
Yes 
  
No 
  
Date administered: __ __ / __ __ / __ __ 
 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
Page 40 of 45 
Cycle #:_________ 
Appendix G: Day of Treatment 
 
1. Vital signs: 
a. HR______ 
b. BP___/___ 
c. RR____ 
d. Temp____ 
e. Height____ 
f. Weight____ 
g. Body Surface Area____ 
 
2. ECOG Performance Status_____ 
 
3. QOL questionnaire administered 
a. EORTC QLQ-C30  
Yes 
  
No 
 
b. EORTC QLQ-LC13  Yes 
  
No 
 
 
4. Documentation of Corticosteroid administration on the day of treatment with 
Pemetrexed? 
Yes 
  
No 
  
Date administered: __ __ / __ __ / __ __ 
 
5. Documentation of continued folic acid supplementation? 
Yes 
  
No
 
 
6. (Every 3 cycles): Documentation of Vitamin B12 administration? 
Yes 
  
No 
  
 
 NA 
    Date administered: __ __ / __ __ / __ __ 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
Page 41 of 45 
Cycle #:_________ 
Appendix H: Post-Treatment 
 
1. CBC results:  (For 1st treatment only) 
Date __ __ /__ __ / __ __ 
a. WBC____ 
b. RBC____ 
c. Hemoglobin____ 
d. Hematocrit____ 
e. MCV____ 
f. MCH____ 
g. MCHC____ 
h. RDW____ 
i. 
Neutrophils____ 
j. 
Lymphocytes____ 
k. Monocytes____ 
l. 
Eosinophils____ 
m. Basophils____ 
n. Platelets____ 
 
 
2. Documentation of Corticosteroid administration the day after treatment with 
Pemetrexed? 
Yes 
  
No 
  
Date administered: __ __ / __ __ / __ __ 
 
 
 
 
 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
 
 
 
 
Page 44 of 45 
Appendix I: Tumor Measurement Form 
 
Instructions: Complete and submit this form as required by the protocol.  Do not leave any entries blank.  Enter -1 to indicate that 
an answer is unknown, unobtainable, not applicable or not done.  Retain a copy for your records and submit original to the 
CCCWFU Data Management Center. 
 
CCCWFU Study Number: __________________________               CCCWFU Patient ID: ________________________________ 
 
Patient Name: ____________________________________               MRN: ___________________________________ 
WFUHS/Affiliate: 
____________________________________________________________________________________________________ 
(Specify) 
 LIST ALL TARGET AND NON-TARGET SITES TO BE USED FOR RESPONSE: 
Date of Observation (mm/dd/yy) 
 
 
 
 
 
 
Cycle: 
 
 
 
 
 
 
TARGET LESIONS 
 
 
 
 
 
 
Response Status (CR, PR, SD, PD) 
 
 
 
 
 
 
List sites for response: 
Means of 
Evaluation 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
1. 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
 
7. 
 
 
 
 
 
 
 
8. 
 
 
 
 
 
 
 
9. 
 
 
 
 
 
 
 
10. 
 
 
 
 
 
 
 
Total sum of LD for all Target Lesions: 
 
 
 
 
 
 
NON-TARGET LESIONS 
Response Status  
(CR, Incomplete Response/SD, PD): 
 
 
 
 
 
 
List sites for response 
Means of 
Evaluation 
 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
1. 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
 
7. 
 
 
 
 
 
 
 
Observer Signature: 
 
 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
 
 
 
 
Page 45 of 45 
Appendix J: Response Criteria  
 
Study Visit: 
 Baseline 
 Week 6 (  1 week) 
 Week 12 (  1 week) 
 Week 18 (  1 week) 
 Week 24 (  1 week) 
 Other visit: (please specify) ________________ 
 
Evaluation of target lesions 
 
   Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm 
 
   Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD 
 
   Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment started 
or the appearance of one or more new lesions (this may include the baseline sum). The 
sum must also demonstrate an absolute increase of at least 5 mm. 
 
   Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
Evaluation of non-target lesions 
 
   Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
 
   Non-CR/Non-PD: Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits. 
 
   Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the review panel (or study chair). 
 
 
Treating Physician Signature: ________________________  Date: ___ ___ / ___ ___ / ___ ___ 
 
PI Signature: ____________________________      
   Date: ___ ___ / ___ ___ / ___ ___ 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
 
 
 
 
Page 46 of 45 
 
BEST OVERALL Response Criteria 
 
Study Visit: 
 Baseline 
 Week 6 (  1 week) 
 Week 12 (  1 week) 
 Week 18 (  1 week) 
 Week 24 (  1 week) 
 Other visit: (please specify) ________________ 
 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria (see section 9.4.1). 
 
 
Target Lesions 
 
Non-target 
Lesions 
 
New Lesions 
 
Overall 
Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Non-CR/Non-PD 
 
No 
 
PR 
 
CR 
 
NE 
 
No 
 
PR 
 
PR 
 
Non-PD or not all 
evaluated 
 
No 
 
PR 
 
SD 
 
Non-PD or not all 
evaluated 
 
No 
 
SD 
 
Not all evaluated 
 
Non-PD 
 
No 
 
NE 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
 
 
 
 
Page 47 of 45 
   Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm 
 
   Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD 
 
   Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment started 
or the appearance of one or more new lesions (this may include the baseline sum). The 
sum must also demonstrate an absolute increase of at least 5 mm. 
 
   Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression, even after discontinuation of treatment. In some circumstances, it may be difficult 
to distinguish residual disease from normal tissue. When the evaluation of complete response 
depends on this determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
 
Confirmatory Measurement/Duration of Response 
 
Confirmation: confirmatory scans should also be obtained 6 weeks following initial 
documentation of objective response. 
 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
 
 
Treating Physician Signature: _______________________   Date: ___ ___ / ___ ___ / ___ ___ 
 
PI Signature: ____________________________      
   Date: ___ ___ / ___ ___ / ___ ___ 
 
 
 


CCCWFU 62115 – Data Collection Form 
 
ORIS ID: _______________________ Date of Study Visit: __ __/__ __/__ __ 
 
Protocol version date 04-13-17 
 
 
 
 
 
Page 48 of 45 
 
Appendix K – Survival Data 
 
 
ORIS Assigned PID:  ___ ___ ___ ___ ___ ___ ___ ___ 
 
 
Visit Date: ____ / ____ / _____ 
 
Visit Interval:   
_____ 6 Wks Post 
    _____ 12 Wks Post   _____ 18 Wks Post    _____  24 Wks Post 
_____ 30 Wks Post    _____ 36 Wks Post   _____ 42 Wks Post     _____ 48 Wks Post    
 _____ Other Wks Post      
 
 
 
DATE OF LAST CONTACT: ____ / ____ / _____ 
DECEASED:  Y____ N____ 
DATE OF DEATH: ____ / ____ / _____ 
 
 
 

ICF_001.pdf: 
Official Title: A Pilot Study Evaluating Pemetrexed in ECOG Performance Status 3 
Patients With Stage IV Non-squamous Non-small Cell Lung Cancer  
NCT02426658
IRB-Approved Date: 3/21/2018


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
Section of Hematology and Oncology
A PILOT STUDY EVALUATING PEMETREXED IN ECOG PERFORMANCE 
STATUS 3 PATIENTS WITH STAGE IV NON-SQUAMOUS NON-SMALL 
CELL LUNG CANCER 
Informed Consent Form to Participate in Research
Stefan C. Grant, MD, JD, MBA, Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have Stage IV non-small cell lung cancer. Your participation is voluntary. 
Please take your time in making your decision as to whether or not you wish to participate. Ask 
your study doctor or the study staff to explain any words or information contained in this 
informed consent document that you do not understand. You may also discuss the study with 
your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to see what effects (good and bad) the chemotherapy drug 
pemetrexed has on you and your condition. Pemetrexed has been approved by the US Food and 
Drug Administration (FDA) for patients with advanced lung cancer, but current cancer treatment 
guidelines limit chemotherapy use to patients who are ambulatory and capable of all self-care. 
Pemetrexed has shown anti-cancer benefit and been well-tolerated in these patients. Side effects 
can be minimized with folic acid, vitamin B12, and corticosteroids. In addition to these patients, 
we believe that pemetrexed can provide anti-cancer benefit and be well-tolerated in patients who 
are capable of only limited self-care.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
We anticipate that 30 people will take part in this study.
WHAT IS INVOLVED IN THE STUDY?
Prior to beginning the study, we will collect information on your demographics, medical history, 
current medications, physical functioning, quality of life, height, weight, and vital signs. We will 
need to draw blood to check your blood counts and to test for pregnancy in women of 
childbearing potential. You will also have a CT scan to take tumor measurements.
Prior to each treatment we will check your blood counts. At each treatment we will check your 
vital signs and collect information about your physical functioning and quality of life. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00032417
Meeting Date Approved 3/21/2018          
Version Valid Until: 3/20/2019


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
Pemetrexed will be given as an intravenous infusion on the first day of each 21-day treatment 
cycle. To help prevent and reduce treatment side effects, you will be given folic acid, vitamin 
B12, and a corticosteroid. You will start taking folic acid once daily at least 7 days before the 
first dose of pemetrexed. You will continue taking folic acid during the full course of therapy 
and for 21 days after the last dose of pemetrexed. In addition to this, you will receive an 
intramuscular injection of vitamin B12 at least 1 week prior to the first dose of pemetrexed and 
at least every 3 cycles thereafter. Dexamethasone is an oral corticosteroid that you will take 
twice daily the day before, the day of, and the day after pemetrexed administration.
You will have a CT scan every 6 weeks to assess the effectiveness of the pemetrexed treatment 
on the tumor.
You will have approximately 1 teaspoon of blood withdrawn from a vein before starting the 
study and then 1 teaspoon during each treatment cycle. The total amount of blood withdrawn 
during the study will be depend on how many treatment cycles you participate in this study.
HOW LONG WILL I BE IN THE STUDY?
You may continue with the study treatment until you decide to withdraw from the study or your 
condition changes in such a way that your physician does not think you should continue on this 
study.
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences.
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. The most common side effects of treatment with Pemetrexed are fatigue, 
nausea, and anorexia. Other less common side effects include a low red blood cell count, low 
platelet count, low white blood cell count, mouth sores, diarrhea, and stomach irritation.
There also may be other side effects that we cannot predict. You should tell the research staff 
about all the medications, vitamins and supplements you take and any medical conditions you 
have. This may help avoid side effects, interactions and other risks.
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  Taking part in this research study may involve providing 
information that you consider confidential or private.  Efforts, such as coding research records, 
keeping research records secure and allowing only authorized people to have access to research 
records, will be made to keep your information safe.
You may experience discomfort, bruising and/or bleeding where the needle is inserted when you 
have blood drawn. Occasionally some people become dizzy lightheaded or feel faint. Infection 
may occur on rare occasions.  Frequent donation of blood can result in low iron in your blood 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00032417
Meeting Date Approved 3/21/2018          
Version Valid Until: 3/20/2019


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
(iron deficient anemia).  
Reproductive Risks and other Issues to Participating in Research
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), Depo-Provera, tubal ligation, or vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship (same partner). An acceptable, 
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. Based on 
experience with Pemetrexed in more physically active patients with lung cancer, researchers 
believe it may be of benefit to patients like you. Because individuals respond differently to 
therapy, no one can know in advance if it will be helpful in your particular case. In addition, we 
hope the information learned from this study will benefit other people in the future.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:
Another clinical trial, best supportive care.
What About My Health Information?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: 
Demographics, medical history, current medications, physical exam details, vital signs, height, 
weight, performance status, tumor measurements, bloodwork (Complete Blood Count (CBC), 
serum chemistry), treatment-related side effects or symptoms. 
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations.
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
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Institutional Review Board 
IRB Number:IRB00032417
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Version Valid Until: 3/20/2019


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
protected computer. Only the following people or organizations will be granted access to your 
Protected Health Information:
1) The study investigator and his/her staff, or others at Wake Forest University Health 
Sciences who oversee research
2) Other people or laboratories providing services for this research project on behalf of 
Wake Forest University Health Sciences and Wake Forest University Baptist Medical 
Center 
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. Any research information entered into your medical record will be kept for as long as 
your medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished. 
You can tell Dr. Stefan Grant that you want to take away your permission to use and share your 
Protected Health Information at any time by sending a letter to this address:
Stefan C. Grant, MD, JD, MBA
Section on Hematology and Oncology
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
WFU School of Medicine 
Institutional Review Board 
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Version Valid Until: 3/20/2019


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. We will 
give you an estimate of what the added cost may be based on your particular situation and 
insurance coverage.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study.
Parking validation will be provided for study-related visits.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the Comprehensive Cancer Center of Wake Forest University. 
The sponsor is providing money or other support to Wake Forest University Health Sciences to 
help conduct this study. The researchers do not, however, hold a direct financial interest in the 
sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00032417
Meeting Date Approved 3/21/2018          
Version Valid Until: 3/20/2019


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Dr. Stefan Grant at 
.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because it is in your best medical interest, your condition worsened, 
new information becomes available, you had an unexpected reaction, you failed to follow 
instructions, or because the entire study has been stopped. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. Stefan Grant, at 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
WFU School of Medicine 
Institutional Review Board 
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Meeting Date Approved 3/21/2018          
Version Valid Until: 3/20/2019


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU 62115
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Adult Consent Form
Version: 03-04-15
IRB Template Version 7-18-2013
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
    
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00032417
Meeting Date Approved 3/21/2018          
Version Valid Until: 3/20/2019