Clinical trial NCT02868892
Conditions: Adenocarcinoma of the Cervix Adenosquamous Cell Carcinoma of the Cervix
Sponsor: Western Regional Medical Center
Start date: 2015-07-01; Completion date: 2017-07-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with advanced or recurrent adenocarcinoma or adenosquamous cell carcinoma of the cervix will receive Pemetrexed.

Detailed description:
Patients will receive Pemetrexed 500 mg/m2 every three week.

On initiation of pemetrexed, on day one of first chemotherapy cycle, patients will begin taking folic acid at a dose of 350 to 600 mcg daily as well as receive an intramuscular injection of 1000 mcg of vitamin B12, with subsequent vitamin B12 injections given every 9 weeks while on study.

Arms: arm 1: Pemetrexed 500 mg/m2 will be administered on an outpatient basis on an every three week schedule. Pemetrexed will be administered as a 10 minutes intravenous (IV) infusion in (for 500-mg vial) 100 ml of saline via peripheral vein or central line on Day 1 of each 21 day cycle.
Interventions: intervention 1: Pemetrexed
Intervention descriptions: intervention 1: Pemetrexed 500 mg/m2

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II Study of Pemetrexed in Recurrent Cervical Adenocarcinomas 
 
 
 
 
Protocol ID: 
CWG2014034 Pemetrexed - cervical  
 
 
 
Site Tracking #: 
WG2014034 
 
 
Principal Investigator:   
John Farley, MD, FACOG, FACS 
Western Regional Medical Center at  
Cancer Treatment Centers of America 
14200 W. Celebrate Life Way 
Goodyear, AZ  85338 
 
Sub-investigator(s): 
Justin Chura, MD 
  
Eastern Regional Medical Center at  
Cancer Treatment Centers of America  
1331 E. Wyoming Ave 
Philadelphia, PA 19124 
 
 
 
 
 
 
 
 
 
 


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I. 
Study Objectives 
Primary Objective: Evaluate the antitumor efficacy, response rate, of pemetrexed in the treatment of 
recurrent cervical adenocarcinoma. 
Secondary Objective: Evaluate PFS and OS for recurrent cervical adenocarcinomas treated with 
pemetrexed. 
 
II. 
Background and Rationale 
Cervical cancer is the third most common gynecologic malignancy occurring in the United 
States1. In the U.S. we can expect 12,340 cases of cervical cancer causing 4,030 deaths1. Cancer of 
the uterine cervix that has metastasized to or recurred at sites not amenable to treatment by surgery or 
radiation portends a grim prognosis. No potentially curative therapy yet exists. The focus of treatment 
has been palliation with chemotherapy. 
Cervical adenocarcinomas (AC) have been found to have a poor prognosis compared to their 
squamous counterparts2. Cervical cancers have been increasing in absolute incidence and the US and 
have increase from 10%-12% of cervical cancers in the 1070s to 20% currently 1,2. A study of early 
stage cervical cancers AC histology was associated with significantly decreased survival compared 
with SCC histology2. Multivariate analysis demonstrated AC histology to be an independent predictor 
of decreased survival in radiation therapy treated groups.  They concluded that adenocarcinoma is an 
independent prognostic indicator of poor survival in early stage cervical cancer patients with 
intermediate and high risk factors, regardless of the type of adjuvant radiotherapy after radical 
hysterectomy. In a study of advanced stage cervical cancer 423 patients with stages IIB-IVA (141 
ACA: 282 SCCA) were evaluated3. The overall complete responses (CR) between AC and SCCA 
were 86.5% and 94.7%, respectively (p=0.004). The 5-year overall survival rates of AC compared to 
SCCA were 59.9% and 61.7% respectively. They concluded that AC in locally advanced cervical 
cancer had poorer response rate from treatment and also used longer time to achieve CR than SCC.   
Despite these observed disparities in survival between AC and squamous cell carcinomas 
(SCCA), cervical cancer patients with AC histology receive the same front-line treatment as those 
with SCC histology. Other cancer such as lung cancer have adopted different approached to the 
treatment of different histologies of cancer4,5. Pemetrexed has emerged in the treatment of 
nonsquamous NSCLC.5. Pemetrexed (LY231514, Eli Lilly and Company, Indianapolis, IN, USA) is 
an antifolate, antineoplastic agent that exerts its action by disrupting folate-dependent metabolic 
processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits 
thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, all 
folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides6.  
Histology has emerged as a predictive factor for pemetrexed efficacy in non-small cell lung cancer 
(NSCLC)5.  One study evaluated the differential efficacy of pemetrexed by histology in the second-
line, first-line, and maintenance settings in the context of these three large phase III studies5. The 
analyses indicated the superior efficacy of pemetrexed in nonsquamous patients and a favorable 
safety profile compared with other standard treatment options. Thus, histology is predictive of the 
improved efficacy of pemetrexed in patients with nonsquamous NSCLC. 
Pemetrexed has been evaluated in the treatment of recurrent cervical cancer in two Phase II 
trials6,7. Pemetrexed has shown modest activity in treatment of recurrent cervical cancers in these 
studies. Patients had a 15% response rate and up to 59% disease stabilization rate. Median 
progression free survival was 3.1 months and overall survival was 7.4 months. These studies 


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however, only had 22%(6)-25%(11) of patients having adenocarcinoma histology and response rate 
and survival were not segregated by histology. It is the objective of this study given the emergence 
and success of pemetrexed in the treatment of nonsquamous NSCLC to evaluate the efficacy of 
pemetrexed in the treatment of recurrent cervical adenocarcinomas. 
 
III. 
Subject Eligibility 
 
Inclusion criteria: 
1. Patients must have had advanced or recurrent adenocarcinoma or adenosquamous cell carcinoma 
of the cervix with documented disease progression. 
2. Patients must have had measurable disease defined as at least one lesion that could be accurately 
measured in at least one dimension, which must have been 20 mm when measured by 
conventional techniques including palpation, plain X-ray, CT, and MRI or 10 mm when measured 
by spiral CT. 
3. 18 years of age or older 
4. Eastern Cooperative Oncology Group (ECOG) performance status score < 2 and a life expectancy 
>3 months. 
5. Life expectancy ≥ 12 weeks 
6. Participants must have measureable disease by RECIST criteria 
7. Absolute neutrophil count > 1500 mm3, platelet count ≥ 100×109 L, hemoglobin ≥ 8.5 g/dL 
8. Creatinine clearance ≥ 45 mL/min using the standard Cockcroft and Gault formula (below) or 
GFR measured by Tc99m-DPTA serum clearance method: 
a. Males: [140 - Age in years] × Actual Body Weight (kg) 72 × Serum Creatinine (mg/dL)  
b. Females:  Estimated creatinine clearance for males × 0.85 
9. Total bilirubin ≤ 2 mg/dL, AST/ALT ≤ 5 times the upper limit of normal range 
10. At least 21 days from administration of chemotherapy 
11. No remaining grade 2 or higher toxicity from prior cancer therapies unless judged to be clinically 
insignificant by the Principal Investigator 
12. At least four (4) weeks from prior major surgery 
13. Willingness to provide permission to access archived tumor samples and additional blood 
samples for evaluation of Foundation One Analysis where available Enterprise wide. 
14. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) 
must be willing to use an acceptable contraceptive method (abstinence, oral contraceptive or 
double barrier method) for the duration of the study and for 30 days following the last dose of 
study drug, and must have a negative urine or serum pregnancy test within 2 weeks prior to 
beginning treatment on this trial. 
 
Exclusion Criteria: 
1. Uncontrolled cardiac disease, congestive heart failure, angina, arrhythmias or 
hypertension. 
2. Myocardial infarction or unstable angina within 2 months of treatment. 
3. Known human immunodeficiency virus (HIV) infection or chronic active Hepatitis B or 
C (patients are NOT required to be tested for the presence of such viruses prior to therapy 
on this protocol). 
4. Active clinically serious infection > CTCAE (version 4.03) Grade 2. 
5. Thrombotic or embolic events such as a cerebrovascular accident including transient 
ischemic attacks within the past 6 months. 


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6. Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of 
study drug. 
7. Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of 
study drug. 
8. Serious non-healing wound, ulcer, or bone fracture. 
9. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study 
drug. 
10. Inability to complete informed consent process and adhere to the protocol treatment plan 
and follow-up requirements. 
11. Concurrent severe illness such as active infection, or psychiatric illness/social situations 
that would limit safety and compliance with study requirements. 
 
IV. 
Subject Registration and Documentation 
A Study Inclusion/Exclusion Checklist will be completed for each subject and study eligibility will be 
verified by the Principal Investigator or Sub-investigator. Subjects must begin treatment within 28 
days of all baseline studies. All original subject documents will be retained by the clinical research 
department. 
Follow Table 1. Schedule of Study Procedures in the Appendix. 
If a procedure or assessment has been completed as part of the standard routine care, and the 
procedure meets the protocol defined criteria and has been performed in the timeframe of the study, 
the test will not be required to be repeated, unless clinically indicated. 
 
V. 
Treatment Protocols 
Pemetrexed 500 mg/m2 will be administered on an outpatient basis on an every three week schedule. 
Pemetrexed will be administered as a 10 minutes intravenous (IV) infusion in (for 500-mg vial) 100 
ml of saline via peripheral vein or central line on Day 1 of each 21 day cycle.  
Premedication with dexamethasone will be per institutional guidelines.  
On initiation of pemetrexed, on day one of first chemotherapy cycle, patients will begin taking folic 
acid at a dose of 350 to 600 mcg daily as well as receive an intramuscular injection of 1000 mcg of 
vitamin B12, with subsequent vitamin B12 injections given every 9 weeks while on study. 
 
Dose Delay or Reduction 
Prior to administration of a subsequent dose of pemetrexed, a subject must meet the following 
criteria: 
• 
Any clinically significant pemetrexed-related toxicity must return to baseline or at least grade 1. 
Laboratory values should meet the parameters in the eligibility criteria unless specifically 
addressed in the dose delay/modification instructions in Table 2 or justification is provided by the 
investigator in the clinical chart. 
In the event that the administration of pemetrexed was delayed for reasons of toxicity, the subject 
may receive subsequent administrations of pemetrexed at a reduced dose. The amount of dose 
reduction will be based on guidelines in Table 2 in the Appendix. 


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In the event of toxicity that necessitates a delay of more than 3 weeks, subjects may be removed from 
study. 
Discontinuation of Protocol Treatment Administration 
Pemetrexed will be discontinued in the event of any of the following: 
• 
Clinically significant progressive disease after at least one (1) cycle of pemetrexed 
• 
Unacceptable adverse event(s) considered secondary to pemetrexed despite appropriate therapy 
• 
Delay of more than 4 weeks of pemetrexed administration 
• 
Withdrawal of consent by the subject 
• 
Lack of compliance by the subject 
• 
Changes in the subject’s medical condition that render further administration of pemetrexed 
unacceptable in the judgment of the Principal Investigator 
• 
Termination of study by CTCA 
Removal of Subject from Study 
Subjects will be removed from further follow-up for any of the following reasons: 
• 
Request by the subject to no longer be followed 
• 
Completion of all study required follow-up and no plans for further administration of pemetrexed 
• 
Death 
• 
Termination of study by CTCA 
Use of Anti-emetics and Supportive Care 
The anti-emetic regimen will be dictated by NCCN guidelines for mild emetogenic chemotherapy. 
Steroids may be included in the anti-emetic regimen. 
Supportive measures should be used as dictated by current standard of care at the CTCA. 
Prohibited Concomitant Medications/Therapies 
• 
Prophylactic use of growth factors such as G-CSF, GM-CSF, and erythropoietin unless treatment 
regimen meets the criteria for use (subjects receiving erythropoietin on a chronic basis at time of 
study entry may continue erythropoietin administration) 
• 
Any other anti-cancer therapy including investigational therapies unless allowed at the time of 
study entry 
 
VI. 
Study Drug 
Pemetrexed is commercially available a listed on NCCN guidelines as an acceptable treatment for 
recurrent cervical cancer 
 
VII. 
REGULATORY AND REPORTING REQUIREMENTS 
The study will be conducted according to the principles of the Declaration of Helsinki (as Scotland 
2000, as clarified in 2002), the International Conference on Harmonization Guidance on Good 
Clinical Practice and the requirements of all local regulatory authorities regarding the conduct of 
clinical trials and the protection of human subjects. 
Adverse event reporting will be as per the current NCI criteria. 


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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
VIII. 
Institutional Review Board (IRB)/Ethics Committee (EC) 
Approval of this study will be obtained from an IRB/EC prior to enrolling subjects on study. 
 
IX. 
Public Trial Registry 
This study will be listed on a Public Trial Registry such as ClinicalTrials.gov shortly after receiving 
IRB approval. 
 
X. 
Written Informed Consent 
Consent forms must be in a language fully comprehensible to the prospective subject, otherwise the 
document must be translated into the subject’s native language per institutional policy. Written, dated 
informed consent for the study must be obtained from all subjects before the start of any protocol 
specified procedures. 
 
XI. 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential 
and disclosure to third parties other than those noted below is prohibited. Subject’s individual 
identifying information will be kept as confidential as possible under local, state, and federal law.  
Data generated as a result of this study are to be available for inspection on request by the following: 
• 
The Office for Human Research Protection (OHRP) in the U.S. Department of Health and Human 
Services 
• 
Government agencies including the Food and Drug Administration (FDA) 
• 
The sponsor’s Human Research Protection Program (HRPP) 
• 
Western Institutional Review Board (WIRB). 
 
Western Regional Medical Center and Eastern Regional Medical Center may retain in its files copies 
of subject medical information required for auditing of case report forms (CRFs). 
 
Individual subject identities will not be disclosed in any report or publication related to the study. 
 
XII. 
Financial Disclosure 
Investigators must be in compliance with the current FDA guidelines and regulations concerning 
financial disclosure. 
 
XIII. 
Data Quality Assurance 
Accurate, consistent, and reliable data will be ensured through the use Good Clinical Practices (GCP) 
guidelines regarding clinical data management practices and procedures. 
 
All data will be collected using the data collection spreadsheet. Eastern Regional Medical Center will 
provide this collection spreadsheet to Dr. Farley when requested for data review.  
 


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XIV. 
Control of the Study Materials 
The Inpatient Pharmacy will account for all standard of care medications. All medications are kept 
under lock in an inaccessible location while in storage. Since all drugs referenced in this protocol are 
standard of care medications, the standard hospital pharmacy record keeping will be completed.  
 
XV. 
Adverse Events 
 
Adverse Event (AE) Definition (using CTCAE version 4.03) 
An AE is any untoward medical event that occurs to a subject following the start of study drug 
administration, whether or not the event is considered drug-related. Pre-existing conditions are not 
considered an AE unless the condition worsens by at least one grade following the start of study 
drug(s) administration. 
 
Death due to disease progression occurring 31 days or more from the day of last study drug 
administration will not be reported as an AE or SAE. 
 
Any drug related AE of grade 2 or higher should be followed for resolution until either 1) the start of 
subsequent anti-cancer therapy or 2) death. 
 
Serious Adverse Event (SAE) Definition 
An SAE is any AE that results in any of the following outcomes: 
• Death 
• A life-threatening experience 
• An inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
 
An event that is not listed above but that requires intervention to prevent one of the outcomes listed 
above is also considered an SAE. 
 
Elective hospitalizations that are not in response to an AE will not be considered an SAE. 
 
Serious Adverse Event Reporting 
All reportable SAEs must be reported to Western Regional Medical Center’s Institutional Review 
Board (IRB) within 24 hours of the Investigator becoming aware of the SAE. 
 
To report an SAE, sites will complete the IRB’s required form and submit the form to Western 
Regional Medical Center’s IRB via email, fax, or online portal.  
 
All reportable SAEs will need to be submitted to HRPP as well. 
 
Site must report all reportable SAEs that occur within 30 days after the last dose of pemetrexed 
treatment while on this study or until the subject receives additional cancer therapy. 
 
Relationship to Pemetrexed 
The relationship of an AE or SAE to pemetrexed will be classified using the following four (4) 
categories: 


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• Definitely related 
• Likely related 
• Unlikely related 
• Definitely not related 
 
XVI. 
Protocol Deviations  
 
All protocol deviations will be noted in the subjects chart and also on WIRB’s Promptly Reportable 
Information form. The site’s PI or Sub-I (if PI is not available) will review the Promptly Reportable 
Information form to determine whether the deviation is reportable to the IRB. If the deviation is not 
reportable, he/she will need to ensure the appropriate box is checked and provide an explanation as to 
why the event is not reportable. All reportable deviations will need to be submitted to WIRB, Dr. 
Farley, and HRPP.  
 
XVII. Statistical And Analytical Considerations 
 
Determination of Sample Size 
The sample size was based on the primary efficacy variable, tumor response.   The historical rate for 
the tumor response is assumed to be 15%.  Using a one-sided significance level of 0.05, power of 
80%, and a tumor response rate of 40% for the pemetrexed treated patients, it was determined that a 
total of 30 patients would need to be enrolled in the study.  The study may be stopped early for futility 
if no objective responses are seen before 8 patients have entered. 
Analysis Datasets 
The definitions of the analysis datasets are as follows: 
• 
The Evaluable for Safety Population will consist of all subjects who receive at least one dose 
of pemetrexed 
• 
The Evaluable for Efficacy Population will consist of all subjects who receive at least one 
dose of pemetrexed and who have had at least one post-baseline disease assessment 
 
General Statistical Considerations 
Statistical summaries for quantitative variables will include the sample size, mean, median, standard 
deviation, minimum, and maximum. For categorical variables summaries will include the number and 
percent of patients in each category observed.  Unless otherwise noted, statistical significance will be 
declared if the two-sided p-value is <0.05. 
 
Subject Disposition 
Data tabulations will summarize the following subject numbers: 
• 
Enrolled 
• 
Received treatment 
• 
Evaluable for safety and efficacy 
• 
Who violate the protocol 
• 
Who complete the protocol 
• 
Who withdraw because of 1) adverse event(s), 2) disease progression, 3) physician’s 
recommendation, or 4) withdrawal of consent 
 


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Subject Characteristics 
Demographic characteristics of subjects will be summarized using descriptive statistics: 
• 
Age 
• 
Sex 
• 
Ethnicity 
• 
Performance status 
• 
Prior therapies 
• 
Tumor type 
 
Efficacy Analysis 
The evaluable for efficacy population will be used for efficacy analysis. Efficacy will be determined 
for each subject in the efficacy population for each of the following 4 outcomes: 
 
The Primary Efficacy Variable 
• 
Tumor Response: Subjects will be assigned one of the following categories based on the response 
criteria outlined in RECIST 1.1 as appropriate for each tumor type: 1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease. An objective response will be defined 
as either a CR or PR. 
   
The Secondary Efficacy Variables 
• 
Time to Response will be determined for subjects with an objective response only. Time to 
Response will be defined as the period of time from the date of first study drug administration 
until the first objective documentation of response (CR or PR). 
• 
Duration of Response will be determined for subjects with an objective response only. Duration 
of Response will be defined as the period of time from the date of first objective response to the 
date of progression. 
• 
Progression-Free Survival is defined as the period of time from the date of first study drug 
administration to the date that the subject is determined to have progressive disease or death due 
to any cause. 
 
Criteria response evaluation and overall response rates will be summarized by proportions together 
with exact binomial 95% confidence intervals for each dose group. The tumor response rate for the 
pemetrexed treated patients will be compared with the historical rate of 15% using a one-sided z-test.  
Durations (time to response, duration of response, and progression-free survival) will be summarized 
by Kaplan- Meier methods. Median survival with 95% confidence intervals will be calculated and 
survival graphs will be presented for all Kaplan-Meier analyses.  
 
Safety Analysis 
All subjects who receive any amount of pemetrexed (Safety Population) will be included in the final 
summaries and listings of safety data. 
 
Detailed information collected for each AE will include: description of the event, MedDRA coding 
including System Organ Class and Preferred Term, duration, whether the AE was serious, 
relationship to study drug, action taken, clinical outcome, and whether or not it was a DLT.  Severity 
of the AEs will be graded according to the CTCAE version 4.03.  Emphasis in the analysis will be 
placed on AEs classified as dose limiting.  Frequencies of subjects experiencing at least one AE will 
be displayed by body system and preferred term according to MedDRA terminology.  Summary 


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tables will present the number of subjects observed with AEs and corresponding percentages.  The 
denominator used to calculate incidence percentages consists of subjects receiving at least one dose of 
study drug for each dose group. Within each table, the AEs will be categorized by MedDRA body 
system and preferred term. Additional subcategories will be based on event severity and relationship 
to study drug.   
 
Deaths and other SAEs will be tabulated as well as described in detail. 
 
Vital signs, including the change from baseline, will be summarized using descriptive statistics.  The 
statistical significance of the mean change from baseline will be determined using a paired t-test. 
 
Summary tables will be prepared to examine the distribution of laboratory measures over time.  Shift 
tables may be provided to examine the distribution of laboratory toxicities. 
 
XVIII. Specimen Collection 
 
Mutation Analysis 
Testing for mutations will be conducted on tumor tissue. Tissue biopsy is optional. If subjects do 
decide to have a tissue biopsy, they will not be charged for the procedure or the cost of the genetic 
testing. In addition, if the subjects have already had genetic testing done on their sample we can use 
the results from that test. 
 
Specimens will be sent for Genetic Testing analysis for patients who respond to pemetrexed (patients 
are on treatment for at least 6 months). 
 
XIX. 
Financial Responsibility 
The medication pemetrexed and other standard chemotherapy agents are commercially available.  The 
costs of treating cancer with these medications and any other treatments received, and the cost of 
treating any side effects from such treatments will be billed to the patient’s health plan or insurance 
company. If medical care is needed as a result of injury while being in this study, medical care will be 
provided to the patient and the insurance company will be billed.  
 
XX. 
References 
 
1. 
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA: a cancer journal for 
clinicians 62:10-29, 2012 
 
2. 
Mabuchi S, Okazawa M, Matsuo K, et al: Impact of histological subtype on survival of 
patients with surgically-treated stage IA2-IIB cervical cancer: adenocarcinoma versus squamous cell 
carcinoma. Gynecol Oncol 127:114-20, 2012 
 
3. 
Katanyoo K, Sanguanrungsirikul S, Manusirivithaya S: Comparison of treatment 
outcomes between squamous cell carcinoma and adenocarcinoma in locally advanced cervical cancer. 
Gynecol Oncol 125:292-6, 2012 
 
4. 
Patel JD, Socinski MA, Garon EB, et al: PointBreak: A Randomized Phase III Study of 
Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and 
Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance 
Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non-Small-Cell Lung Cancer. J Clin 
Oncol, 2013 


V5.0 29Mar2016 
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5. 
Scagliotti G, Brodowicz T, Shepherd FA, et al: Treatment-by-histology interaction 
analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung 
cancer. J Thorac Oncol 6:64-70, 2011 
 
6. 
Miller DS, Blessing JA, Bodurka DC, et al: Evaluation of pemetrexed (Alimta, 
LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II 
study of the Gynecologic Oncology Group. Gynecol Oncol 110:65-70, 2008 
 
7. 
Lorusso D, Ferrandina G, Pignata S, et al: Evaluation of pemetrexed (Alimta, LY231514) 
as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study 
of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group. 
Ann Oncol 21:61-6, 2010 
 
 
Appendix 
Table 1. Schedule of Study Procedures 
Parameter 
Baseline 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycles 
4+ 
Follow
-up 
Day of cycle 
-28 to 1 
1 
1 
1 
1 
 
Informed consent 
X 
 
 
 
 
 
Complete medical history, 
height 
X 
 
 
 
 
 
Complete physical exam 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
Vital signs (BP, HR, RR, temp) 
and weight 
X 
X 
X 
X 
X 
X 
Review con meds, AEs 
X 
X 
X 
X 
X 
X 
Disease status (baseline and 
prior to C3, C5, C7, C9, etc.) 
X 
 
 
X 
(X) 
(X) 
Urinalysis 
X 
 
 
 
 
 
Pregnancy test 
(X) 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
Serum chemistries 
X 
X 
X 
X 
X 
X 
Genetic Testing mutational 
analysis* 
 
 
 
 
 
(X) 
Pemetrexed administration 
 
X 
X 
X 
X 
 
Survival assessment  
 
 
 
 
 
X 
 
General 
• 
Blood draws and vital signs are performed prior to dosing of pemetrexed 
• 
Study visits and procedures may occur +/- 7 days of the day given unless otherwise indicated 
• 
X – required event 


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• 
(X) – as indicated 
Follow-up – Follow-up visit should occur 30 days (+/- 7 days) after last dose of pemetrexed 
Cycle 2+ – Cycle 2 and subsequent cycles will start +/- 7 days of day 22 of the prior Cycle. 
Disease status –All subjects should have their disease status monitored with at least a chest, abdominal, 
and pelvic CT and any other scans as appropriate for their disease.  Scans completed within 28 days of 
start of treatment do not need to be repeated (for screening).  Scans are performed at baseline and prior to 
Cycle 3, Cycle 5, Cycle 7, Cycle 9, etc.  
CBC with differential – WBC, ANC, RBC, HGB, HCT, platelets, MCV, and differential. If completed 
within 3 days prior to start of C1D1 – no need to repeat 
Serum chemistries – Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, 
calcium, AST, ALT, total bilirubin, alkaline phosphatase, total protein, albumin.  If completed within 3 
days prior to start of C1D1 – no need to repeat. 
*Genetic Analysis – If subject consents to Genetic Analysis, Genetic Testing mutation status collected 
from tumor tissue of patients remaining on pemetrexed without progression for at least 6 months.    
 
Table 2 
 
Hematologic dose modifications for pemetrexed  
Absolute Neutrophil Count (ANC) ≥1000/mm3 and 
platelet count (PC) ≥100,000/mm3 
Maintain 100% of full dose 
ANC <500/mm3 and platelet count ≥ 50,000/mm3 
Administer 75% of full dose  
Platelet count <50,000/mm3 without bleeding 
regardless of ANC nadir 
Administer 75% of full dose 
Platelet count <50,000/mm3 with bleeding (CTC 
G2) regardless of ANC nadir 
Administer 50% of full dose 
 
Non hematologic dose modifications for pemetrexed  
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