Clinical trial NCT00394147
Conditions: Head and Neck Cancer
Keywords: advanced head neck cancer
Sponsor: Fox Chase Cancer Center
Start date: 2006-10-01; Completion date: 2009-12-01
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to look at how well the combination of two chemotherapy drugs, pemetrexed (Alimta) and gemcitabine (Gemzar) work to treat your cancer.

Detailed description:
This research study is being done because we have not yet been able to find the best treatment for recurrent or advanced head and neck cancer (SCCHN). Pemetrexed and gemcitabine have helped fight against SCCHN when each was given by itself. This study is different from others because it tests these two drugs together, which has not been tried before in patients with SCCHN. We will see how well these drugs can work to help to control or shrink your cancer.

We also want to find out what effects (good and bad) gemcitabine and pemetrexed have on you and your head and neck cancer. We do not know if these drugs will help you. Your cancer might get better or it might get worse. It might not have any effect on your condition. We can use what we learn from this research study to help other people with the same cancer.

Arms: arm 1: pemetrexed 500mg/m2 and gemcitabine 1500mg/m2 given on day 1 and day 15 of each 28 day cycle
Interventions: intervention 1: pemetrexed intervention 2: gemcitabine
Intervention descriptions: intervention 1: pemetrexed 500mg/m2 given on day 1 and day 15 of each 28 day cycle intervention 2: gemcitabine 1500mg/m2 given on day 1 and day 15 of each 28 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol 
Phase II Study of Pemetrexed and Gemcitabine in 
Patients with Advanced Head and Neck Cancer (SCCHN) 
PEMETREXED (LY231514) 
Eli Lilly and Company 
 
Principal Investigator: 
Corey Langer, M.D. 
333 Cottman Ave. 
Philadelphia, PA 19111 
 
Co-investigator: 
Roger Cohen, M.D. 
333 Cottman Ave. 
Philadelphia, PA 19111 
 
 
Statistician:                                    Samuel Litwin, PhD 
 
 
 
 
 
333 Cottman Ave 
 
 
 
 
 
Philadelphia, PA 19111 
 
 
Study Coordinator:  
 
Holly Tuttle, R.N, M.S.N. 
Fox Chase Cancer Center Extramural Research 
Program (FER) 
 
 
 
 
 
50 Huntingdon Pike 2nd Floor 
 
 
 
 
 
Rockledge, PA 19046 
 
 
 
 
 
Phone:  215-728-2451 
 
 
 
 
 
Fax: 215-728-4784 
 
 
 
Version 
 
 
 
 
6/22/06 
Amendment 1 
 
 
 
1/09/2007


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
 
Phase II Study of Pemetrexed and Gemcitabine in 
Patients with Advanced Head and Neck Cancer (SCCHN) 
Table of Contents 
 
1. Introduction ................................................................................................................ 4 
1.1. Pemetrexed ............................................................................................................ 4 
1.2. Gemcitabine .......................................................................................................... 6 
1.3. Phase I and II pemetrexed plus Gemcitabine results ............................................ 7 
1.4. Treatment of metastatic Head and Neck Cancer in general .................................. 8 
2. Objectives.................................................................................................................. 10 
2.1. Primary Objective ............................................................................................... 10 
2.2. Secondary Objective ........................................................................................... 10 
3. Summary of Study Design ....................................................................................... 10 
4. Study Population ...................................................................................................... 11 
4.1. Inclusion Criteria ................................................................................................ 11 
4.2. Exclusion Criteria ............................................................................................... 12 
4.3. Discontinuations ................................................................................................. 12 
4.4. Pretreatment Studies ........................................................................................... 13 
    4.5.    Registration Procedure………………………………………………………….14 
5. Treatment and Dose Modifications ........................................................................ 14 
5.1. Treatments Administered .................................................................................... 14 
5.2. Materials and Supplies ........................................................................................ 14 
5.3. Dose Adjustments ............................................................................................... 17 
    5.4.    Concomitant Therapy…………………………………………………………   20 
6. Efficacy and Safety Evaluations ............................................................................. 20 
6.1. Efficacy Measures………………………………………………………………20 
6.2. Disease Status ..................................................................................................... 21 
6.3. Objective status (to be recorded at each evaluation) .......................................... 21 
6.4. Best Response ..................................................................................................... 22 
6.5. Definition of Efficacy Measures ......................................................................... 23 
6.6. Safety Evaluations .............................................................................................. 24 
6.7. Post-Therapy Follow-up ..................................................................................... 27 
6.7.1. Safety ............................................................................................................... 27 
6.7.2. Efficacy ............................................................................................................ 27 
7. Statistical Considerations ........................................................................................ 27 
7.1. Targeted Response Rate ...................................................................................... 27 
7.2. Qualifications for Efficacy Analysis ................................................................... 28 
7.3. Qualifications for Safety Analysis ...................................................................... 28 
7.4. Primary Outcome ................................................................................................ 28 
7.5. Secondary Outcomes .......................................................................................... 28 
7.6. Safety Analyses ................................................................................................... 29 
7.7. Criteria for Study Termination............................................................................ 30 
8. Informed Consent, Ethical Review, and Regulatory Considerations ................. 30 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
8.1. Informed Consent................................................................................................ 30 
8.2. Ethical Review .................................................................................................... 31 
8.3. Regulatory Considerations .................................................................................. 31 
 
9.    Study Agent Information………………………………………………………….31 
    9.1     Pemetrexed …………………………………………………………………….31 
    9.2     Gemcitabine ……………………………………………………………………33 
    9.3     Drug Ordering and Accountability……………………………………………..35 
10. Bibliography………………………………………………………………………..36 
 
APPENDIX 
1)  Folic Acid and Vitamin B12 Supplementation …………………………………40 
2)  American Joint Committee on Cancer Staging Criteria……………………….44 
3)  Performance Status Scale………………………………………………………...51 
4)  Study Schedule…………………………………………………………………….53 
5)  Clinical Laboratory Tests………………………………………………………...56 
6)  Abbreviations and Definitions……………………………………………………58 
 
 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
1. Introduction 
1.1. Pemetrexed 
1.1.1. Background and Phase 1 Results 
Inhibition of the enzyme thymidylate synthase (TS) is the primary mechanism of 
action of pemetrexed, a folate antimetabolite(1,2).  Thymidylate synthase, a folate-
dependent enzyme, catalyzes the transformation of deoxyuridine monophosphate 
(dUMP) to deoxythymidine monophosphate (dTMP).  Inhibition of TS results in a 
decrease in thymidine, a pyrimidine necessary for DNA synthesis(3,4). 
Pemetrexed also inhibits dihydrofolate reductase (DHFR) and glycinamide 
ribonucleotide formyl transferase (GARFT), a folate-dependent enzyme that is 
involved in purine synthesis(2).  These targets are related to the cytotoxicity of 
pemetrexed, since both thymidine and hypoxanthine are required to circumvent 
cellular death caused by pemetrexed(5).  Pemetrexed gains entry to the cell via the 
reduced folate carrier and once localized is an excellent substrate for 
folylpolyglutamate synthetase (FPGS).  The pentaglutamate form of pemetrexed 
is the predominant intracellular form and is >60-fold more potent in its inhibition 
of TS than the monoglutamate(6). 
Phase 1 studies were conducted exploring three treatment schedules:  daily times 
5 every 21 days; weekly times 4 every 42 days; and once every 21 days.  The 10-
minute infusion once every 21 days was found to be the schedule that allowed the 
delivery of the highest dose intensity(7).  The dose limiting toxicities (DLTs) on 
this schedule were neutropenia, thrombocytopenia, and fatigue.  Patients who 
developed rashes received dexamethasone 4 mg twice daily for 3 days starting 1 
day prior to treatment with pemetrexed, which improved or prevented the rash 
during subsequent cycles of therapy.  The current dose being investigated in 
Phase 2 studies is 500 mg/m2 every 21 days. 
1.1.2. Single Agent Phase 2 Studies 
Pemetrexed is administered as a single agent once every 21 days at 500 to 600 
mg/m2. It has demonstrated activity in multiple tumor types.  These include 
mesothelioma, non-small cell lung cancer (NSCLC), breast, colorectal, pancreas, 
bladder, head and neck, and cervical cancer (Lilly 2000). Patients treated in these 
early studies did not receive folic acid or vitamin B12 supplementation.   
1.1.3. Folic Acid and Vitamin B12 Supplementation 
Although pemetrexed has clinically marked activity in a number of tumor types, a 
high incidence of hematologic toxicity has been associated with this antifolate.  
Studies with other antifolate agents inhibiting DHFR and TS have suggested that 
poor nutritional status contributes to the likelihood a patient will experience 
severe toxicity when exposed to these drugs(8-11).  More specifically, these 
studies have investigated the relationship between folic acid and toxicity of these 
agents and have concluded that the addition of folic acid significantly reduces 
toxicity while preserving the antitumor activity of the drug. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
In initial Phase 1 and 2 trials, pemetrexed was administered at 500 and 600 mg/m2 
every 21 days without folic acid or vitamin B12 supplementation.  
Myelosuppression was the principal drug-related toxicity, with a frequency of 
Grade 3/4 neutropenia of 40% to 50% and Grade 3/4 thrombocytopenia of 15% (n 
= 880).  Since data in mid-1999 suggested an increasing death rate might be 
associated with the combination of severe gastrointestinal toxicity and severe 
neutropenia, a multivariate analysis based on 880 patients without folic acid and 
vitamin B12 supplementation was performed to determine which predictors might 
correlate with drug-related death.  This analysis led to the conclusion that Grade 4 
neutropenia accompanied by Grade 3/4 infection, Grade 3/4 diarrhea, and tumor 
type were all significantly associated with drug-related death. 
A second multivariate analysis was performed on 305 patients who had baseline 
vitamin markers measured and recorded.  Multiple factors potentially affecting 
the risk of severe toxicity were included in the analysis.  Patients who received 
folic acid supplementation at any point during therapy or who received any dosing 
regimen other than LY231514 500 to 600 mg/m2 were removed from the analysis, 
leaving a final sample size of 246 patients.  Results of this analysis showed that an 
elevated homocysteine level at baseline was highly correlated with severe toxicity 
(that is, neutropenia, neutropenia accompanied by infection, diarrhea)(12).  More 
details of this multivariate analysis are available in Protocol Appendix 1. 
However, one consultant expert was concerned that some patients with 
homocysteine levels in the normal range could be relatively folic acid and/or B12 
deficient and thus also at increased risk for severe toxicity.  Therefore, the 
decision was made to supplement all patients receiving pemetrexed with dietary 
folic acid (350 to 1000 µg) and vitamin B12 (1000 µg IM injection).  Vitamin B12 
was included in the supplementation because approximately 15% of patients were 
not expected to achieve lower homocysteine levels with the supplementation of 
daily folic acid only.  
A recent safety assessment of the impact of folic acid and vitamin B12 
supplementation on the severe toxicities related to pemetrexed therapy has been 
completed.  The overall objectives of this report were to assess the impact of folic 
acid and vitamin B12 supplementation on homocysteine levels over time and to 
compare the incidence of severe toxicities and drug-related deaths associated with 
pemetrexed therapy between patients with and without folic acid and vitamin B12 
supplementation.  The analysis confirmed the hypothesis that the administration 
of vitamin B12 and daily folic acid reduces homocysteine and results in a 
significant reduction of death and toxicity associated with pemetrexed. 
1.1.4. Pemetrexed and Head and Neck Cancer 
No chemotherapy agent has proven to be superior to methotrexate monotherapy 
for metastatic head and neck cancer in terms of survival. Unfortunately, the 
response rate is low (response rate of 10% in SWOG study by Forastiere et al(13)). 
Investigating pemetrexed in head and neck cancer makes sense since it does work 
similarly to methotrexate by interfering with folate metabolism, yet appears to be 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
more active than methotrexate in other solid tumors. A phase II study by Pivot et 
al(14) appears very promising with an objective response rate of 26.5% and a 
median response duration of 5.6 months (the median survival for methotrexate in 
the SWOG study was 5.6 months). It would be logical to investigate pemetrexed 
in a combined-drug regimen. The logical chemotherapy to combine with 
pemetrexed would be cisplatin as was done in a pivotal phase III study for 
mesotholioma(15); however, there are several problems with this approach. The 
first is that many patients have already received cisplatin in the locally advanced 
disease setting. This may mean that subjects are more resistant to cisplatin than 
other agents. Furthermore, the accumulative toxicity of cisplatin (neuropathy, 
audiotoxicity, and renal toxicity) may make it difficult to continue using the drug. 
Also, patients with head and neck cancer are suspected to having significant 
comorbidity(16), probably due to the risk factors that are associated with the 
disease (tobacco and alcohol use). Considering the significant toxicities associated 
with cisplatin, this may make it difficult for subjects with head and neck cancer to 
tolerate this agent. Furthermore, cooperative groups have been inexplicably 
pushing the addition of taxanes in the locally advanced setting which can increase 
problems with neurotoxicity. It would make sense to evaluate chemotherapy 
agents that are not strongly associated with neurotoxicity. While carboplatin could 
also be considered, this agent has already been shown to be inferior to cisplatin in 
this disease setting by the same SWOG study mentioned above(13). Preclinical 
data has suggested that gemcitabine may have a synergistic effect with 
pemetrexed. While it has not been well-studied as a single agent in this setting, 
many physicians who treat this disease believe that it does have activity. 
Furthermore, the combination of gemcitabine and pemetrexed does not have any 
serious cross-toxicities with cisplatin or the taxanes. 
1.2. Gemcitabine 
Gemcitabine (difluorodeoxycytidine), an analog of cytosine arabinoside (ara-C), 
is a pyrimidine antimetabolite(17).  The mechanism of action of gemcitabine has 
been well characterized.  Gemcitabine is deaminated by deoxycytidine deaminase 
to difluorodeoxyuridine or activated by deoxycytidine kinase to 
difluorodeoxycytidine monophosphate (dFdCMP).  Difluorodeoxyuridine is 
inactive, while dFdCMP is further metabolized to difluorodeoxycytidine 
diphosphate (dFdCDP) and difluorodeoxycitidine triphosphate (dFdCTP), which, 
when incorporated into DNA, results in chain termination.  In comparison to ara-
C incorporation into DNA, dFdCTP is less readily excised from DNA by DNA 
exonuclease.  Thus, dFdCTP accumulates intracellularly to a greater degree than 
ara-C.  This may account, in part, for its different spectrum of preclinical and 
clinical activity.  In addition, gemcitabine inhibits ribonucleotide reductase, an 
enzyme that produces deoxynucleotides that are required for DNA synthesis.  
Gemcitabine is active in a variety of murine solid tumors and leukemias, as well 
as several human tumor xenografts(18). 
Initial Phase 1 studies using a short infusion schedule, with drug given weekly for 
3 weeks followed by 1 week of rest, established 790 mg/m2/week as the 
maximum tolerated dose (MTD).  Dose-limiting toxicity (DLT) was 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
myelosuppression with thrombocytopenia being more significant than 
granulocytopenia(19).  More recent Phase 1 and 2 trials have established 
1250 mg/m2/week as a well-tolerated dose(20,21).  Principal toxicities reported 
were hematological, with World Health Organization (WHO) Grade 4 
neutropenia and thrombocytopenia occurring rarely; reversible elevation in 
hepatic transaminases; proteinuria; mild skin rash with and without pruritus; and 
nausea and vomiting.  A review of 201 patients treated with 1250 mg/m2/week 
who had not received prior chemotherapy revealed the following toxicity profile:  
neutropenia WHO Grade 3 and 4 in 23% and 6%, respectively; reversible 
elevation in hepatic transaminases WHO Grade 3 and 4 in 6% and 2%, 
respectively; WHO Grade 3 proteinuria occurred in less than 1%; WHO Grade 3 
nausea and vomiting in 10%; and mild skin rash in 26% with pruritus occurring in 
10%(22).  Other Phase 1 studies have been conducted using other different dosing 
schedules (i.e., twice weekly and daily times five).  These studies reported 
significantly more nonhematologic toxicities such as flu-like symptoms and rash 
with DLT being thrombocytopenia(23,24).  The daily times five Phase 1 trial was 
stopped because of sporadic fever and occasional WHO Grade 3 and 4 
hypotension(25). 
The pharmacokinetics of gemcitabine has been evaluated(19,26-28).  The maximum 
plasma gemcitabine concentration was directly proportional to the dose.  Plasma 
concentrations at 800 to 1000 mg/m2 infused over 30 minutes exceed 50 M.  
Elimination, due principally to deamination to diflorodeoxyuridine (dFdU), is 
rapid with a median terminal half-life of 14 hours and is the only metabolite 
detected in plasma or urine.  In a bi-weekly schedule gemcitabine 
pharmacokinetics were determined at 13 different doses (40 to 4560 mg/m2), 
administered every 2 weeks as a 30-minute infusion to 45 patients with refractory 
solid cancer.  Gemcitabine and its uridine metabolite, dFdU, measured using high-
performance liquid chromatography (HPLC), reached plasma peak levels of 50 to 
100 M at 1500 mg/m2; gemcitabine was eliminated rapidly with a t1/2  of 4 to 
20 minutes, while dFdU was still present at a plateau of ± 20 M from 4 to 24 
hours at doses greater than or equal to 960 mg/m2.  Up to 1500 mg/m2, linear 
pharmacokinetics were observed for gemcitabine and dFdU.  Gemcitabine 
clearance varied between 1705 to 7368 mL/m2/min; its volume of distribution 
was 49 to 200 L/m2. 
In clinical studies, gemcitabine alone or in combination with other chemo-agents 
has shown activity across tumor types in lung, head and neck, breast, ovary, 
pancreas, and bladder cancer, and sarcoma.  
1.3. Phase I and II pemetrexed plus Gemcitabine results 
A Phase 1 study investigating the combination of pemetrexed and gemcitabine 
was completed at the Mayo Clinic Cancer Center(29).  In this study, patients with 
solid tumors were enrolled into one of two cohorts.  Patients in the original cohort 
received gemcitabine on Days 1 and 8 of each 21-day cycle, and pemetrexed on 
Day 1 given 90 minutes after gemcitabine administration.  On this dosing 
schedule, neutropenia led to Day-8 gemcitabine dose reductions in more than 50% 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
of cycles.  After the maximum tolerated dose was defined using the original 
dosing schedule, a second cohort was employed, in which patients received 
gemcitabine on Day 1 and gemcitabine followed 90 minutes later by pemetrexed 
on Day 8.  Of note, there was no vitamin supplementation in this study.  
Preliminary results indicate that the treatment schedule incorporated into the 
second cohort is better tolerated and should be carried forward into Phase 2 
studies.  The regimen selected for testing in Phase 2 trials is gemcitabine 1250 
mg/m2 administered on Days 1 and 8 of each 21-day cycle, and pemetrexed 500 
mg/m2, administered on Day 8 of each 21-day cycle. 
A phase 2 study (Study JMDL), which is investigating the effects of the 
combination of pemetrexed plus gemcitabine for the treatment of pancreas cancer, 
has completed enrollment, with follow-up ongoing.  Of the 40 patients enrolled, 
39 received study drug and were included in a preliminary analysis.  All but 6 of 
the treated patients received folic acid and vitamin B12 supplementation.  
Preliminary efficacy results revealed a response rate of 15% (6/39 patients) and an 
estimated progression-free survival of 3.6 months (95% CI, 2.8 to 4.9 months).  
With 30% censoring (10 patients alive and 4 patients on treatment), the median 
survival is 6.5 months.  A preliminary safety analysis on data from 35 patients 
available to date showed CTC Grade 4 neutropenia (15 patients), Grade 3/4 
fatigue (3 patients), and Grade 3/4 febrile neutropenia (4 patients) (preliminary 
data on file as of March 2001).  One death has been reported that may have been 
treatment-related (case number: US_010157273) (Lilly 2001). 
A phase II study with pemetrexed and gemcitabine in advanced non-small cell 
lung cancer showed a low overall response rate (17%), but noted an excellent 
median time to progression (5.1 months), median survival (11.3 months), and 1-
year survival (46%)(30). 
While many current studies are examining the combination of gemcitabine on 
days 1and 8 with pemetrexed on day 8 of a 21-day cycle, there has always been 
concern about white blood cell count nadir delaying chemotherapy. Generally, 
pemetrexed has a nadir period of 7-10 days after administration. Phase I and II 
studies of gemcitabine with other agents (e.g., paclitaxel(31), vinorelbine(32)) have 
been found to be active and safe. This has led to a recent phase I clinical study 
investigating the combination of pemetrexed and gemcitabine biweekly (Study 
JMGC). Gemcitabine was infused over 30 minutes, followed immediately by 
pemetrexed given intravenously over 10 minutes once on Day 1 and every 14 
days. Phase I results on 24 patients identified a maximum tolerated dose of 
Gemcitabine 1500mg/m2 and pemetrexed 600mg/m2 with two patients out of 6 
experiencing neutropenic fever. Therefore, the Phase 2 recommended dose is 
Gemcitabine 1500mg/m2 and pemetrexed 500mg/m2. Preliminary response 
suggests activity across multiple dose levels and a need to examine this regimen 
in a number of tumor types(33). 
1.4. Treatment of metastatic Head and Neck Cancer in general 
Single-agent methotrexate is the historic standard drug of choice for these patients.  
Cisplatin has equivalent activity.  Higher-dose schedules of methotrexate and 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
cisplatin have both been investigated in randomized trials.  There is no evidence that 
they improve survival, yet are associated with greater potential toxicity(34). 
A number of randomized trials have compared treatment with a single agent to 
treatment with combination chemotherapy. These trials have been previously 
reviewed(34) and fail to demonstrate a significant survival advantage with the use of 
combination chemotherapy in these patients. Three recently published randomized 
trials are summarized in the following table and are representative of the literature in 
this area(13,35,36). 
 
 
RECENT RANDOMIZED TRIALS: RECURRENT/METASTATIC DISEASE 
Author 
Drugs 
Pts 
CR + PR 
Med Surv       
(Mos) **     
Jacobs et al. (35) 
Cisplatin 
83 
   17% 
    5.0 
 
5-FU 
83 
   13% 
    6.1 
 
Cisplatin 
5-FU 
79 
   32%* 
    5.5 
Forastiere et al.(13)  
Methotrexate  
88 
   10% 
    5.6 
 
Carboplatin 
5-FU 
86 
   21%# 
    5.0 
 
Cisplatin 
5-FU 
87 
   32%+ 
    6.6 
Clavel et al.(36)  
Cisplatin 
113 
   15% 
    5.3 
 
Cisplatin 
5-FU 
116 
   31%## 
    6.2 
 
Cisplatin 
Methotrexate 
Bleomycin 
Vincristine 
127 
   34%++ 
    8.2 
*  P = .035 vs. cisplatin, P = .005 vs. 5-FU; # P = .05 vs. MTX; + P = .001 vs. MTX 
## P  = .003 vs. cisplatin; ++ P <.001 vs. cisplatin 
** Median survivals are estimated from survival curves in the trial by Clavel et al(36)  
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
2. Objectives 
2.1. Primary Objective 
2.1.1. To assess the response rate of pemetrexed and gemcitabine given every 2 
weeks in patients with unresectable or metastatic squamous cell carcinomas 
of the head and neck. 
2.2. Secondary Objective 
2.2.1. Evaluate time to progression. 
2.2.2. Evaluate overall survival. 
2.2.3. Assess safety and toxicity of this combination in SCCHN. 
3. Summary of Study Design 
A standard 2-step phase II design will be used. All patients with unresectable or 
metastatic squamous cell cancer of the head and neck (SCCHN) who are found eligible 
and enter the study will be treated with pemetrexed 500 mg/m2 followed by 
gemcitabine 1500 mg/m2 every 2 weeks. A cycle length will be 4 weeks. After every 2 
cycles, repeat radiographic studies will be done to restage. 
Patients will receive protocol therapy until: tumor progression is documented; 
unacceptable toxicity is experienced; or patient withdraws consent; patient is unable to 
fulfill the responsibilities of study participation as determined by the treating physician 
or the principal investigator. 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
          
 
 
 
                      
 
 
         
 
 
         
 
 
 
 
 
Study Entry & Enrollment 
* A cycle length is defined as 28 days (or 2 treatments). 
           Repeat scans q 2 cycles 
Folic acid (350-100µg) daily beginning 5-7 days prior to 1st dose of 
pemetrexed.  Must have completed 5 doses.  Vitamin B12 (1000µg) 
as intramuscular injection up to 2 weeks before 1st dose of 
pemetrexed.  May be given on Day 1. 
 
Pemetrexed 500mg/m2  followed by Gemcitabine 1500mg/m2 q 2 
weeks  IV with both drugs administered on Day 1 and 15. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
 
4.  Study Population 
4.1Inclusion Criteria 
4.1.1  Histologic or cytologic diagnosis of a SCCHN that is either unresectable (as 
determined by a physician) or metastatic. Must have disease that is not curable by 
standard treatments. 
4.1.2  Karnofsky Performance status of greater than or equal to 60%(37). 
4.1.3  Up to one prior systemic chemotherapy, immunotherapy, or biological 
therapy regimen allowed in the advanced disease or metastatic setting. This does 
not include prior chemotherapy, immunotherapy, or biological treatment used 
with radiotherapy (i.e., concurrent with radiation therapy or as an induction 
regimen prior to definitive radiation therapy). 
4.1.4  At least 4 weeks from previous radiation therapy or chemotherapy. Patient 
must recover from the acute toxic effects of the treatment prior to study 
enrollment.  
4.1.5  Disease status must be that of measurable disease as defined by RECIST 
criteria(38). 
 Measurable disease.  The presence of at least one measurable 
lesion.  
 Measurable lesions:  Lesions that can be accurately measured in 
at least one dimension with the longest diameter  20 mm using 
conventional techniques or  10 mm using spiral CT scans. 
CT (including spiral CT) scans and MRI are the preferred methods 
of measurement; however, chest x-rays are acceptable if the lesions 
are clearly defined and surrounded by aerated lung.  Clinically 
detected lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  For the 
case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion is required. 
4.1.6  Adequate organ function including the following: 
4.1.6.1Adequate bone marrow reserve:  absolute neutrophil 
(segmented and bands) count (ANC) 1.5  109/L, platelets 100  
109/L. 
4.1.6.2Hepatic:  bilirubin 1.5 times the upper limit of normal ( 
ULN), alkaline phosphatase (AP), aspartate transaminase (AST) and 
alanine transaminase (ALT) 3.0  ULN (AP, AST, and ALT 5  
ULN is acceptable if liver has tumor involvement). 
4.1.6.3Renal:  calculated creatinine clearance (CrCl) 45mL/min based on the 
standard Cockroft and Gault formula.  Enrollment and dosing decisions based 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
on creatinine clearance may be made using local lab values (calculated using 
the standard Cockroft and Gault formula).   
4.1.6.4  Female patients of child-bearing potential must test negative for 
pregnancy within 14 days of treatment, based on a serum pregnancy test. Men and 
women must agree to use a reliable method of birth control during the study and 
for 3 months following the last dose of study drug. 
4.1.6.5  Patients must sign an informed consent document and HIPAA consent. 
4.1.6.6  Patients must be at least 18 years of age. 
4.1.6.7Must be able to take and absorb enteral medications 
4.2  Exclusion Criteria 
4.2.1  Prior treatment with gemcitabine or pemetrexed within the previous year, 
unless the chemotherapy agent was used concurrently with radiation therapy (see 
4.1.3).  
4.2.2  Pregnancy or breast-feeding. 
4.2.3  Serious concomitant systemic disorders (eg, active infection) that, in the 
opinion of the investigator, would compromise the safety of the patient or 
compromise the patient’s ability to complete the study. 
4.2.4  Symptomatic, uncontrolled or untreated brain metastases. If brain 
metastases have been treated, patients must have been off of steroids used to 
control neurological symptoms for at least 2 weeks. 
4.2.5  Inability or unwillingness to take folic acid, vitamin B12 supplementation, 
or dexamethasone. 
4.2.6  Have received treatment within the last 30 days with a drug that has not 
received regulatory approval for any indication at the time of study entry.  
4.2.7  Inability to interrupt an NSAID or salicylate with a long half-life (eg, 
piroxicam or nabumetone) for a 5-day period 
4.2.8Presence of clinically relevant (by physical exam) third-space fluid 
collections (for example, ascites or pleural effusions) that cannot be controlled by 
drainage or other procedures prior to study entry. 
4.2.9  Active, concurrent, invasive malignancy requiring ongoing treatment. 
4.2.10  Corticosteroids impermissible unless used for adrenal failure, septic shock 
or as temporizing measure for symptomatic pain, breathing, or rash. 
4.3  Discontinuations 
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be withdrawn from the 
study and Lilly or its designee must be contacted.  An exception may be granted in very 
rare circumstances where there is a compelling safety reason to allow the patient to 
continue.  In these rare cases, the treating investigator or designee  must submit 
supporting documentation on a FER Investigator Initiated Study Protocol Exception form 


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to the project manager.  The request will be presented to the PI and final approval to 
allow the subject to remain on study will be at Lilly’s discretion. 
In addition, patients will be discontinued from the study drug and/or from the study in the 
following circumstances. 
 The investigator decides that the patient should be withdrawn from the 
study.  If this decision is made because of a serious adverse event or a 
clinically significant laboratory value, the study drug is to be discontinued 
and appropriate measures are to be taken.  Lilly or its designee is to be 
notified immediately of all SAEs.  See Safety Section 6.6.  
 The patient or attending physician requests that the patient be withdrawn 
from the study.  
 The patient, for any reason, requires treatment with another therapeutic 
agent, including radiation therapy, that has been demonstrated to be 
effective for treatment of the study indication.  In this case, 
discontinuation from the study occurs immediately upon introduction of 
the new agent.  
 The investigator, for any reason, stops the study or stops the patient's 
participation in the study. 
 Evidence of progressive disease exists. 
 The drug exhibits unacceptable toxicity. 
 The patient requires a 3rd dose reduction as per protocol guidelines. 
 Treatment delay for any reason > 29 days. 
 The patient becomes pregnant or fails to use adequate birth control (for 
those patients who are able to conceive). 
 The patient is noncompliant with study procedures. 
 The patient is lost to follow-up. 
 The patient experiences symptomatic deterioration in the absence of objective 
disease progression. 
 
4.4  Pretreatment Studies (see Appendix 4) 
 Within 28 days before enrollment 
 Radiologic test for tumor measurement as defined in section 4.1.5. 
 Chest X-ray (PA and Lateral) 
 Within 14 before the start of treatment 
 Physical Examination, Medical History, blood pressure and pulse 
measurements  
 Body Surface Area (Height and Weight) 
 Performance Status Assessment. (See Appendix 3). 
 Laboratory Studies (Hematology, Chemistry See Appendix 5). 
 Pregnancy test (for women of child bearing potential) 


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4.5  Registration Procedure 
 Subjects will be registered through FER by calling the project manager, 
Monday through Friday between 9:00 am and 5:00 pm, at 215-728-2451 to 
alert that the site has a subject for registration.  The site will fax the 
Registration Form and the Inclusion and Exclusion Checklists signed by the 
site PI to FER at 215-728-4784.  FER will notify the site by phone and return 
the completed  Registration Form, including study identification number, by 
fax once eligibility has been confirmed.  Subjects must be registered and have 
received a study identification number prior to the initiation of study therapy. 
 
5.  Treatment and Dose Modifications 
5.1  Treatments Administered 
 
Each cycle is defined as a twenty-eight (28) day treatment period consisting of 
two treatments 2 weeks apart (D1, D15 = 1st cycle; D29, D43 = 2nd cycle) A cycle is 
comprised of one treatment of pemetrexed followed by gemcitabine with each agent 
administered Day 1 and Day 15 every 28 days (cycle = 28 days). The actual dose of 
pemetrexed or gemcitabine will be determined by calculating the body surface area at the 
beginning of each cycle.  A 5% variance in the calculated total dose will be allowed for 
ease of dose administration.  A delay of cycle as a result of holidays, weekends, bad 
weather, or other unforeseen circumstances will be permitted and not counted as a 
protocol violation, and will not require waiver.  The reason for the schedule change must 
be documented in the subject’s chart.  The reason must be captured in the remarks section 
of the Case Report Form (CRF). 
 
The investigator or a designee is responsible for explaining the correct use of the 
investigational agent(s) to the patient and site personnel, verifying that instructions 
are followed properly, maintaining accurate drug accountability records including 
receipt, dispensing and waste of all unused medication according to the site’s policy 
and procedure. 
5.2  Materials and Supplies 
5.2.1  Pemetrexed (supplied by Eli Lilly) 
The freeze-dried drug product is composed of LY231514 disodium and 
mannitol in a 1:1 ratio.  Sodium hydroxide and/or hydrochloric acid solution 
may be added during processing to adjust the pH.  The vial size is 500 mg.  
Each vial contains LY231514 disodium equivalent to 102 mg, or 510 mg of the 
base compound, LY231514.  The vials contain a 2% excess to facilitate the 
withdrawal of the label amount from the 500-mg vial.  The drug product is 
stable when stored at room temperature. 
Reconstituting the 500 mg vial contents with 10 mL to 50 mL of sodium 
chloride injection gives a clear solution with a concentration of 10 mg/mL to 50 
mg/mL.  The reconstituted formulation is in the pH range of 6.8 to 7.5 and has 
been shown to be chemically stable for 72 hours at refrigerated or room 


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temperature.  Vial contents should be inspected for particulate matter before and 
after the drug product is withdrawn from a vial into a syringe. 
The concentrated solution cannot be administered without further dilution.  For 
purposes of clinical administration an appropriate quantity of the contents of the 
reconstituted vial must be further diluted into an infusion solution of 75 to 125 
mL of 0.9% sodium chloride for injection.  After dilution the shelf-life of the 
product is 24 hours at room temperature.  LY231514 is not sensitive to light.  
Vials of LY231514 contain no anti-microbial preservative, and they are single-
use vials.  Any unused portion of a vial may not be stored for future use or used 
for other patients, and unused portions of product in a vial must be discarded. 
LY231514 is incompatible in solution with acidic medications or media and 
must not be mixed or administered simultaneously through the same infusion 
line.  The infusion line should be flushed prior to administration of any 
concomitant medication.  LY231514 is compatible with standard PVC 
administration sets and IV solution bags. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit.  
See Table 1 for dose and timing. 
5.2.2  Gemcitabine (supplied by Eli Lilly) 
Gemcitabine is supplied as a lyophilized powder in sterile vials containing 
200 mg or 1 g of gemcitabine as the hydrochloride salt, mannitol, and sodium 
acetate.  The lyophilized product should be stored at controlled room 
temperatures (20°C to 25°C).  To reconstitute, add 5 mL 0.9% Sodium Chloride 
to the 200mg vial or 25 mL of normal saline to the 1 gm vial.  Each dilution 
yields a gemcitabine concentration of 38 mg/mL.  The appropriate amount of 
drug may be administered as prepared or further diluted with 0.9% Sodium 
Chloride to concentrations as low as 0.1 mg/ml.  Once the drug has been 
reconstituted it should be stored at room temperature and used within 24 hours.  
Solutions of reconstituted gemcitabine should not be refrigerated, as 
crystallization may occur. 
Any unused portion of a vial may not be stored for future use or used for other 
patients, and unused portions of product in a vial must be discarded. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit.  
See Table 1 for dose and timing. 
 
5.2.3  Folic Acid (commercial) 
Folic Acid (350-1000 µg) orally, must be given daily beginning approximately 
5-7 days (at least 5 doses) prior to first dose of pemetrexed and continuing daily 
until 3 weeks after the last dose of study therapy. 
5.2.4  Vitamin B12 (commercial) 


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Vitamin B12 (1000 µg) will be administered as an intramuscular injection up to 2 
weeks prior to first dose of pemetrexed and repeated every 2 to 3 cycles  (i.e., 
approximately every 8 weeks) starting with the third cycle until 3 weeks after the last 
dose of study therapy. The second and subsequent injections may be given + 1 week in 
order to time it for the same day as chemotherapy treatment.  The first dose may be 
given on D1 of treatment as long as it is given prior to the pemetrexed infusion. 
5.2.5  Dexamethasone (commercial) 
Dexamethasone (4 mg orally or equivalent) will be prescribed by the 
investigator in whatever formulation is available locally.  Patients should be 
premedicated according to the outline(s) in Table 1. 
 
Table 1 
 
Drug 
Dose 
Time 
pemetrexed 
500 mg/m2 IVinfusion 
10 minutes (8 to 15). To be given before 
gemcitabine.  D1 & D15 
Sodium chloride for injection 
100 mL IV infusion 
IV infusion at least 15 minutes after pemetrexed 
infusion.  D1 & D15 
Gemcitabine IV Administration 
1500 mg/m2  IV infusion 
Day 1 & D15 after sodium chloride infusion, over 
30 minutes 
Folic acid Oral dose 
350-1000 mcg 
Dose per MD discretion  
Daily beginning 5-7 days prior to the first dose of 
pemetrexed (must have received 5 doses), and 
continuing daily until 3 weeks after the last dose 
of pemetrexed.  Delay for insufficient folic acid 
treatment prior to pemetrexed administration is 
defined in Section 5.3.2. 
Vitamin B12 
1000 µg intramuscular injection 
Up to 2 weeks prior to the first dose of 
pemetrexed (may be given on D1 prior to 
pemetrexed) and repeated every 2 to 3 cycles 
(i.e., approximately every 8 weeks) starting 
with the third cycle until 3 weeks after the last 
dose of study therapy. The second and 
subsequent injections may be given + 1 week 
in order to time it for the same day as 
chemotherapy treatment.  Delay for 
insufficient Vit B12 prior to pemetrexed 
administration is defined in section 5.3.2 
Dexamethasone 
4 mg, orally twice per day 
(or equivalent) 
Should be taken on the day before, the day of, and 
the day after each dose of 
pemetrexed/gemcitabine, unless clinical 
contraindications exist.  Higher or additional 
doses are permitted for reasons other than routine 
rash prophylaxis (eg, antiemetic prophylaxis). 
 


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5.3  Dose Adjustments or Delays for Subsequent Cycles 
Dose reductions (with the exception of mucositis, diarrhea, renal, and 
hematologic toxicities which are detailed in separate sections below) are 25% of 
the initial targeted dose.  Subsequent dose reduction is an additional 25% of initial 
target dose (i.e. 50%).  Any patient who requires a dose reduction will continue to 
receive a reduced dose for the remainder of the study.  Any patient with 2 prior 
dose reductions who experiences a toxicity that would cause a third dose 
reduction must be withdrawn from study therapy. Treatment may be delayed for 
up to 29 days from the time it is due to resume, to allow a patient sufficient time 
to recover from study drug-related toxicity or intercurrent co-morbidity.  Patients 
who are unable to resume treatment in this 29 day period will be withdrawn from 
study.  Omitted doses mid-cycle (day 15) will not be made up; for instance, if day 
15 dosing is withheld because of toxicity, it will not be made up on day 22 of that 
treatment cycle.  
 
5.3.1 Toxicity 
 
Hematologic Toxicity 
ANC must be 1.5  109/L and platelets 100  109/L prior to the 1st cycle. Dose 
adjustments at the start of a subsequent cycle of therapy will be based on platelet and 
neutrophil counts from the day of scheduled treatment.    Treatment should be delayed to 
allow sufficient time for recovery.  Upon recovery, if treatment is resumed, it should be 
according to the guidelines in Table 2 
Table 2 
Dose Adjustments for Pemetrexed and Gemcitabine  
ANC ( 109/L)  
 
Platelets ( 109/L)  
Percent of Previous Dose  
 
 
 
 
1000  
and  
100 
100% 
500 and < 1000
And/or 
50 and <100 
50% 
< 500 
or 
<50 
Day  15 dosing is omitted. 
Day  1 dosing will be delayed  for 1 week. If 
repeat counts are adequate, treat with the 
dose according to this table. If counts are still 
inadequate, delay one or  more weeks. 
Remove from the study, if treatment delay > 
29 days. 
 
Diarrhea 
In the event of diarrhea requiring hospitalization (or of at least Grade 3), treatment should 
be delayed until diarrhea has resolved to Grade ≤ 1 before proceeding.  Treatment should 
be resumed at 75% of the previous dose level.  
 
 
Mucositis 
Table 3 documents the relevant dose adjustments in case of mucositis. 


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Table 3 
Dose Modifications for Pemetrexed and Gemcitabine for 
Mucositis 
CTC Toxicity Grade 
Percent of Previous Dose 
Grade 0-1 
100% 
Grade 2 
50% 
Grade 3-4 
withhold 
Recurrence of Grade 3 or 4 after treatment at two 
dose reductions  
 
Withdraw patient from study 
 
Renal Toxicity 
The standard Cockcroft-Gault formula must be used to calculate CrCl for 
enrollment or dosing.  No dosage adjustment is needed in patients with creatinine 
clearance > 45 mL/min. Insufficient numbers of patients have been studied with 
creatinine clearance <45 mL/min to give a dose recommendation. Therefore, 
Pemetrexed should not be administered to patients whose creatinine clearance is 
<45 mL/min. However, gemcitabine, at appropriate dose, can be continued.  
Pemetrexed can be resumed once creatinine clearance is > 45mL/min 
 
 
For males: 
 
CrCl (mL/min) =  
(140-age) x (weight in kg) 
 
72 x serum creatinine in mg/dL 
For females: 
 
CrCl (mL/min) =  
 
0.85 x 
(140-age) x (weight in kg) 
 
 
72 x serum creatinine in mg/dL 
 
Other Non-hematologic Toxicities 
For other attributable, nonhematologic toxicities > Grade 3 (with the exception of 
Grade 3 transaminase elevations, nausea, or vomiting), treatment should be 
delayed until resolution to less than or equal to the patient’s baseline value before 
proceeding.  Treatment should resume at 75% of the previous dose level for both 
medications if deemed appropriate by the treating physician.   
 
5.3.2   Treatment Delays As a Result of Insufficient Folic Acid or Vitamin B12 
Supplementation 


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Delay the first dose of study drug until the patient has taken folic acid for at least 
5 of the 7 days before Day 1 of Cycle 1, and until the vitamin B12 injection has 
been administered.   
Delay subsequent doses until the patient has taken folic acid for at least 14 of the 
21 days before Day 1 of the cycle. 
 
5.3.3  Leucovorin 
Because folic acid and vitamin B12 supplementation has significantly reduced the 
number of episodes of Grade 4 hematologic and Grade 3/4 nonhematologic 
toxicities associated with Pemetrexed therapy, a need for leucovorin as rescue 
agents is not anticipated. However, this section provides information should 
rescue be necessary.  
In clinical trials, leucovorin was permitted for CTC grade 4 leukopenia lasting > 3 
days, CTC Grade 4 neutropenia lasting > 3 days, and immediately for CTC Grade 
4 thrombocytopenia, bleeding associate with Grade 3 thrombocytopenia, or Grade 
3 or 4 muscositis. The following intravenous doses and schedules of leucovorin 
were recommended for intravenous use: 100mg/m2, intravenously once, followed 
by leucovorin, 50 mg/m2, intravenously or orally every 6 hours for up to 8 doses.  
Resumption of therapy must be delayed until leucovorin is completed or 
discontinued. 
 
5.3.4  Therapy for diarrhea 
In the event of CTC Grade 3 or 4 diarrhea, the following supportive measures are 
allowed:  hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with 
fever or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be 
prescribed.  Patients with severe diarrhea or any diarrhea associated with severe 
nausea or vomiting must be hospitalized for intravenous hydration and correction 
of electrolyte imbalances and administration of leucovorin 
5.3.5  Clinically significant effusions 
For patients who develop or have baseline clinically significant pleural or 
peritoneal effusions (on the basis of symptoms or clinical examination) before 
Pemetrexed therapy, consideration should be given to draining the effusion prior 
to dosing.  However, if, in the investigator's opinion, the effusion represents 
progression of disease, the patient should be discontinued from study therapy.  
Ideally, cytologic confirmation is required to designate progressive disease status. 
5.3.6  Therapy for Febrile Neutropenia 
Patients experiencing febrile neutropenia, especially with diarrhea, should be 
managed in a hospital setting according to standard procedures, with the urgent 
initiation of intravenous antibiotic therapy. 


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5.4  Concomitant Therapy 
Patients are allowed to receive full supportive care therapies concomitantly during 
the study.  Steroids may be administered for adrenal failure, septic shock, or as 
temporizing measure for symptomatic pain, breathing, or rash.  Megace 
(Megesterol acetate) or similar agents as appetite stimulants are allowed.  No 
other chemotherapy, immunotherapy, hormonal cancer therapy, radiation therapy, 
surgery for cancer, or experimental medications (with the exception of thymidine) 
will be permitted while the patients are participating in this study.  Any disease 
progression requiring other forms of specific antitumor therapy will be cause for 
early discontinuation of study therapy.  The following concomitant therapies 
warrant special attention. 
5.4.1  Colony Stimulating Factors 
Routine use of colony stimulating factor (CSF) is not permitted during this study.  
Patients should not receive prophylactic granulocyte colony stimulating factor (G-
CSF) in any cycle.  G-CSF may be used only for patients who have ANC <0.5  
109/L, neutropenic fever, or documented infections while neutropenic.  Duration 
of uncomplicated neutropenia before initiation of G-CSF treatment is left to the 
investigator’s discretion.  G-CSF must be discontinued at least 24 hours prior to 
the start of the next cycle of chemotherapy. Use of erythropoietin is allowed.  Use 
of stimulators of thrombopoiesis is not allowed. 
5.4.2  Nonsteroidal Anti-Inflammatory Drugs  
Patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or salicylates will 
not take the NSAID or salicylate 2 days before, the day of, and 2 days after 
receiving pemetrexed.  If a patient is taking an NSAID or salicylate with a long 
half-life (eg, piroxicam or nabumetone), it should not be taken 5 days before, the 
day of, and 2 days after receiving pemetrexed. 
 
6.  Efficacy and Safety Evaluations 
6.1  Efficacy Measures 
Within 28 days of enrollment, baseline tumor measurement(s) will be performed on 
each patient.  CT (including spiral CT) scans and MRI are the preferred methods of 
measurement, but chest x-ray is acceptable if the lesion(s) is clearly defined and 
surrounded by aerated lung.  Ultrasound will not be permitted as a method of tumor 
measurement.  The same method used at baseline must be used consistently for 
tumor assessment and will be repeated every 8 weeks (-1 week)(prior to every other 
cycle).  


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6.2  Disease Status 
 Measurable disease is defined as the presence of at least one measurable 
lesion.  If only one lesion is present, the neoplastic nature of the disease 
site should be confirmed by cytology and/or histology.  Lesions should be 
accurately measured in at least one dimension (with the longest diameter 
recorded)  20 mm using conventional techniques or  10 mm using spiral 
CT scans.  All measurements should be in metric notation and made using 
either a ruler or calipers.  For the case of skin lesions, documentation by 
color photography, including a metric ruler to estimate the size of the 
lesion is required. 
If conventional CT or MRI is used, the cuts should be contiguous and 10 mm per 
slice in thickness.  Cuts for spiral CT scans should be 5 mm when a contiguous 
reconstruction algorithm is used.  Chest x-rays, although not preferred, are 
acceptable if the lesions are clearly delineated and the surrounding lung is aerated. 
 Non-measurable disease is defined as all other lesions including small 
lesions (longest diameter < 20 mm using conventional techniques or < 10 
mm with spiral CT scans).  These include bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and abdominal masses that are 
not confirmed/followed by imaging techniques. 
All measurable lesions (referred to as target lesions) up to a maximum of 5 lesions 
per organ and 10 lesions per patient are to be followed.  Selected lesions should 
be representative of all organs involved and should be selected based on size 
(longest diameter) and the suitability for accurate repeated measurements.  The 
sum of the longest diameters of all target lesions will be calculated and recorded 
at the baseline measurement.  This sum will be used as a reference by which to 
characterize the objective tumor response. 
If a measurable lesion is hidden or obliterated by a surrounding process (eg, 
pleural effusion, enlarging lymph nodes), an asterisk should be placed in the 
appropriate space for the dimension, and an explanation should be given for the 
failure to measure the lesion. 
All other lesions (measurable and nonmeasurable) will be documented at baseline.  
While measurements of these nontarget lesions are not required, the presence or 
absence of each site should be recorded at each follow up. 
Included in the evaluations are the following standard criteria: 
6.3  Objective status (to be recorded at each evaluation) 
 Complete response (CR):  Disappearance of all target and nontarget 
lesions and normalization of tumor marker level.  No new lesions.  No 
disease-related symptoms.  All target lesions must be assessed using the 
same technique as baseline.  Refers to clinical CR.  


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 Partial response (PR):  Greater than or equal to a 30% decrease from 
baseline in the sum of the longest diameters of the target lesions and either 
incomplete response/stable disease or lack of disease progression of the 
nontarget lesions.  Incomplete response/stable disease is defined as the 
persistence of one or more nontarget lesions and/or the maintenance of 
tumor marker levels above normal limits.  No new lesions.  All 
measurable lesions and sites must be assessed using the same techniques 
as baseline. 
 Stable disease (SD):  Target lesions do not qualify for CR, PR, or 
progression and nontarget lesions do not progress.  No new lesions.  All 
lesions must be assessed using the same techniques as baseline. 
 Progressive disease (PD):  Greater than or equal to a 20% increase in the 
sum of the longest diameters of the target lesions as referenced to the 
smallest sum of the longest diameters recorded since treatment started 
and/or the appearance of one or more new lesions and/or progression of 
nontarget lesions. 
 Confirmation:  To be assigned a status of PR or CR, changes in tumor 
measurements must be confirmed by repeat studies that should be performed no 
less than 4 weeks after the criteria for response are first met. 
Exceptions:  In cases for which initial tumor flare reaction is possible 
(hypercalcemia, increased bone pain, erythema of skin lesions), either 
symptoms must persist beyond 4 weeks or there must be additional 
evidence of progression.  Lesions that appear to increase in size as a result 
of the presence of necrotic tissue will not be considered to have 
progressed. 
 Unknown:  Symptomatic deterioration in the absence of  documented 
progression  with one or more measurable sites not assessed. 
Notes 
1) Patients with a global deterioration of their health requiring discontinuation from 
the study who have not progressed at the time of discontinuation should be 
labeled as having symptomatic deterioration.  Every attempt should be made to 
follow the patient until disease progression is noted. 
2) It may be difficult to determine residual disease from normal tissue.  If an 
evaluation of CR depends on this determination, then residual lesion should be 
investigated by fine needle aspirate or biopsy before confirming the CR. 
3) For nontargeted lesions, the objective response cannot be PR.  
4) All lesions used for measurement must be prospectively selected.   
6.4  Best Response 
The best overall response is the best response recorded from the start of treatment 
until disease progression/recurrence (taking as reference for progressive disease 
the smallest measurements recorded since the treatment started).  In general, the 


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patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.  Table 4 provides overall responses for all 
possible combinations of tumor responses in target and non-target lesions with or 
without the appearance of new lesions. 
Table 4. 
Overall response 
Overall response 
Target lesions 
Nontarget lesions 
New lesions 
CR 
CR 
CR 
No 
PR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
SD 
SD 
Non-PD 
No 
PD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
Abbreviations:  CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease. 
 
6.5  Definition of Efficacy Measures 
6.5.1  A responder will be defined as any patient who exhibits a CR or 
PR. 
6.5.2  Time to objective tumor response is defined as the time from 
study enrollment to the first observation of an objective tumor response. 
6.5.3  The duration of a CR or PR is defined as the time from first 
objective status assessment of CR or PR to the first time of progression or 
death as a result of any cause. 
Progression-free survival time is defined as the time from study 
enrollment to the first date of disease progression or death as a result of 
any cause.  Progression-free survival time will be censored at the date of 
the last follow-up visit for patients who are still alive and who have not 
progressed. 
Time-to-treatment failure is defined as the time from study enrollment to 
the first observation of disease progression, death as a result of any cause, 
or early discontinuation of treatment.  Time to treatment failure will be 
censored at the date of the last follow-up visit for patients who did not 
discontinue early, who are still alive, and who have not progressed. 
Time to disease progression is defined as the time from study enrollment 
to the first date of disease progression.  Time to disease progression will 
be censored at the date of death for patients who have not had documented 
disease progression. 


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6.5.4  Overall survival time is defined as the time from study enrollment to time 
of death as a result of any cause.  Survival time will be censored at the date of the 
last follow-up visit for patients who are still alive. 
6.6  Safety Evaluations 
Investigators are responsible for monitoring the safety of patients who have entered 
this study and for alerting FER to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient. 
The investigator is responsible for appropriate medical care of patients during the 
study. 
The investigator remains responsible for following, through an appropriate health 
care option, adverse events that are serious or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is 
resolved or explained.  Frequency of follow-up is left to the discretion of the 
investigator. 
6.6.1  Adverse Events 
Lilly has standards for reporting adverse events that are to be followed 
regardless of applicable regulatory requirements that may be less stringent.  For 
purposes of collecting and evaluating all information about Lilly drugs used in 
clinical trials we will use the following procedure. 
 
Adverse event (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medical treatment or procedure regardless of whether it is 
considered related to the medical treatment or procedure (NCI CTEP Guidelines 
January 2001).  Lack of drug effect is not an adverse event in clinical trials 
because the purpose of the clinical trial is to establish drug effect. 
 
Serious Adverse Event (SAE) is one that is fatal or life threatening, 
permanently disabling, requires inpatient hospitalization or prolongation of 
existing hospitalization, or is a congenital anomaly, or results in any important 
medical event when based upon appropriate medical judgment, may jeopardize 
the subject and may require medical or surgical intervention to prevent any of 
the above outcomes.  A “life-threatening” adverse event places the patient at 
immediate risk of death in the judgment of the investigator. 
 
Severity Ratings The investigator will evaluate the severity of each adverse 
event utilizing the  NCI Common Toxicity Criteria Version 3.0  Severity is 
expressed in numerical grade using the following definitions: 
 
Grade 1: Mild-noticeable to the patient, does not interfere with the 
patient’s daily activities, usually does not require additional therapy, dose 
reduction, or discontinuation of the study drug. 


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 
Grade 2: Moderate-interferes with the patient’s daily activities, possibly 
requires additional therapy, but does not require discontinuation of study 
drug. 
 
Grade 3: Severe-severely limits the patient’s daily activities and may 
require discontinuation of the study drug. 
 
Grade 4: Life-threatening or disabling  
 
Grade 5: Fatal 
 
Relationship to Study Drug/Attribution 
 
Definite –clearly related 
 
Probably Related-the event occurs within a reasonable time period 
following drug administration or follows a known response for the drug 
and cannot be reasonably explained by known patient characteristics 
(including use of concomitant medications). 
 
Possible –may be related 
 
Unlikely –doubtfully related 
 
Definitely Not Related-the event is not known to be caused by the study 
drug. 
 
Expected Adverse Event is one where the specificity or severity is consistent 
with the current information available from the resources. 
 
Unexpected Adverse Event is one not identified in nature, severity, or 
frequency in the Investigator’s Brochure or the product package insert for the 
study drug. 
 
PROCEDURE: 
 
Prior to enrollment, study site personnel will note the occurrence and nature of 
each patient’s medical condition(s) in the appropriate section of the medical 
record to be captured in the case report form.  During the study, site personnel 
will again note any change in the condition(s) and the occurrence and nature of 
any adverse events.  
If a patient experiences an adverse event after the informed consent document is 
signed (entry) but the patient is never assigned to treatment (enrollment), the 
event will ONLY be reported if the investigator believes that the event may 
have been caused by a protocol procedure. 
 
If a patient's dosage is reduced or treatment is discontinued as a result of an 
adverse event, study site personnel must clearly document the circumstances 
and data leading to any such dosage reduction or discontinuation of treatment in 
the medical record to be captured in the case report forms. 
 
 


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Investigator Reporting Responsibilities: 
1. Upon identification of an AE, the investigator will utilize the above definitions to 
properly classify the event.  Each category listed above must be recorded for each 
event. 
 
2. All AEs and SAEs will be recorded in the case report forms on the “AE/Toxicity 
Form” with details about the grade and attribution of each episode.  The action 
taken with respect to the study drug, and the patient’s outcome should be recorded 
in the remarks section of the “Treatment Flow Sheet”.  All events will be recorded 
on case report forms each cycle until they resolve. 
 
3. All SAEs will be recorded on “FDA Form 3500 MedWatch” and faxed to the 
FER project manager at 215-728-4784.  The site should call the FER project 
manager to alert them of an incoming SAE fax.  After submitting the initial report 
it may be necessary to submit additional reports by the investigator should the 
event require further investigation. 
 
4. Each investigator is responsible to report all AEs/SAEs to IRB following 
guidelines set by that IRB.  FER reserves the right to request an event be reported 
to the IRB at their discretion.  Copies of all documentation of events reviewed by 
the IRB must be sent to FER Clinical Research Office. 
 
5. Reporting SAEs: 
Study site personnel must report to FER immediately, any serious adverse 
event.   
Adverse events must be reported to regulatory authorities according to the 
definitions and timelines specified in the local laws and regulations: 
 Unexpected Event: Grade 2-3 with possible, probably or definite 
attribution requires written report to FER within 3 working days. 
 Unexpected Grade 4-5 regardless of attribution requires report by 
phone/fax within 24 hours and a written report within 3 working days.  
This includes deaths within 30 days of last study drug. 
 Expected Event: Grade 4-5 regardless of attribution requires report by 
phone/fax within 24 hours and a written report within 3 working days 
 
6. If the results of an investigator or FER investigation show an adverse event not 
initially determined to be reportable is so reportable, the investigator will report 
the event following the above guidelines based on the date the determination is 
made. 
 
7. Any serious or unexpected adverse event that is possibly, probably or definitely 
related to the study will be reported by FER in writing to Lilly within 5 working 
days of notification of the event.  Death from any cause will be reported  
immediately by FER to Lilly.  The report will be distributed to all investigational 
sites within 15 working days of notification of the event for review by each 
respective IRB 


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8. Lilly is responsible for notifying the FDA of all applicable events. 
 
The FER fax number for SAEs is 215-728-4784 
FER will forward all reports to the required places.  
6.7  Post-Therapy Follow-up 
6.7.1  Safety 
After each patient discontinues study therapy, the investigator should make every 
effort to continue to evaluate the patient for delayed toxicity by clinical and 
laboratory evaluations as clinically indicated.  Every attempt should be made to 
obtain hematology, and chemistry approximately 30 days after the last dose of 
pemetrexed and gemcitabine.  The patient must be followed approximately every 30 
days until toxicity resolves. 
6.7.2  Efficacy 
To obtain meaningful data on tumor responses and time to event variables, 
assessments of disease status will be made at regular intervals after patients 
discontinue from the study.  A CT or MRI scan (same method as at baseline) must 
be done no less than 4 weeks after the first documentation of a response, to confirm 
the response.  Other than for response confirmation, a CT or MRI scan will be 
performed approximately every 8 weeks for 6 months post-study or until disease 
progression, whichever occurs first.  After 6 months, clinical assessment will be 
done every 12 weeks, and CT or MRI scans will be done as clinically indicated 
until progression of disease.  During this time information will be collected 
regarding date of disease progression or death, and any post-study chemotherapy, 
radiotherapy, or surgical intervention.  Each patient’s assessments will continue 
until death. 
If patient decides to follow-up at a different institution, attempts to obtain data will 
still be made unless patient withdraws consent. 
 
7.   Statistical Considerations 
7.1  Targeted Response Rate 
For a total of 32 subjects, 16 will be accrued during stage 1 and 16 during stage 2. 
Given that the 'true' response probability is 10%, there is a 51.47% probability of 
ending the trial during stage 1. However, if the 'true' response probability is 25%, then 
there is an 6.35% probability that the trial will be stopped in stage 1. The type I error 
of the design is 0.0882, and the power is 0.825. If 1 or fewer responses are observed 
during the first stage, then the trial is stopped early.  If 5 or fewer responses are 
observed by the end of the trial, then no further investigation of the drug is warranted. 
Operating characteristics of this design are summarized in the table below: 
 
n2  a2  n1  a1 
32   5  16   1 


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      p1 = 0.1000             p2 = 0.2500 
 
 p(S.le.a1|n1): 0.5147   p(S.le.a1|n1): 0.0635 
 p(S.gt.a2|n2): 0.0882   p(S.gt.a2|n2): 0.8253 
 p(early stop): 0.5147   p(early stop): 0.0635 
 ASN:             23.8   ASN:             31.0 
 
 overall type I error: 0.0882 
 overall power:        0.8253 
----------------------------- 
 
We will assume there will be a 10% rate of inevaluable patients, so 3 additional 
subjects will be accrued in stage 2. Therefore we expect to accrue a minimum of 16 
patients and a maximum of 35 patients using this design. 
7.2  Qualifications for Efficacy Analysis 
All enrolled patients meeting the following criteria will be evaluated for efficacy: 
 Histologic or cytologic diagnosis of SCCHN that is not amenable to 
curative therapy. 
 No concurrent systemic chemotherapy except for study treatment. 
 Presence of one-dimensional measurable disease as defined in Section 6.2, 
and the investigator has consistently followed protocol guidelines for 
tumor measurement. 
 Treatment with at least one dose of pemetrexed and gemcitabine. 
7.3  Qualifications for Safety Analysis 
All patients who receive at least one dose of pemetrexed and gemcitabine will be 
evaluated for safety. 
7.4  Primary Outcome 
7.4.1  The primary objective of the study is the tumor response rate. Please refer 
to Section 6.2 for definitions of response categories. The study tumor response 
rate will be reported, including a 95% confidence interval. The estimate of tumor 
response rate will be given by: 
 
Response Rate
Sum of # of PRs and#of CRs observed
#  of patients qualified for efficacy analy 
 
7.5  Secondary Outcomes 
The secondary objectives will be to measure time to progression and overall survival. 
All patients who meet the efficacy criteria for qualifications will be evaluated. The 


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analysis will include Kaplan-Meier curves. Time to progression will be from the date 
of the first treatment to the time that any of the following conditions are met: 
 There is progression of disease as defined in Section 6.3. 
 Death of any cause. 
 The initiation of new treatment (e.g., radiation therapy, chemotherapy, 
immunotherapy). 
7.6  Safety Analyses 
All patients who are treated with pemetrexed and gemcitabine will be evaluated for 
safety.  Safety analyses will include the following: 
 Summaries of the number of blood transfusions required. 
 Summaries of the adverse event rates and laboratory changes. 
 Listings and frequency tables categorizing laboratory and nonlaboratory adverse 
events by maximum CTC toxicity grade and relationship to study drug. 
All adverse events will be summarized 1) without regard to causal relationship and 2) 
by causal relationship to study drugs, based on the Investigator’s opinion.  Worst 
toxicity grades per patient will be tabulated for selected adverse events and laboratory 
measurements.  Any serious adverse event or adverse event resulting in premature 
and permanent discontinuation of any study drug will be described in detail.  Adverse 
events and other symptoms will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. 
A Data Safety Monitoring Plan has been implemented to monitor safety parameters 
during the study.  Ongoing, on site monitoring will confirm proper conduct of this 
study for each subject and identify any protocol violations and unreported adverse 
events in a timely manner.  Any events determined to be significant will be reported 
immediately to the principal investigator.  FER administrative staff will review data 
regularly with the principal investigator or his designee.  Data will be collected from 
individual case report forms when the subject has completed the study and all queries 
are resolved.  This review will include complete accrual listing demographic 
information, response, toxicity tables, summaries of incidence severity and resolution 
of adverse events, including laboratory results abnormalities, summary of any 
pertinent findings from monitoring/auditing visits and a description of all known or 
suspected protocol violations. 
 
Each participating practice must designate a single on-site principal investigator with 
primary responsibility for the conduct of the study in his practice.  This site-specific 
principal investigator is responsible for identification of all adverse events at their site 
and must verify that appropriate procedures are being followed.  SAE’s experienced 
by a subject participating in a clinical trial must be reported according to section 6.6.1 
adverse event reporting in clinical trials. FER is responsible for collecting and 
reporting serious adverse events to the study principal investigator, Lilly, and to other 
participating sites for IRB submission.  Each practice must designate an IRB for this 
study and follow any by-laws regarding the use of an IRB set forth by the terms of 


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their employment or determined by the institution in which they practice.  
Investigators must supply their designated IRB with ongoing progress reports for the 
study and a formal review of each study will be conducted at least every 364 days or 
more frequently as designated by the IRB.  The IRB may suspend, terminate or 
restrict the study as appropriate. 
 
FER will manage the flow of documents to participating sites and external agencies 
(including reports of serious adverse events) to facilitate ongoing and timely review 
of the protocol. FER will monitor the medical and study records of each participant 
accrued at each site throughout the course of the study.  In addition, FER will audit, 
collect and report data to the study Principle Investigator who will review these data 
on a regular basis at a rate dependent on subject accrual.  All serious adverse events 
(SAE’s) will be reviewed on a real time basis first by the study site PI and 
subsequently by Dr.Langer. 
7.7  Criteria for Study Termination 
This study will be considered complete six months after the last patient is enrolled or 
after 80% of the enrolled patients have progressed, whichever is later. Data generated 
to this point will be collected and entered into the clinical trial database.  Data 
collected up to this point (after cleaning and locking) will be used to write the clinical 
study report. 
After completion of the trial (as defined in the previous paragraph), data will continue 
to be collected on all surviving patients who are still under therapy.  This data 
collection will continue until all patients have either progressed or are off study 
therapy.  This post-lock data will be combined with the data in the locked database 
and stored in a data library separate from the locked database.  The clinical study 
report will not be revised to reflect this additional data. 
 
8.   Informed Consent, Ethical Review, and Regulatory Considerations 
8.1  Informed Consent 
The investigator is responsible for ensuring that the patient understands the risks and 
benefits of participating in the study, including answering any questions the patient 
may have throughout the study and sharing any new information that may be relevant 
to the   patient's willingness to continue his or her participation in the trial in a timely 
manner. 
The informed consent document will be used to explain the risks and benefits of study 
participation to the patient in simple terms before the patient is entered into the study, 
and to document that the patient is satisfied with his or her understanding of the risks 
and benefits of participating in the study and desires to participate in the study.   
The investigator is responsible for ensuring that informed consent is given by each 
patient’s legal representative. This includes obtaining the appropriate signatures and 
dates on the informed consent document prior to the performance of any protocol 
procedures and prior to the administration of study drug. 


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8.2  Ethical Review 
The investigator will provide Lilly with documentation of ethical review board 
approval of the protocol and the informed consent document before the study may 
begin at the investigative site(s). Any member of the ethical review board who is 
directly affiliated with this study as an investigator or as site personnel must abstain 
from the ethical review board’s vote on the approval of the protocol.  The ethical 
review board(s) will review the protocol as required. 
8.3Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and that are consistent with good clinical 
practices and the applicable laws and regulations.  The investigator or designee will 
promptly submit the protocol to applicable ethical review board(s). 
An identification code assigned by the PI or designee to each patient will be used in 
lieu of the patient's name to protect the patient's identity when reporting adverse 
events and/or other trial-related data. 
9.0 Study Agent Information 
9.1 Pemetrexed Disodium 
9.1.1 Other Names 
                        Pemetrexed, MTA, LY231515 
9.1.2 Classification 
Antifolate antimetabolite 
9.1.3 Mode of Action 
Multitargeted antifolate compound that has been shown to inhibit several 
enzymes in the folate pathway including thymidylate synthase, 
dihydrofolate reductase, and glycinamide ribonucleotide 
formyltransferase. 
9.1.4 Storage and Stability 
The drug product is stable when stored at room temperature.  
Reconstituting the 500 mg vial contents with 10 mL to 50 mL of sodium 
chloride injection gives a clear solution with a concentration of 10 mg/mL 
to 50 mg/mL.  The reconstituted formulation is in the pH range of 6.8 to 
7.5 and has been shown to be chemically stable for 72 hours at refrigerated 
or room temperature.  After dilution the shelf-life of the product is 24 
hours at room temperature.  If pemetrexed disodium is reconstituted with 
sterile water for injection and is stored for up to 24 hours before 
administration to the patient, it must be refrigerated during this time. 
LY231514 is not sensitive to light.  Vials of LY231514 contain no anti-
microbial preservative, and they are single-use vials.  Any unused portion 
of a vial may not be stored for future use, and unused portions of product 
in a vial must be discarded. 


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9.1.5 Preparation and administration 
The freeze-dried drug product is composed of LY231514 disodium and 
mannitol in a 1:1 ratio.  Sodium hydroxide and/or hydrochloric acid solution 
may be added during processing to adjust the pH.  The vial size is 500 mg.  
Each vial contains LY231514 disodium equivalent to 102 mg, or 510 mg of the 
base compound, LY231514.  The vials contain a 2% excess to facilitate the 
withdrawal of the label amount from the 500-mg vial.  Vial contents should be 
inspected for particulate matter before and after the drug product is withdrawn 
from a vial into a syringe. 
The concentrated solution cannot be administered without further dilution.  For 
purposes of clinical administration an appropriate quantity of the contents of the 
reconstituted vial must be further diluted into an infusion solution of 75 to 125 
mL of 0.9% sodium chloride for injection.  LY231514 is incompatible in 
solution with acidic medications or media and must not be mixed or 
administered simultaneously through the same infusion line.  The infusion line 
should be flushed prior to administration of any concomitant medication.  
LY231514 is compatible with standard PVC administration sets and IV solution 
bags. 
Administer as an intravenous infusion over 10 minutes (8 to 15). 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
9.1.6 Incompatibilities 
Do not infuse pemetrexed disodium with other drugs concurrently. 
9.1.7 Drug Interaction 
Salicylates and NSAIDs should not be given for a 5 day period (2 days 
before, the day of, and 2 days following administration of pemetrexed 
disodium)   While pemetrexed is structurally related to methotrexate, the 
actual effect on renal excretion with concurrent NSAIDs and salicylates is 
not yet characterized. 
9.1.8 Side Effects 
1. Hematologic:  Myelosuppression with anemia, leucopenia, neutropenia 
and thrombocytopenia.  Elevated homocycteine levels increase risk of 
neutropenic sepsis. 
2. Dermatologic: Rash, pruritis, alopecia, skin discoloration. 
3. Gastrointestinal: Nausea, vomiting, stomatitis, diarrhea, constipation, 
anorexia, hematemesis, abdominal pain, melena, dyspepsia, flatulence. 
4. Genitourinary: Renal dysfunction, dehydration, hematuria, dysuria, 
UTI. 
5. Hepatic: Hyperbilirubinemia, elevated liver transaminases, jaundice. 


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6. Cardiac: Tachycardia, vasodilatation, hypotension, hypertension, 
edema. 
7. Neurologic: Dizziness, insomnia, somnolence, blurred vision, 
headache, back and chest pain, anxiety, paresthesia, malaise, taste 
perversion, depression, confusion. 
8. Allergic: Fever, rigors, allergic reaction. 
9. Ocular: Conjunctivitis, eye disorder or pain. 
10. Pulmonary:  very uncommon but may include: cough, effusions, 
pneumonitis and fibrosis. 
11. Other: Myalgia, sweating, pharyngitis, epistaxis, facial edema, 
dysphagia, ascites, hiccups, weight loss, hyperglycemia, bone pain, 
asthenia. 
9.1.9 Nursing/Patient Implications 
1. When handling, preparing, or administering pemetrexed, follow 
recommended procedures and guidelines for the safe handling of a 
cytotoxic agent. 
2. Administer antiemetics as indicated. 
3. Monitor for hematologic toxicity. 
4. Observe for gastrointestinal toxicity (stomatitis, diarrhea, nausea, 
vomiting). 
5. Pemetrexed must be given with folate and vitamin B12 rescue.  
Educate patient and significant other about importance of compliance 
with medication schedule. 
6. Any acute change in mental status should prompt immediate 
notification of medical staff. 
9.2 Gemcitabine 
9.2.1 Other name: 
 2’-deoxy-2’,2’ difluorocytidine-monohydrochloride, Gemzar. 
Gemcitabine is commercially available and supplied as a lyophilized 
powder in sterile vials containing 200mg or 1g of gemcitabine as the 
hydrochloride salt (expressed as free base), mannitol and sodium acetate.  
 
9.2.2 Storage 
The lyophilized powder should be stored below 30C. Drug vials will be 
reconstituted with normal saline added to the vial to make a solution 
ideally containing 10mg/ml or less. The concentration for 200mg and 1 g 
vials should be no greater than 40mg/ml.  
 
9.2.3 Administration  


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The drug will be infused intravenously over 30 minutes. Once the drug has 
been reconstituted it should be stored at room temperature and used within 
24 hours.  
 
9.2.4 Side effects 
Allergic: bronchospasm was reported for less then 2% of patients with 
anaphylactoid reactions rarely reported. Gemcitabine is contraindicated in 
patients with a known hypersensitivity to this drug.  
 
Cardiovascular: 2% of patients discontinued therapy due to cardiovascular 
event like myocardial infarction, cerebrovascular accident, arrhythmia and 
hypertension. Many of these patients had a prior history of cardiovascular 
disease.  
Hematologic: myelosuppression is the principal dose-limiting factor. Dose 
adjustment for hematologic toxicity are needed but <1% of patients 
require discontinuation of therapy.   
 
Gastrointestinal: nausea and vomiting are frequent but usually mild or 
moderate. Diarrhea and stomatitis occur less frequently.  
 
Hepatic: transient elevations of serum transaminase occur in about 2/3 of 
patients  
 
Renal-Mild proteinuria and hematuria are frequently reported. Clinical 
findings consistent with the hemolytic uremic syndrome (HUS) were 
reported in 6 out of 2429 patients (0.25%) receiving gemcitabine in 
clinical trials. Four patients developed HUS while on gemcitabine therapy, 
two immediately post-therapy. Renal failure may not be reversible even 
with discontinuation of therapy and dialysis may be required.  
 
Fever: the incidence of fever is 41%. This is in contrast to the incidence of 
infection 16%. The fever may be present in the absence of infection. It 
may have associated flu-like symptoms and is usually mild and clinically 
manageable.  
 
Rash: reported in 1/3. It is typically a macular or finely granular maculo-
papular pruritic eruption of mild to moderate severity involving the trunk 
and extremities.  
 
Pulmonary: dyspnea was reported in 23%, severe dyspnea in 3%. It may 
be due to underlying lung cancer (40% of study population) or pulmonary 
manifestations of other malignancies. Dyspnea was occasionally 
accompanied by bronchospasm (<2% of patients). Rare reports of 
parenchymal lung toxicity consistent with drug induced pneumonitis have 
occurred.  
  


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Edema: 13%, peripheral edema 20% and generalized edema have been 
reported. Less than 1% of patients required discontinuation of therapy due 
edema.  
 
Flu like symptoms. Reported for 19% of patients. Fever, asthenia, 
headache, cough, chills and myalgia were commonly reported. Fever and 
asthenia were reported as isolated symptoms.  Insomnia, sweating, rhinitis 
and malaise were reported infrequently.  
 
Infection: reported for 16% of patients. Sepsis has been rarely reported.  
 
Alopecia: Hair loss reported in 15% of patients.  
 
Neurotoxicity: 10% incidence of mild paresthesias and a 1% incidence of  
severe paresthesia.  
 
9.2.5 Extravasation 
Gemcitabine is not a vesicant. 4% had documented injection site related 
event with no reports of injection site necrosis.  
 
9.2.6 Overdosage 
There is no known antidote for overdosage. Myelosuppression, and severe 
rash were the principal toxicities documented when a single dose as high 
as 5700mg/m2 was administered by IV infusion over 30min every 2 
weeks to several patients in a phase I trial. In the event of overdose the 
patient should be monitored with blood counts weekly and supportive 
growth factor as necessary.  
 
 
            9.3  Drug Ordering and Accountability 
 
9.3.1  Pemetrexed and Gemcitabine will both be supplied by Eli Lilly.   
During each site initiation visit, the drug ordering process and forms will be reviewed and 
distributed.  Drug orders may not be placed until all required regulatory documents have 
been received by the FER project manager and forwarded and approved by the Lilly 
representative.  Each site is responsible for maintaining current records of product 
disposition.  Records or logs must comply with applicable regulations and guidelines and 
include: 
 Amount received and placed in storage area 
 Amount currently in storage area 
 Label ID number or batch number 
 Dates and initials of person responsible for each site product inventory 
entry/movement 


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 Amount dispensed to and wasted per subject including unique subject identifier 
 Amount transferred to another are for dispensing or storage 
 Non-study disposition (wasted, broken) 
FER will provide forms to facilitate inventory control if the staff at the site does not have 
an established system that meets these requirements or the NCI Investigational Agent 
Accountability Record can be utilized (available online). 
 
 
 
 
 
 
 
 
 
 
 
 
10.0  Bibliography 
 
1.  Grindey GB, Shih C, Barnett C, al. e: LY231514, a novel pyrrolopyrimidine antifolate 
that inhibits thymidylate synthase (TS), Proc Am Assoc Cancer Res, 1992, pp 411. 
Abstract 2451 
2. Shih C, Gossett L, Gates SB, al. e: LY231514 and its polyglutamates exhibit potent 
inhibition against both human dihydrofolate reductase (DHFR) and thymidylate sythase 
(TS): multiple folate enzyme inhibition, Ann Oncol, 1996, pp 85. Abstract 289 
3.  Grem J: Fluorinated pyrimidines, in Chabner B, Collins J (eds): Cancer chemotherapy: 
principles and practice. Philadelphia (PA), Lippincott, 1990, pp 180-224 
4.  Schilsky R: Antimetabolites., in Perry M (ed): The chemotherapy source book. 
Baltimore (MD), Williams & Wilkins, 1992, pp 301-17 
5.  Schultz R, Andis S, Chen V, al. e: Comparative antitumor activity of the multitargeted 
antifolate LY231514 and the thymidylate synthase (TS) inhibitor ZD1694, 1996, pp 85. 
Abstract 290 
6.  Chen V, Bewley JR, Gossett L, al. e: Activity of LY231514 against several enzymes 
in the folate-dependent pathways, Proc am Assoc Cancer Res, 1996, pp 381. Abstract 
2598 
7. Rinaldi D, Burris H, Dorr F, al. e: A phase I evaluation of LY231514, a novel multi-
targeted antifolate, administered every 21 days., Proc Am Soc Clin Oncol., 1996, pp 489. 
Abstract 1559 


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8.  Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, Alarcon 
GS: The effect of folic acid supplementation on the toxicity of low-dose methotrexate in 
patients with rheumatoid arthritis. Arthritis Rheum 33:9-18, 1990 
9.  Mendelsohn LG, Gates SB, Habeck LL, Shackelford KA, Worzalla J, Shih C, Grindey 
GB: The role of dietary folate in modulation of folate receptor expression, 
folylpolyglutamate synthetase activity and the efficacy and toxicity of lometrexol. Adv 
Enzyme Regul 36:365-81, 1996 
10.  Smith GK, Amyx H, Boytos CM, Duch DS, Ferone R, Wilson HR: Enhanced 
antitumor activity for the thymidylate synthase inhibitor 1843U89 through decreased host 
toxicity with oral folic acid. Cancer Res 55:6117-25, 1995 
11.  Alati T, Worzalla JF, Shih C, Bewley JR, Lewis S, Moran RG, Grindey GB: 
Augmentation of the therapeutic activity of lometrexol -(6-R)5,10-
dideazatetrahydrofolate- by oral folic acid. Cancer Res 56:2331-5, 1996 
12.  Niyikiza C: LY231514 (MTA) Safety Analysis, 3 December 1999. Submitted to the 
FDA as Serial Number 95 to IND#40,061. On file., 1999 
13. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, 
McClure S, VonFeldt E, Williamson SK, et al.: Randomized comparison of cisplatin plus 
fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-
cell carcinoma of the head and neck: a Southwest Oncology Group study. J. Clin. Oncol. 
10:1245-51, 1992 
14. Pivot X, Raymond E, Laguerre B, Degardin M, Cals L, Armand JP, Lefebvre JL, 
Gedouin D, Ripoche V, Kayitalire L, Niyikiza C, Johnson R, Latz J, Schneider M: 
Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell 
carcinoma of the head and neck. Br. J. Cancer 85:649-55, 2001 
15.  Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, 
Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P: Phase III study of 
pemetrexed in combination with cisplatin versus cisplatin alone in patients with 
malignant pleural mesothelioma. J. Clin. Oncol. 21:2636-44, 2003 
16. Piccirillo JF: Importance of comorbidity in head and neck cancer. Laryngoscope 
110:593-602, 2000 
17.  Hertel L, Kroin J, Misner J, al. e: Synthesis of 2-deoxy-2',2'-difluoro-D-ribose and 2-
deoxy-2',2'-difluoro-D-ribofuranosyl nucleosides. J Org Chem 53:2406-9, 1988 
18.  Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GB: 
Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). 
Cancer Res 50:4417-22, 1990 
19.  Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi 
S, Tarassoff P, Satterlee W, Raber MN, et al.: A phase I clinical, plasma, and cellular 
pharmacology study of gemcitabine. J Clin Oncol 9:491-8, 1991 
20.  Fossella F, Lippman S, Tarassoff P, al. e: Phase 1/2 study of gemcitabine, an active 
agent for advanced non-small cell lung cancer (nsclc), Proc ASCO, 1995, pp A1144 
21.  Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, 
Trochanowski B, Tarassoff PG: Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) 
in patients with adenocarcinoma of the pancreas. Invest New Drugs 12:29-34, 1994 
22. Tonato M: Gemcitabine safety overview, in: gemcitabine, novel combination of 
efficacy and tolerability., Proc Eur Cont Clin Oncol 7. Satellite Symposium, Jerusalem, 
Israel, November, 1993, pp 14-6 


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23.  Poplin E, Redman B, Flaherty L, al. e: Difluorodeoxycytidine: a phase I study. Proc 
Am Assoc Clin Res 30:282, 1989 
24.  Poplin EA, Corbett T, Flaherty L, Tarasoff P, Redman BG, Valdivieso M, Baker L: 
Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study. Invest New Drugs 10:165-
70, 1992 
25.  O'Rourke T, Brown T, Havlin K, al. e: Phase I clinical trial of difluorodeoxycytidine 
(LY188011) given as an intravenous bolus on five consecutive days. Invest New Drugs 
7:380, 1989 
26.   
Grunewald R, Kantarjian H, Du M, Faucher K, Tarassoff P, Plunkett W: 
Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J 
Clin Oncol 10:406-13, 1992 
27.  Plunkett W: Pharmacology of gemcitabine. Ann Oncol 3:191, 1992 
28.   Pollera C, Ceribelli A, Crecco M, Zeuli M, Bortini S, Calabresi F: Prolonged 
infusion of gemcitabine; a preliminary report of a Phase I study. Ann Oncol 44:1819-27, 
1992 
29.  Adjei AA, Erlichman C, Sloan JA, Reid JM, Pitot HC, Goldberg RM, Peethambaram 
P, Atherton P, Hanson LJ, Alberts SR, Jett J: Phase I and pharmacologic study of 
sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced 
solid tumors. J. Clin. Oncol. 18:1748-57, 2000 
30.  Ettinger DS, Monnerat C, Kelly K, Novello S, Brahmer JR, Readett D, Rusthoven J, 
Bunn PA, Chevalier TL: Phase II trial of pemetrexed + gemcitabine in patients with 
advanced non-small cell lung cancer: importance of survival over response. Proc Am Soc 
Clin Oncol 21:Abstract 1243, 2002 
31.  Vici P, Foggi P, Capomolla E, Santiccioli S, Cauchi C, Giacinti L, Lopez M: 
Biweekly paclitaxel/gemcitabine (P/G) as salvage treatment in breast cancer patients 
(pts): preliminary results. Proc Am Soc Clin Oncol 21:Abstract 2054, 2002 
32.  Hitt R, Castellano D, Cortes-Funes H, Colomer R: Biweekly Gemcitabine Plus 
Vinorelbine: A Dose-Finding Phase I Study in Advanced Cancer. Proc Am Soc Clin 
Oncol 18:Abstract 821, 1999 
33.  Dudek A, Larson T, Mellskog CE, Bloss LP, Obasaju C: A phase I clinical study of 
biweekly pemetrexed and gemcitabine in patients with advanced solid tumors. Journal of 
Clinical Oncology 22:2141, 2004 
34.  Urba SG, Forastiere AA: Systemic therapy of head and neck cancer: most effective 
agents, areas of promise. Oncology (Huntington) 3:79-88; discussion, 1989 
35. 
  Jacobs C, Lyman G, Velez-Garcia E, Sridhar KS, Knight W, Hochster H, 
Goodnough LT, Mortimer JE, Einhorn LH, Schacter L: A phase III randomized study 
comparing cisplatin and fluorouracil as single agents and in combination for advanced 
squamous cell carcinoma of the head and neck. J. Clin. Oncol. 10:257-63, 1992 
36.  Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, 
Tueni EA, Verweij J, Wildiers J, Clerico M: Randomized comparison of cisplatin, 
methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) 
versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and 
neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann. 
Oncol. 5:521-6, 1994 


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37.  Karnofsky DA, Bruchenal JH: The clinical evaluation of chemotherapeutics in 
cancer, in McLeod CM (ed): Evaluation of chemotherapeutic agents. New York, 
Columbia University, 1949, pp 191-205 
38. 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 
Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New 
guidelines to evaluate the response to treatment in solid tumors. European Organization 
for Research and Treatment of Cancer, National Cancer Institute of the United States, 
National Cancer Institute of Canada. J. Natl. Cancer Inst. 92:205-16, 2000 
39.  Simon R: Optimal two-stage designs for phase II clinical trials. Control. Clin. Trials 
10:1-10, 1989 
 
 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 1. 
Folic Acid and Vitamin B12 Supplementation 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
A recent safety assessment of the impact of folic acid and vitamin B12 supplementation 
on the severe toxicities related to pemetrexed therapy has been completed and a report 
submitted to the FDA (Serial number 323 to IND #40,061 on June 4, 2001).  The overall 
objectives of this report were to assess the impact of folic acid and vitamin B12 
supplementation on homocysteine levels over time and to compare the incidence of 
severe toxicities and drug-related deaths associated with pemetrexed therapy between 
patients with and without folic acid and vitamin B12 supplementation.  For this analysis, 
two groups of patients with solid tumors treated with pemetrexed for at least two cycles 
of therapy and who had a baseline homocysteine concentration obtained were selected for 
this analysis.  The first group included 394 patients who were never supplemented with 
folic acid and vitamin B12 at any time during their therapy with pemetrexed 
500 to 600 mg/m2, while the second group included 196 patients supplemented with 
vitamin B12 and daily folic acid during their treatment with pemetrexed 500 mg/m2.  All 
toxicities reported were based on the CTC grading scale. 
The data showed that folic acid and vitamin B12 supplementation caused a statistically 
significant reduction in plasma homocysteine concentrations over time, from 9.4 µM at 
baseline to 7.7 µM at Cycle 7.  This reduction was observed after one cycle of therapy 
and was maintained throughout the study. 
The analysis assessed cumulative toxicities related to pemetrexed therapy occurring 
within the first seven cycles of therapy.  The analysis focused on those severe 
hematologic (Grade 4 neutropenia and thrombocytopenia) and nonhematologic (Grade 
3/4 infection, diarrhea, and mucositis) toxicities associated with pemetrexed therapy.  The 
incidence of both Grade 4 hematologic and Grade 3/4 nonhematologic toxicities 
decreased markedly in those patients supplemented with vitamins (Table 4).  These data 
indicate a marked improvement in the incidence of severe toxicities associated with 
pemetrexed therapy when patients are supplemented with folic acid and vitamin B12. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Table 4. 
Incidence of Severe Toxicities Related to pemetrexed 
Therapy in Patients with and without Folic Acid and Vitamin 
B12 Supplementation Occurring within the First 7 Cycles 
 
Without folic 
acid/B12 
supplementation 
(n=394) 
With folic acid/B12 
supplementation 
(n=196) 
P value* 
Grade 4 hematologic and Grade 
3/4 nonhematologic toxicitiesa 
33% 
12% 
<0.0001 
Grade 4 neutropenia 
28% 
9% 
<0.0001 
Grade 4 thrombocytopenia 
6% 
1% 
0.001 
Grade 3/4 mucositis 
5% 
0.5% 
0.002 
Grade 3/4 diarrhea 
5% 
4% 
NS** 
Grade 3/4 infection 
3% 
1% 
NS 
Grade 4 neutropenia + Grade 3/4 
mucositis 
3% 
0% 
0.002 
Grade 4 neutropenia + Grade 3/4  
diarrhea 
3% 
1% 
NS 
Grade 4 neutropenia +G3/4 
infection 
1% 
1% 
NS 
*Determined by Chi-Square test. 
**Not statistically significant. 
 
Seven of 504 patients (1.4%) supplemented with folic acid and vitamin B12 died as a 
result of toxicities possibly or probably related to pemetrexed therapy compared to 49 of 
1169 patients (4.2%) not supplemented with folic acid and vitamin B12.  These results 
indicate that folic acid and vitamin B12 supplementation results in a marked improvement 
in the incidence of pemetrexed-related death. 
The analysis confirmed the hypothesis that the administration of daily folic acid and 
vitamin B12 reduces homocysteine and in turn results in a significant reduction of death 
and toxicity associated with pemetrexed.  The results from this analysis support the 
following conclusions: 
 Supplementation with folic acid and vitamin B12 causes a statistically 
significant reduction in homocysteine levels and these levels are maintained 
while on study as long as the patient continues to take the vitamins.  
 Folic acid and vitamin B12 supplementation results in a reduction of 
pemetrexed-related deaths. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
 Folic acid and vitamin B12 supplementation significantly reduces the number 
of episodes of Grade 4 hematologic and Grade 3/4 nonhematologic toxicities 
associated with pemetrexed therapy. 
 Folic acid and vitamin B12 supplementation acts quickly to protect the patient 
from the increased risk of developing severe toxicities and from drug-related 
death.  This protection continues throughout study therapy with LY231514. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 2. 
American Joint Committee on Cancer 
Staging Criteria 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 2   
AJCC Staging Criteria for Lip and Oral Cavity tumors 
 
Primary Tumor (T)  
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4 (lip) 
Tumor invades adjacent structures (e.g., through cortical 
bone, inferior alveolar nerve, floor of mouth, skin of face) 
T4 (oral cavity) 
Tumor invades adjacent structures (e.g., through 
cortical bone, into deep [extrinsic] muscle of tongue, maxillary sinus, skin. 
Superficial erosion alone of bone/tooth socket by gingival primary is not 
sufficient to classify as T4) 
 
 
Regional Lymph Nodes (N)  
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest 
dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not 
more than 6 cm in greatest dimension; or in multiple ipsilateral lymph 
nodes, none more than 6 cm in greatest dimension; or in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension 
N2a Metastasis in single ipsilateral lymph node more than 3 cm but not 
more than 6 cm in greatest dimension  
 N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm 
in greatest dimension  
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 
6 cm in greatest dimension  
N3 
Metastasis in a lymph node more than 6 cm in greatest dimension 
 
 
Distant Metastasis (M)  
MX 
Distant metastasis cannot be assessed  
M0 
No distant metastasis  
M1 
Distant metastasis  
 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Stage Grouping  
Stage 0 
Tis 
N0 
M0 
Stage I 
T1 
N0 
M0 
Stage II 
T2 
N0 
M0 
Stage III 
T3 
N0 
M0 
  
 
T1 
N1 
M0 
  
 
T2 
N1 
M0 
  
 
T3 
N1 
M0 
Stage IVA T4 
N0 
M0 
  
 
T4 
N1 
M0 
  
 
Any T N2 
M0 
Stage IVB Any T N3 
M0 
Stage IVC Any T Any N M1 
 
 
 
Protocol Appendix 2   
AJCC Staging Criteria for Pharynx tumors 
 
Primary Tumor (T)  
TX 
Primary tumor cannot be assessed  
T0 
No evidence of primary tumor  
Tis 
Carcinoma in situ  
 
 
Nasopharynx  
T1 
Tumor confined to the nasopharynx 
T2 
Tumor extends to soft tissues of oropharynx and/or nasal fossa 
     T2a 
without parapharyngeal extension 
     T2b 
with parapharyngeal extension 
T3 
Tumor invades bony structures and/or paranasal sinuses 
T4 
Tumor with intracranial extension and/or involvement of cranial 
nerves, infratemporal fossa, hypopharynx, or orbit 
 
 
Oropharynx  
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4 
Tumor invades adjacent structures (e.g., pterygoid muscle, 
mandible, hard palate, deep muscle of tongue, larynx) 
 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Hypopharynx  
T1 
Tumor limited to one subsite of hypopharynx and 2 cm or less in 
greatest dimension 
T2 
Tumor involves more than one subsite of hypopharynx or an 
adjacent site, or measures more than 2 cm but not more than 4 cm in 
greatest diameter without fixation of hemilarynx 
T3 
Tumor measures more than 4 cm in greatest dimension or with 
fixation of hemilarynx 
T4 
Tumor invades adjacent structures (e.g., thyroid/cricoid cartilage, 
carotid artery, soft tissues of neck, prevertebral fascia/muscles, thyroid 
and/or esophagus) 
 
Regional Lymph Nodes (N): Nasopharynx 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Unilateral metastasis in lymph node(s), 6 cm or less in greatest 
dimension, above the supraclavicular fossa 
N2 
Bilateral metastasis in lymph node(s), 6 cm or less in greatest 
dimension, above the supraclavicular fossa 
N3 
Metastasis in a lymph node(s) 
     N3a 
greater than 6 cm in dimension 
     N3b 
extension to the supraclavicular fossa 
 
Regional Lymph Nodes (N): Oropharynx and Hypopharynx  
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest 
dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not 
more than 6 cm in greatest dimension, or in multiple ipsilateral lymph 
nodes, none more than 6 cm in greatest dimension, or in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension 
     N2a 
Metastasis in a single ipsilateral lymph node more than 3 cm 
but not more than 6 cm in greatest dimension 
     N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 
6 cm in greatest dimension 
     N2c 
Metastasis in bilateral or contralateral lymph nodes, none 
more than 6 cm in greatest dimension 
N3 
Metastasis in a lymph node more than 6 cm in greatest dimension 
 
 
Distant Metastasis (M)  


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
MX 
Distant metastasis cannot be assessed  
M0 
No distant metastasis  
M1 
Distant metastasis  
 
 
Stage Grouping: Nasopharynx 
Stage 0 
Tis 
N0 
M0 
Stage I 
T1 
N0 
M0 
Stage IIA 
T2a N0 
M0 
Stage IIB 
T1 
N1 
M0 
  
 
T2 
N1 
M0 
  
 
T2a N1 
M0 
  
 
T2b N0 
M0 
  
 
T2b N1 
M0 
Stage III 
T1 
N2 
M0 
  
 
T2a N2 
M0 
  
 
T2b N2 
M0 
  
 
T3 
N0 
M0 
  
 
T3 
N1 
M0 
  
 
T3 
N2 
M0 
Stage IVA T4 
N0 
M0 
  
 
T4 
N1 
M0 
  
 
T4 
N2 
M0 
Stage IVB Any T N3 
M0 
Stage IVC Any T Any N M1 
 
 
Stage Grouping: Oropharynx, Hypopharynx  
Stage 0 
Tis 
N0 
M0 
Stage I 
T1 
N0 
M0 
Stage II 
T2 
N0 
M0 
Stage III 
T3 
N0 
M0 
  
 
T1 
N1 
M0 
  
 
T2 
N1 
M0 
  
 
T3 
N1 
M0 
Stage IVA T4 
N0 
M0 
  
 
T4 
N1 
M0 
  
 
Any T N2 
M0 
Stage IVB Any T N3 
M0 
Stage IVC Any T Any N M1 
 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 2   
AJCC Staging Criteria for Larynx tumors 
 
 
Primary Tumor (T)  
TX 
Primary tumor cannot be assessed  
T0 
No evidence of primary tumor  
Tis 
Carcinoma in situ  
 
 
Supraglottis  
T1 
Tumor limited to one subsite of supraglottis with normal vocal cord 
mobility 
T2 
Tumor invades mucosa of more than one adjacent subsite of 
supraglottis or glottis or region outside the supraglottis (e.g., mucosa of 
base of tongue, vallecula, medial wall of pyriform sinus) without fixation of 
the larynx 
T3 
Tumor limited to larynx with vocal cord fixation and/or invades any of 
the following: postcricoid area, pre-epiglottic tissues 
T4 
Tumor invades through the thyroid cartilage, and/or extends into soft 
tissues of the neck, thyroid, and/or esophagus 
 
 
Glottis  
T1 
Tumor limited to the vocal cord(s) (may involve anterior or posterior 
commissure) with normal mobility 
     T1a 
Tumor limited to one vocal cord 
     T1b 
Tumor involves both vocal cords 
T2 
Tumor extends to supraglottis and/or subglottis, and/or with impaired 
vocal cord mobility 
T3 
Tumor limited to the larynx with vocal cord fixation 
T4 
Tumor invades through the thyroid cartilage and/or to other tissues 
beyond the larynx (e.g., trachea, soft tissues of neck, including thyroid, 
pharynx) 
 
 
Subglottis  
T1 
Tumor limited to the subglottis 
T2 
Tumor extends to vocal cord(s) with normal or impaired mobility 
T3 
Tumor limited to larynx with vocal cord fixation 
T4 
Tumor invades through cricoid or thyroid cartilage and/or extends to 
other tissues beyond the larynx (e.g., trachea, soft tissues of neck, 
including thyroid, esophagus) 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
 
 
Regional Lymph Nodes (N)  
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest 
dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not 
more than 6 cm in greatest dimension, or in multiple ipsilateral lymph 
nodes, none more than 6 cm in greatest dimension, or in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension 
     N2a 
Metastasis in a single ipsilateral lymph node more than 3 cm 
but not more than 6 cm in greatest dimension 
     N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 
6 cm in greatest dimension 
     N2c 
Metastasis in bilateral or contralateral lymph nodes, none 
more than 6 cm in greatest dimension 
N3 
Metastasis in a lymph node more than 6 cm in greatest dimension 
 
 
Distant Metastasis (M)  
MX 
Distant metastasis cannot be assessed  
M0 
No distant metastasis  
M1 
Distant metastasis  
 
 
Stage Grouping  
Stage 0 
Tis 
N0 
M0 
Stage I 
T1 
N0 
M0 
Stage II 
T2 
N0 
M0 
Stage III 
T3 
N0 
M0 
  
 
T1 
N1 
M0 
  
 
T2 
N1 
M0 
  
 
T3 
N1 
M0 
Stage IVA T4 
N0 
M0 
  
 
T4 
N1 
M0 
  
 
Any T N2 
M0 
Stage IVB Any T N3 
M0 
Stage IVC Any T Any N M1 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 3. 
Performance Status Scale 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Karnofsky Performance Status 
 
100 
 Normal; no complaints; no evidence of disease. 
90 
 Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
 Normal activity with effort; some signs or symptoms of 
disease. 
70 
 Cares for self; unable to carry on normal activity or to 
do active work. 
60 
 Requires occasional assistance, but is able to care for 
most of one’s needs. 
50 
 Requires considerable assistance and frequent medical 
care. 
40 
 Disabled; requires special care and assistance. 
30 
 Severely disabled; hospitalization indicated although 
death not imminent. 
20 
 Very sick; hospitalization necessary; active, supportive 
treatment necessary. 
10 
 Moribund, fatal processes progressing rapidly. 
0 
 Dead 
 
 
 
  


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 4. 
Study Schedule 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
 
BL 
During Therapy 
PS 
Cycle/Visit 
 
Cycles (every 28 days) 
 
Relative Day in a Cycle 
 
1 
8 
15 
22 
 
Procedure 
 
 
 
 
 
 
Informed consent (before 
procedures/tests) 
X 
 
 
 
 
 
Physical examination 
X 
Xa 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Blood pressure and pulse 
measurements 
X 
Xa 
 
X 
 
 
Body Surface Area 
calculation 
X 
Xa 
 
 
 
 
Concomitant med. notation 
X 
Xa,b 
 
 
 
 
Performance Status 
X 
Xa 
 
 
 
 
Tumor measurement 
(palpable)c 
X 
 
 
 
X c 
 
Radiologic tests for tumor 
measurement d 
X 
 
 
 
X d 
 
Serum pregnancy test (if 
indicated) 
X 
 
 
 
 
 
Chemistrye 
X 
X 
 
X 
 
X 
Hematologye 
X 
X 
 
X 
 
X 
Calculated creatinine 
clearancee 
X 
X 
 
X 
 
 
CTC v3.0  grading 
X 
Xa 
 
Xa 
 
Xh 
Folic acid supplementationf 
X 
X 
X 
X 
X 
X 
Vitamin B12 injectiong 
X 
 
 
 
 
X 
Pemetrexed  
 
X 
 
X 
 
 
Gemcitabine  
 
X 
 
X 
 
 
Abbreviations:  BL = Baseline, PS = Post study is 30 days after the last dose of study drug 
a – Prior to infusion 
b – Include non-study vitamin supplementation and number of units required for transfusions at every cycle 
c – Baseline:  No more than 2 weeks before enrollment.  On-study therapy:  Prior to infusion at every 
other cycle, starting with the third cycle.  Post-therapy follow-up:  Approximately every 8 weeks for 6 
months or until disease progression, whichever occurs first.  Thereafter, repeated as clinically indicated 
in follow-up visits.  Response confirmation:  Responses must be confirmed.  Confirmation should be 
performed 3 – 4 weeks (minimum 21 days) after initial response documentation. 
d – Baseline:  CT or MRI scan (where available) and/or plain x-ray no more than 28 days prior to study 
enrollment.  On study therapy:  CT or MRI scans or plain x-ray (same method as baseline) are done 0-
7 days prior to every other cycle.  Post-therapy follow-up:  Post-therapy radiological measurements – 
CT or MRI scan or plain x-ray (same method used for on study therapy assessment) – will be repeated 
approximately every 8 weeks for 6 months or until disease progression, whichever occurs first.  
Thereafter, they will be repeated as clinically indicated in follow-up visits.  Response confirmation:  
Responses must be confirmed using the same method (CT, MRI, or plain x-ray) as at baseline.  
Confirmation should be performed 3 – 4 weeks (minimum 21 days) after initial response 
documentation. 
e – Within 14 days of study enrollment, within 2 days of Day 15 for chemistry and hematology, within 4 
days prior to each cycle, and if possible approximately 30 days after the last dose of study therapy.  If 
any result that would justify dose modification is abnormal, lab must be repeated within 24 hours of 
treatment. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
f – Daily beginning 5-7 days prior to first dose of pemetrexed and continuing daily until 3 weeks after the 
last dose of study therapy. Must have completed 5 doses prior to first dose of pemetrexed.  Compliance 
will be monitored via medical interview as documented in the patient chart and by review of the Patient 
Daily Diary for Folic Acid and Decadron.. 
g – Given as an intramuscular injection approximately up to 2 weeks prior to first dose of pemetrexed (may 
be given on D1 prior to first dose of pemetrexed) and repeated approximately every 2 to 3 cycles (i.e., 
approximately every 8 weeks) starting with the third cycle until 3 weeks after the last dose of study 
therapy. The second and subsequent injections may be given + 1 week in order to time it for the same 
day as chemotherapy treatment. 
h-Toxicities that are felt to be possibly, probably or definitely related to treatment should be followed at 
least monthly until resolved. 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 5. 
Clinical Laboratory Tests 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
 
Clinical Laboratory Tests 
 
 
Hematologya: 
Clinical Chemistry:  
Hemoglobin 
Total bilirubin 
Erythrocyte count (RBC) 
Alkaline phosphatase (AP) 
Leukocytes (WBC) 
Alanine aminotransaminase (ALT/SGPT) 
Platelets 
Aspartate aminotransaminase (AST/SGOT) 
Neutrophils, (sum of segmented and bands) 
Blood urea nitrogen (BUN) 
Lymphocytes 
Serum creatinine 
Monocytes 
Calculated creatinine clearance (CrCl)b 
 
Sodium 
 
Potassium 
 
Magnesium 
 
 
 
Serum Pregnancy Test  
 
 
a Assayed by local laboratory. 
 
 
 
 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Protocol Appendix 6. 
Abbreviations and Definitions 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
Abbreviations and Definitions 
pemetrexed 
pemetrexed, LY231514, multitargeted antifolate 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AP 
alkaline phosphatase 
AST 
aspartate transaminase 
Audit 
A systematic and independent examination of the trial-related activities and 
documents to determine whether the evaluated trial-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, sponsor’s standard operating procedures (SOPs), 
Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 
BUN 
blood urea nitrogen 
Compliance 
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) 
requirements and the applicable regulatory requirements. 
CR 
Complete response 
CrCl 
creatinine clearance 
CSF 
colony stimulating factors 
CT 
computed tomography 
CTC 
common toxicity criteria 
DHFR 
dihydrofolate reductase 
DLT 
dose limiting toxicity 
dTMP 
deoxythymidine monophosphate 
dUMP 
deoxyuridine monophosphate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
Enroll 
See Study Entry Terms 
Enter 
See Study Entry Terms 
FPGS 
folylpolyglutamate synthase 
GARFT 
glycinamide ribonucleotide formyl transferase 
GCP 
good clinical practice 
G-CSF 
granulocyte colony stimulating factor 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial 
is conducted by a team of individuals at a trial site, the investigator is the 
responsible leader of the team and may be called the principal investigator. 
IRB/ERB 
Institutional review board/ethical review board:  a board or committee 
(institutional, regional, or national) composed of medical professional and 
nonmedical members whose responsibility is to verify that the safety, welfare, 
and human rights of the subjects participating in a clinical trial are protected. 
LBW 
lean body weight 


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Amendment 1  01/09/2007                                  Fox Chase Cancer Center Extramural Research Program 
LCSS 
Lung Cancer Symptoms Scale 
Legal 
Representative 
An individual or judicial or other body authorized under applicable law to 
consent, on behalf of a prospective subject, to the [patient's/subject's] 
participation in the clinical trial. 
LY231514 
pemetrexed, pemetrexed, multitargeted antifolate 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MQA 
Lilly Medical Quality Assurance 
NS 
not statistically significant 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
PD 
progressive disease 
PR 
partial response 
RBC 
red blood cells (erythrocyte count) 
RECIST 
Response Evaluation Criteria in Solid Tumors (see Therasse et al. 2000) 
Screen 
See Study Entry Terms 
SD 
stable disease 
Study Entry Terms 
Enter/Consent 
The act of obtaining informed consent for participation in a clinical trial from 
patients deemed eligible or potentially eligible to participate in the clinical trial.  
patients entered into a trial are those who sign the informed consent document 
directly or through their legally acceptable representatives. 
Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the 
trial are those who have been assigned to a treatment. 
TS 
thymidylate synthase 
ULN 
upper limit of normal 
WBC 
white blood cell (leukocyte count)