A Phase 1B Study to Evaluate the Safety and Induction of Immune Response of CRS-207 in Combination With Pemetrexed and Cisplatin as Front-line Therapy in Adults With Malignant Pleural Mesothelioma
Phase: PHASE1
Conditions: Malignant Pleural Mesothelioma
Sponsor: Aduro Biotech, Inc.

Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
CLINICAL PROTOCOL 
TITLE OF STUDY: 
A Phase 1B Study to Evaluate the Safety and Induction of Immune Response of CRS-207 
in Combination with Pemetrexed and Cisplatin as Front-line Therapy in Adults with 
Malignant Pleural Mesothelioma 
Protocol ID: 
Sponsor: 
IND: 
Date of Issue: 
Affiliation 
Sponsor: 
ADU-CL-02 
Aduro Biotech, Inc. 
740 Heinz Avenue 
Berkeley, CA 94710-2224 
Phone: 510-848-4400 
13,389 
08 March 2018, Version 8 
Signatures of Approval for Protocol (Version 8) 
Name 
Signature 
Natalie Sacks, MD 
l'v~ ,j~~ 
Date: 
C)g Mr)_.(_ "1ol? 
NCT Number:
NCT01675765

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
Version 8, 08 March 2018 
Page ii 
This study is to be performed in accordance with Good Clinical Practice, the ethical principles that have their 
origin in the Declaration of Helsinki: Title 21 of the Code of Federal Regulations (CFR) Parts 50 (Protection of 
Human Subjects), 56 (IRBs), and 312 (INDA); and ICH E6 (Guideline for Good Clinical Practice). 
Study Sponsor: 
Aduro Biotech, Inc. 
 
740 Heinz Avenue 
 
Berkeley, CA 94710 
 
Phone: 510-848-4400 
 
Fax: 510-848-5614 
 
 
Lead Investigator: 
Raffit Hassan, M.D. 
 
Thoracic and GI Oncology Branch 
 
Head, Solid Tumor Immunotherapy Section 
 
Principal Investigator 
 
National Cancer Institute 
 
10 Center Drive 
 
Building 37, Room 5116 
 
Phone: 301-451-8742 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
Version 8, 08 March 2018 
Page iii 
STUDY SYNOPSIS 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6·7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
Title of Study: A Phase 1B Study to Evaluate the Safety and Induction of Immune Response of CRS-207 in 
Combination with Pemetrexed and Cisplatin as Front-line Therapy in Adults with Malignant Pleural Mesothelioma 
Primary Investigator: Raffit Hassan, M.D. 
Number of Sites: Up to 7 
Phase of Development: Phase 1B 
Treatment Period: 25 Weeks 
Study Duration: 7 years 
Objectives:  
Primary: To determine the safety of CRS-207 (with or without low-dose cyclophosphamide [Cy] given one day prior 
CRS-207) when administered in combination with pemetrexed and cisplatin and to evaluate the induction of immune 
response to mesothelin as measured by IFN-gamma ELISPOT assay prior to treatment and at time points during and 
after treatment. 
Secondary: To evaluate objective tumor response, progression free survival, time to progression, overall survival, and 
the predictive value of serum mesothelin for therapeutic response for each treatment regimen. 
Exploratory: i) conduct immune subset analysis (e.g. CD4, CD8, Treg) and gene expression profiling of tumor tissue 
pre- and post-vaccination; ii) to assess induction of anti-mesothelin humoral immune response; iii) to measure tumor 
marker kinetics as biomarkers of tumor response; iv) evaluate the association between pulmonary function 
improvement and tumor response; v) evaluate the relationship of tumor response to overall survival.  
Methodology:  
This is a phase 1B study to evaluate the safety and induction of immune response of CRS-207 (with or without Cy) in 
combination with pemetrexed and cisplatin in front-line therapy of adults with malignant pleural mesothelioma 
(MPM). 
 
Up to 16 subjects were originally planned to be enrolled in this study.  Up to an additional 44 subjects will be enrolled 
in an expansion phase of this study (for a total of up to 60 subjects) to obtain additional safety, immune and efficacy 
data.  Subjects will be enrolled into 2 mutually exclusive cohorts described below.   
 
Cohort 1: At least 32 subjects will receive 2 infusions (prime vaccinations; PV) of CRS-207 (1 × 109 CFU given 
intravenously [i.v.] over approximately 1 hour) 2 weeks apart followed 2 weeks later by up to 6 cycles of pemetrexed 
and cisplatin 3 weeks apart.  Three weeks after completion of chemotherapy, subjects will receive an additional 2 
infusions (boost vaccinations; BV) of CRS-207 3 weeks apart.  Subjects enrolled in Cohort 1 include the 16 subjects 
originally planned plus a minimum of the first 16 subjects enrolled into the expansion phase. 
 
Cohort 2: The remaining subjects enrolled in the expansion phase (up to 28 total) will receive CRS-207 in 
combination with chemotherapy at the dose and schedule described above, however, these subjects will also receive 
low-dose Cy (200 mg/m2) intravenously over 30 minutes one day prior to each CRS-207 infusion (i.e. prior to each 
PV and BV infusion).  Low-dose Cy inhibits regulatory T cells and enhances immune responses when given in 
context with vaccines1-3.  Preclinical studies of low-dose Cy given prior to CRS-207 in mouse tumor models have 
shown improved immunogenicity and survival (Section 1.3). 
 
All subjects will return to the clinic 4 weeks after their 2nd boost vaccination for an End of Course (EOC) visit.  
Subjects will have follow-up visits 4 weeks after the EOC visit and every 8 weeks thereafter until treatment 
I 

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page iv 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6·7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
discontinuation.  Subjects who continue to meet dosing eligibility will receive additional CRS-207 infusions 
(maintenance vaccinations; MV), with or without Cy following their original schedule, at every follow-up visit.  
Subjects may continue on treatment with radiographic disease progression if subject is clinically stable and 
investigator believes the treatment may be providing benefit. 
 
See figure below for dosing schedule (based on full regimen of 6 chemotherapy cycles).  
 
 
*Or investigator believes subject is no longer receiving benefit if treatment continued beyond radiographic progression 
 
Safety and follow-up: 
The initial safety of CRS-207 (with or without Cy), pemetrexed and cisplatin treatment will be monitored closely.  
Subjects will be followed for AEs and dose-limiting toxicities (Section 3.6) which may warrant either CRS-207 dose 
reduction or halting treatment after review by the lead investigator, sponsor and medical monitor.  A 7-day course of 
oral amoxicillin or trimethoprim/sulfamethoxazole (in penicillin-allergic subjects) will be administered to eliminate 
any residual CRS-207 beginning 7 days following the second dose (prime vaccination) of CRS-207 during the 
induction phase and after the final study dose of CRS-207.  All subjects will complete an End of Study (EOS) visit no 
more than four weeks following the final dose of study medication or prior to receipt of other cancer-related 
CRS-207
q 2 weeks
x 2 infusions
4
3
14
Weeks
5
8
11
17
20
23
26
Pemetrexed plus Cisplatin
q 3 weeks x up to 6 cycles
CRS-207
q 3 weeks 
x 2 infusions
q8wks
-
Screening
30
Immune Analysis
Follow-up
(beginning 
Week 34)
Until Disease
Progression*
1
Prime Vaccination 
(PV)
Chemotherapy Treatment
(CY)
Boost Vaccination 
(BV)
Maintenance 
Vaccinations (MV) 
CRS-207 (with or without 
CY given one day prior) 
q 8 weeks (eligible 
subjects)
(with or without CY 
given one day prior)
(with or without CY 
given one day prior)
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Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page v 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6·7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
treatment. To eliminate any potentially residual CRS-207, subjects will be administered a 7-day course of antibiotics 
beginning at the EOS visit and prior to receiving any subsequent cancer-related therapy.  Blood will be collected at 
EOS to assess the clearance of CRS-207 . 
 
Subjects will return to the study site for an End of Course (EOC) visit approximately 4 weeks after their 2nd boost 
vaccination for safety, clinical response, and immune response evaluations.  Thereafter, subjects will have follow-up 
visits 4 weeks after the EOC visit and every 8 weeks thereafter until treatment discontinuation.  Subjects will continue 
to receive maintenance vaccinations (MV) with (Cohort 2) or without Cy (Cohort 1) following their original schedule 
at each follow-up visit if they are clinically stable and continue to meet dosing eligibility. 
Number of subjects (planned):  
Up to 16 subjects with MPM who meet all eligibility criteria were originally planned to be enrolled in the study.  Up 
to 44 additional subjects (for a total of 60 subjects) with MPM who meet all eligibility criteria will be enrolled in an 
expansion phase of the study.   
Subject discontinuation:  
A subject may be removed from the study for the following reasons: 
(1) Occurrence of an adverse event that presents an unacceptable consequence or risk to the subject 
(2) Development of an illness or complication (including progressive disease) that justifies withdrawal from the 
study, as determined by the investigator and medical monitor 
(3) Noncompliance: failure to receive clinical study medication or treatment as mandated by the protocol, or failure to 
comply with protocol requirements 
(4) Study discontinued by the sponsor 
 
Subjects who withdraw consent or are removed from the study before completing at least 4 cycles of chemotherapy 
may be replaced at the discretion of the investigator and Aduro Biotech, Inc. (Aduro).  Subjects may continue on 
treatment with radiographic disease progression if subject is clinically stable and the investigator believes the 
treatment is providing benefit. 

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page vi 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6ꞏ7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
Inclusion criteria: Subjects must meet all of the following criteria to be eligible to participate in the study: 
(1) 
Subjects must have histologically-confirmed epithelial or biphasic pleural mesothelioma not amenable to 
potentially curative surgical resection at the time of study entry (subjects with biphasic tumors that have a 
predominantly (≥50%) sarcomatoid component will be excluded) 
(2) 
Measurable disease, as defined by modified RECIST for MPM 4 
(3) 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
(4) 
Normal organ and marrow function, as defined by: 
 
ANC ≥ 1,500/µl 
 
Platelet count ≥ 100,000/µl 
 
Bilirubin ≤ 1.5 × upper limit of normal (ULN), or bilirubin ≤ 3× ULN if due to Gilbert’s disease 
 
AST and ALT ≤ 2.5× ULN  
 
Albumin ≥ 2.5 g/dL 
 
Creatinine clearance ≥ 50 mL/min per Cockcroft-Gault formula (Creatinine Clearance = {[(140-age) x weight 
in kilograms] x [0.85 if female]}/[72 x creatinine in mg/dL]) 
 
CD4 ≥ 0.2×109/L 
 
Hemoglobin ≥9.0 g/dL 
(5) 
Age 18 years and over 
(6) 
Must have pulmonary function testing with documented values for VC and FEV1 > 45% of predicted value and 
oxygen saturation ≥ 90% on room air, as measured by pulse oximeter 
(7) 
Anticipated life expectancy greater than 6 months 
(8) 
Female subjects of childbearing potential must consent to use a medically acceptable method of highly effective 
contraception (oral hormonal contraceptive, condom plus spermicide, or hormone implants) throughout the study 
period and for 28 days after their final study drug administration (A barrier method of contraception must be 
employed by all subjects (male and female), regardless of other methods) 
(9) 
Subject provides informed consent and is willing and able to comply with all study procedures 
Exclusion criteria: Subjects must not meet any of the following criteria to be eligible to participate in the study: 
(1) 
Be a candidate for curative surgery at the time of study entry 
(2) 
Have had surgery or pleurodesis within 2 weeks prior to dosing 
(3) 
Have had prior radiotherapy (except palliative extra-thoracic localized radiotherapy) or biologic therapy for 
MPM within 3 weeks prior to dosing 
(4) 
Have had prior systemic chemotherapy for MPM. Prior intracavitary cytotoxic drugs or immunomodulators are 
not permitted, unless given for the purpose of pleurodesis 
(5) 
Have an active malignancy with the exception of any of the following:  
 
adequately treated basal cell carcinoma  
 
squamous cell carcinoma of the skin, or in situ cervical cancer  
 
adequately treated Stage I cancer from which the subject is currently in remission and has been in 
remission for ≥3 years  
 
Stage I prostate cancer that does not require treatment 
 
any other cancer from which the subject has been disease-free for ≥ 2 years 
(6) 
Have documented and ongoing central nervous system (CNS) involvement with their malignant disease [history 
of CNS involvement is not an exclusion criterion but the CNS metastases should have been adequately treated 

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page vii 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6ꞏ7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
(radiation or surgical resection) and subjects are neurologically stable for 3 months off steroids]   
(7) 
Have any evidence of clinically significant ascites   
(8) 
Have clinically significant pleural effusion 
(9) 
Have clinically significant heart disease (such as uncontrolled angina, myocardial infarction within 3 months, 
congestive heart failure of New York Heart Association III or IV) 
(10) Have valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis, consistent with 
American Heart Association (AHA) guidelines 
(11) History of any autoimmune disease, including patients with a history of inflammatory bowel disease, (including 
ulcerative colitis and Crohn’s Disease), patients with a history of symptomatic disease (e.g. rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g. 
Wegener’s granulomatosis]); central nervous system or motor neuropathy considered of autoimmune origin (e.g. 
Guillain-Barre Syndrome, Myasthenia gravis, multiple sclerosis). Patients with Graves’, Hashimoto’s Disease, 
vitiligo, and diabetes type 1 will be allowed 
(12) Have any immunodeficiency disease or immune-compromised state (e.g. use of immunosuppressive agents) 
within 28 days of study treatment 
(13) Baseline coagulopathy > Grade 3 unless due to anticoagulant therapy 
(14) Peripheral neuropathy ≥ Grade 2 
(15) Use of systemically-active steroids within 14 days of study treatment 
(16) Use of more than 3 grams per day of acetaminophen 
(17) Use of aspirin or other nonsteroidal anti-inflammatory drugs for 2 days before, during, and for 2 days after each 
administration of pemetrexed disodium (5 days before, during, and 2 days after each administration of 
pemetrexed disodium for piroxicam, naproxen, diflunisal, or nabumetone) 
(18) Have received an investigational product within 28 days of study treatment  
(19) Have a known allergy to both penicillin and sulfa drugs 
(20) Have known or suspected allergy or hypersensitivity to yeast or any other component of CRS-207 (e.g. glycerol), 
Platinol or platinum-containing compounds, or pemetrexed 
(21) Have received a diagnosis of HIV, hepatitis B, or hepatitis C (exception: clear evidence of natural immunity, 
immunity subsequent to vaccination, or successful eradication of the virus following antiviral therapy)  
(22) Be a woman who is pregnant or breastfeeding 
(23) Have prosthetic heart valves; major implant(s) or device(s) (e.g. artificial joints and prosthetics) placed within 12 
months of study screening; or current or prior history of infection or clinically significant adverse events (AEs) 
associated with an exogenous implant(s) or device(s) that cannot be easily removed 
(24) Have had major surgery or significant traumatic injury occurring within 28 days prior to CRS-207 administration 
or anticipated surgery or procedure requiring general anesthesia or deep sedation during study participation 
(including 28 days after last dose of CRS-207) (Minor procedures [dental work, skin biopsy, etc.] celiac plexus 
block, and biliary stents are allowed.) 
 

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page viii 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6ꞏ7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
Exclusion criteria, continued:  
(25) Have an unhealed wound which increases risk for bacterial infection 
(26) Be unable to avoid intimate contact with another individual known to be at high risk of listeriosis (e.g. newborn 
infant, pregnant female, etc.) for at least 7 days after receiving a CRS-207 infusion 
(27) Have an intercurrent illness that is either life-threatening or of clinical significance such that it might limit 
compliance with study requirements (including, but not limited to, ongoing or active infection, metabolic (e.g. 
diabetes) or neurologic disease, peripheral vascular disease, or psychiatric illness/social situations) 
(28) Have insufficient peripheral venous access to permit completion of the study dosing and compliance with study 
phlebotomy regimen 
(29) Have a history of alcohol dependence or use of illicit drugs that could potentially interfere with adherence to 
study procedures or requirements (e.g. opioids, cocaine, amphetamines, hallucinogens, etc.)  
Dose eligibility: 
Subjects must have adequate organ function as defined by the laboratory values in Table 1 before dosing of CRS-207.  
Laboratory tests may be done up to 3 days prior to CRS-207 dosing or 2 days prior to Cy for subjects receiving Cy.  
Delayed doses will be discussed with the medical monitor. 
 
Table 1. Dosing-Eligibility Requirements 
Hematologic 
Renal 
Hepatic 
ANC ≥1,500/µL 
Platelets ≥100,000/µl 
Hemoglobin ≥9 g/dL 
CD4 ≥ 0.2×109/L prior to 1st post-
chemotherapy CRS-207 boost vaccination  
Creatinine ≤2.0 × ULN 
AST/ALT ≤2.5× ULN 
Bilirubin ≤1.5× ULN or 
bilirubin ≤ 3× ULN if due to 
Gilbert’s disease 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal; WBC = white 
blood cell. 
* Cockcroft-Gault formula: Creatinine Clearance = {[(140-age) x weight in kilograms] x [0.85 if female]}/[72 x creatinine in mg/dL] 

Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
STUDY SYNOPSIS (continued) 
Version 8, 08 March 2018 
Page ix 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6·7H2O 
Cisplatin: PtCl2H6N2
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
Prohibited medications: 
The following therapies are not permitted during the study and may result in early termination of the subject from 
treatment: 
•
Non-study chemotherapy or immunotherapy (approved or investigational)
•
Systemically active steroids for more than 3 days or use of any systemic steroids within 14 days before or after
dosing, with exception of study-prescribed steroids.
•
TNF pathway inhibitors or PI3 kinase inhibitors
•
Any other investigational product
In addition, the following therapies should not be administered unless medically necessary, and approval must be 
obtained from the medical monitor for a subject to continue dosing if therapy is given concurrently with study 
participation: 
•
General anesthesia or deep sedation
•
Aspirin >325 mg/d (chronic daily use of aspirin ≤325 mg/d and heparin flushes for central lines are allowed)
•
More than 4 g/d of acetaminophen
•
Systemic antibiotics
If subjects receive immunosuppressive medications on or after study, prophylactic antibiotics to prevent CRS-207 
infection are strongly recommended for the duration of the treatment with the immunosuppressant (recommended oral 
80 mg trimethoprim / 400 mg sulfamethoxazole once daily or 160 mg trimethoprim / 800 mg sulfamethoxazole (DS) 
three days a week). 
Filgrastim (Neupogen or G-CSF) or Sargramostin (Leukine or GM-CSF) should not be administered 14 days prior to 
or 14 days after any CRS-207 dose.  Approval must be obtained from the medical monitor for a subject to continue 
dosing if administered within this timeframe. 
Prophylactic vaccines (e.g. pneumococcal vaccine, influenza vaccine) should not be administered 28 days prior to or 
28 days after any CRS-207 dose.  Approval must be obtained from the medical monitor for a subject to continue 
dosing if a prophylactic vaccine is administered within this timeframe.   

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page x 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6·7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
Test product, dose, and mode of administration:  
CRS-207 [Cohort 1 and Cohort 2]: CRS-207, live-attenuated Lm encoding human mesothelin, will be given i.v. 
over approximately 1 hour at 1 × 109 colony-forming units (CFU); reconstituted in approximately 100 mL 0.9% 
sodium chloride for 2 infusions (prime vaccinations) 2 weeks apart prior to receiving pemetrexed and cisplatin 
chemotherapy, and for 2 infusions (boost vaccinations) 3 weeks apart following chemotherapy.  Subjects who 
continue to meet dosing eligibility will receive maintenance vaccinations of CRS-207 beginning at the first follow-up 
visit and every 8 weeks thereafter during follow-up phase. 
Pemetrexed [Cohort 1 and Cohort 2]: ALIMTA®, pemetrexed disodium heptahydrate (pemetrexed), has a 
recommended dose of 500 mg/m2 body surface area (BSA) in 100mL 0.9% sodium chloride administered over 10 
minutes as an intravenous infusion on Day 1 of a 21-day cycle.  Up to 6 cycles of pemetrexed and cisplatin will be 
given after the initial 2 infusions of CRS-207. 
Cisplatin [Cohort 1 and Cohort 2]: Cisplatin, USP (cis-diamminedichloroplatinum), has a recommended dose of 75 
mg/m2 BSA in 1L 0.9% sodium chloride with mannitol 30g/L infused over 2 hours, beginning approximately 30 
minutes after the end of pemetrexed administration on Day 1 of each 21-day cycle.  Up to 6 cycles of pemetrexed and 
cisplatin will be given after the initial 2 infusions of CRS-207. 
Cyclophosphamide [Cohort 2]: 200 mg/m2 in 100 mL normal saline administered by i.v. infusion over 30 minutes 
one day prior to CRS-207. 
Study duration:  
The duration of one full treatment course [i.e. CRS-207 with or without Cy (2 infusions, 2 weeks apart), pemetrexed 
(500 mg/m2) and cisplatin (75 mg/m2) every 3 weeks × 6 cycles, CRS-207 with or without Cy (2 infusions, 3 weeks 
apart)] is 25 weeks.  Subjects enrolled in Cohort 1 will receive CRS-207 and pemetrexed and cisplatin per the 
schedule described above.  Subjects enrolled in Cohort 2 will receive Cy/CRS-207 and pemetrexed and cisplatin per 
the schedule described above.  Clinical and immune response assessments will be performed 4 weeks after EOC.  
Eligible subjects will receive maintenance vaccinations of CRS-207 (with or without Cy) beginning at the first follow-
up visit and every visit thereafter.   
Reference therapy, dose, and mode of administration:  
There is no reference therapy or placebo administered in this study.   
Criteria for Evaluation: 
Safety: Safety will be assessed by collection of data on AEs, vital signs, physical examination, clinical hematology, 
serum chemistry, deaths, and blood cultures for CRS-207 clearance.   
Efficacy: Induction of immune response to mesothelin will be evaluated by IFN-gamma ELISPOT assay prior to 
treatment and at time points during and after treatment.  Other evaluations will include immune subset analysis (e.g. 
CD4, CD8, Treg) by immunohistochemistry and gene expression profiling of tumor tissue pre and post vaccination, 
evaluating induction of anti-mesothelin humoral immune response by ELISA, assessing tumor marker kinetics by 
measuring serum levels of mesothelin and CA-125 and plasma osteopontin.  Objective tumor response, progression 
free survival and time to progression will be measured using modified RECIST for assessment of response in MPM 
(Appendix A) and immune-related response criteria (irRC; Appendix B).  Pulmonary function will be measured by 
forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and vital capacity (VC).   
Data analysis: 
The sample size of the study was originally planned to enroll up to 16 subjects in order to evaluate the induction of 

 
 
 
 
Aduro Biotech, Inc. 
Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
 
 
 
 
 STUDY SYNOPSIS (continued) 
  
 
Version 8, 08 March 2018 
Page xi 
Name of Sponsor Company: 
Aduro Biotech, Inc. 
Individual Study Table 
Referring to Part of the Dossier 
 
Volume: 
 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
CRS-207; pemetrexed; cisplatin; 
cyclophosphamide 
Name of Active Ingredients: 
Pemetrexed: C20H19N5Na2O6·7H2O 
Cisplatin: PtCl2H6N2 
CRS-207: Lm ΔactA/ΔinlB/hMeso 
Cyclophosphamide (Cy): 
C7H15Cl2N2O2P•H2O 
immune response to mesothelin and initial safety of CRS-207 combined with pemetrexed and cisplatin chemotherapy.  
Up to 44 additional subjects will be enrolled in an expansion phase to obtain additional safety, immune and 
preliminary efficacy data.  At least 32 subjects will be enrolled in Cohort 1 and up to 28 subjects will be enrolled in 
Cohort 2.  The expansion cohort of up to 44 additional subjects, including subjects receiving Cy one day prior to 
CRS-207 (Cohort 2) is intended to obtain additional safety, immune and efficacy data for future study planning.  The 
expansion sample size is based on practical rather than statistical considerations.   
These data will be summarized in tables listing the mean, standard deviation, median, minimum, maximum, and 
number of subjects in a group for continuous data; in tables listing count and percentage for categorical data; and 
median and standard error for time-to-event data.  Data will be listed for each subject.  Statistical analyses will be 
performed and data appendices will be created by using SAS.  The effects of noncompliance, dropouts, and covariates 
will be assessed to determine the impact on the general applicability of results from this study.   
Efficacy analyses will be conducted on the full analysis set and per protocol analysis set.  The full analysis set will 
consist of all subjects who receive at least one dose of any study treatment.  The per protocol analysis set will consist 
of all subjects with MPM who receive the initial 2 prime vaccinations with CRS-207 (with or without Cy) and at least 
4 cycles of pemetrexed and cisplatin. 

 
 
 
 
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TABLE OF CONTENTS 
 
Page 
STUDY SYNOPSIS .............................................................................................................................................. iii 
LIST OF FIGURES AND TABLES .................................................................................................................... xv 
LIST OF APPENDICES ..................................................................................................................................... xvi 
LIST OF ABBREVIATIONS ............................................................................................................................ xvii 
1.0 
INTRODUCTION .................................................................................................................................. 1 
1.1 
BACKGROUND...................................................................................................................................... 1 
1.1.1 
Current Therapies for Malignant Mesothelioma ...................................................................... 1 
1.1.2 
Mesothelin ............................................................................................................................... 1 
1.1.3  
Listeria monocytogenes (Lm)-Based Vaccine Therapy ........................................................... 2 
1.2 
RATIONALE FOR COMBINATION OF CRS-207 AND CHEMOTHERAPY .................................... 5 
1.3 
RATIONALE FOR USE OF LOW-DOSE CYCLOPHOSPHAMIDE AND CRS-207 .......................... 7 
2.0 
OBJECTIVES ........................................................................................................................................ 9 
2.1 
PRIMARY OBJECTIVE ......................................................................................................................... 9 
2.2 
SECONDARY OBJECTIVES ................................................................................................................. 9 
2.3 
EXPLORATORY OBJECTIVES ............................................................................................................ 9 
3.0 
STUDY DESIGN .................................................................................................................................. 10 
3.1 
BASIC DESIGN CHARACTERISTICS ............................................................................................... 10 
3.2 
STUDY POPULATION ........................................................................................................................ 12 
3.2.1 
Inclusion Criteria ................................................................................................................... 12 
3.2.2 
Exclusion Criteria .................................................................................................................. 13 
3.2.3 
Dosing Eligibility .................................................................................................................. 16 
3.3 
ENDPOINTS ......................................................................................................................................... 17 
3.3.1 
Primary Endpoint ................................................................................................................... 17 
3.3.2 
Secondary Endpoints ............................................................................................................. 17 
3.3.3 
Exploratory Endpoints ........................................................................................................... 17 
3.4 
RANDOMIZATION AND BLINDING ................................................................................................ 18 
3.5 
REPLACEMENT OF DROPOUTS ....................................................................................................... 18 
3.6 
DOSE-LIMITING TOXICITIES ........................................................................................................... 18 
4.0 
DRUGS AND DOSAGES .................................................................................................................... 20 
4.1 
IDENTIFICATION AND DESCRIPTION OF CLINICAL TRIAL MATERIAL (CTM) ................... 20 
4.1.1 
CTM ...................................................................................................................................... 20 
4.1.2 
Labeling ................................................................................................................................. 21 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE .................................................................................... 21 
4.2.1  
Cyclophosphamide ................................................................................................................ 21 
4.2.2 
CRS-207 ................................................................................................................................ 21 
4.2.3 
Pemetrexed ............................................................................................................................ 23 
4.2.4 
Cisplatin ................................................................................................................................. 23 
4.2.5 
Delayed Dosing ..................................................................................................................... 24 
4.3 
STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL .................................................. 24 
4.3.1 
Cyclophosphamide ................................................................................................................ 24 
4.3.2 
CRS-207 ................................................................................................................................ 25 
4.3.3 
Environmental Precautions .................................................................................................... 25 

 
 
 
 
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4.4 
PRODUCT ACCOUNTABILITY ......................................................................................................... 26 
4.5 
PRIOR, CONCOMITANT, AND EXCLUDED THERAPY ................................................................ 26 
5.0 
EXPERIMENTAL PROCEDURES ................................................................................................... 29 
5.1 
OVERVIEW: SCHEDULE OF TIME AND EVENTS ......................................................................... 29 
5.2 
STUDY PROCEDURES........................................................................................................................ 36 
5.2.1 
Screening Period (28 days prior to first study dose) .............................................................. 36 
5.2.2 
Treatment Period ................................................................................................................... 38 
5.2.3 
Study Follow-up Period/End of Study (EOS) ........................................................................ 45 
5.3 
LABORATORY EVALUATIONS ....................................................................................................... 46 
5.3.1 
Immune Monitoring Assessments ......................................................................................... 46 
5.3.2 
Tumor Markers ...................................................................................................................... 47 
5.3.3 
Tumor Biopsy ........................................................................................................................ 48 
5.3.4  
Blood Cultures for CRS-207 Surveillance ............................................................................. 49 
6.0 
PROCEDURES FOR HANDLING AES AND SAES ....................................................................... 50 
6.1 
DEFINITION OF AN ADVERSE EVENT ........................................................................................... 50 
6.2 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ................................................................. 51 
6.3 
RECORDING AEs AND SAEs ............................................................................................................. 52 
6.4 
ASSESSMENT OF GRADE ................................................................................................................. 53 
6.5 
ASSESSMENT OF CAUSALITY ......................................................................................................... 54 
6.6 
REPORTING OF SAEs ......................................................................................................................... 55 
6.7 
FOLLOW-UP OF AEs AND SAEs ....................................................................................................... 57 
6.8 
ADVERSE EVENTS OF SPECIAL INTEREST .................................................................................. 57 
6.8.1 
Suspected Infection with CRS-207 or Listeria ...................................................................... 57 
7.0 
STUDY OR STUDY SITE TERMINATION AND SUBJECT DISCONTINUATION................. 59 
7.1 
PREMATURE STUDY OR STUDY SITE TERMINATION ............................................................... 59 
7.2 
SUBJECT DISCONTINUATION ......................................................................................................... 59 
7.2.1 
Adverse Event ....................................................................................................................... 60 
7.2.2 
Intercurrent Illness ................................................................................................................. 60 
7.2.3 
Noncompliance ...................................................................................................................... 60 
7.2.4 
Refusal of CTM Administration ............................................................................................ 61 
8.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS .......................... 62 
8.1 
DATA COLLECTION AND PROCESSING ........................................................................................ 62 
8.2 
STATISTICAL ANALYSIS .................................................................................................................. 63 
8.2.1 
General Overview .................................................................................................................. 63 
8.2.2 
Populations of Interest ........................................................................................................... 63 
8.2.3 
Baseline Comparability ......................................................................................................... 63 
8.2.4 
Efficacy Analysis ................................................................................................................... 64 
8.2.5 
Safety Analysis ...................................................................................................................... 65 
8.2.6 
Pharmacokinetic Analysis ..................................................................................................... 65 
8.2.7 
Interim Analysis .................................................................................................................... 65 
8.2.8 
Sample Size ........................................................................................................................... 65 
 

 
 
 
 
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9.0 
CLINICAL STUDY ADMINISTRATION ........................................................................................ 67 
9.1 
INFORMED CONSENT AND AUTHORIZATION FOR USE AND DISCLOSURE OF PHI ........... 67 
9.2 
STUDY DOCUMENTATION .............................................................................................................. 67 
9.2.1 
Investigator Information ........................................................................................................ 67 
9.2.2 
Investigator Study Files ......................................................................................................... 67 
9.2.3 
CRFs and Source Documentation .......................................................................................... 68 
9.2.4 
Retention of Study Documents .............................................................................................. 68 
9.3 
CONFIDENTIALITY ............................................................................................................................ 69 
9.3.1 
Data ....................................................................................................................................... 69 
9.3.2 
Subject Anonymity ................................................................................................................ 69 
9.4 
PROTOCOL COMPLIANCE ................................................................................................................ 69 
9.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY ............................................................. 70 
9.6 
GENERAL INFORMATION ................................................................................................................ 70 
10.0 
REFERENCES ..................................................................................................................................... 71 
 

 
 
 
 
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LIST OF FIGURES AND TABLES 
 
Page 
 
Figure 1.  
Cyclophosphamide Followed by CRS-207 Improves Vaccine Potency. .......................................... 8 
Figure 2.  
Study Treatment Timeline, Doses Scheduled and Follow-up ......................................................... 11 
Table 1. 
Dosing-Eligibility Requirements .................................................................................................... 16 
Table 2a. 
CRS-207 and Pemetrexed/Cisplatin [Cohort 1] .............................................................................. 30 
Table 2b. 
Schedule of Procedures – Low-dose Cy/CRS-207 and Pemetrexed/Cisplatin [Cohort 2] .............. 33 
Table 3. 
Assessment of Causality/Relatedness of AEs ................................................................................. 55 
 
 

 
 
 
 
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LIST OF APPENDICES 
 
 
Appendix A 
Modified RECIST for Assessment of Response in MPM 
Appendix B 
Immune-related Response Criteria (irRC) Quick Reference 
Appendix C 
ALIMTA Prescribing Information 
Appendix D 
PLATINOL Prescribing Information 
Appendix E 
CYCLOPHOSPHAMIDE Prescribing Information 
 

 
 
 
 
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LIST OF ABBREVIATIONS 
 
ActA 
Listeria monocytogenes protein encoded by actA gene  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
code of federal regulations 
CFU 
colony-forming unit 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
common terminology criteria for AEs 
CTM 
clinical trial material 
Cy 
cyclophosphamide 
DLTs 
dose-limiting toxicities 
DTH 
delayed type hypersensitivity 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
ELISPOT 
enzyme-linked immunosorbent spot 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography   
FEV1 
forced expiratory volume in 1 second 
FNA 
fine needle aspiration 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
hMeso 
human mesothelin 
IB 
Investigator’s Brochure 
IBC 
institutional biosafety committee 
ICF 
informed consent form 
ICH 
international conference on harmonisation 
InlB 
protein encoded by inlB gene  
IRB 
institutional review board 
irRC 
immune-related response criteria 
i.v. 
intravenous 
LDH 
lactate dehydrogenase 
Lm 
Listeria monocytogenes 
MPM 
malignant pleural mesothelioma 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NIH OBA 
National Institutes of Health Office of Biotechnology Activities 
PBMC 
peripheral blood mononuclear cells 
PHI 
protected health information 
p.o. 
per oral 
PT 
prothrombin time 
RECIST 
response evaluation criteria in solid tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
SPM 
study procedures manual 
UA 
urinalysis 
ULN 
upper limit of normal 
VC 
vital capacity 
WBC 
white blood cell 
 

 
 
 
 
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1.0 
INTRODUCTION 
1.1 
BACKGROUND 
Malignant mesothelioma is a rare tumor that arises from mesothelial cells.  
Approximately 2,000 to 4,500 new cases of mesothelioma are diagnosed in the 
United States each year.5,6  Pleural mesothelioma is most common, but 
mesothelioma can also occur in the peritoneum and pericardium.  In the United 
States, the majority of mesotheliomas occur in men (approximately 80%).  These 
are most often of pleural origin, and 90% or more of these tumors are caused by 
asbestos.6-8  
1.1.1 
Current Therapies for Malignant Mesothelioma 
The best-documented, potentially curative approach to malignant pleural 
mesothelioma (MPM) has been extrapleural pneumonectomy, followed by 
chemotherapy and radiotherapy in selected patients with earlier stages of 
disease,6,9 but the majority of patients present with advanced disease and are not 
candidates for surgical resection.  For patients whose disease is unresectable or 
who otherwise are not candidates for curative surgery, pemetrexed in combination 
with cisplatin is the standard of care.  In a randomized Phase 3 clinical trial 
treatment with pemetrexed and cisplatin led to an improvement in overall survival 
of 12.7 months compared to 9.3 months with cisplatin alone.  The objective 
response rate was 41%.10,11  It is clear that new therapies are needed, and 
immunotherapy offers the promise of improving outcomes in these patients by 
developing specific immune responses against tumor antigens.  In support of this 
notion, the presence of high levels of CD8+ tumor-infiltrating lymphocytes is 
associated in better prognosis in patients undergoing extrapleural pneumonectomy 
for MPM.12 
1.1.2 
Mesothelin 
Mesothelin is a cell surface tumor differentiation antigen present on normal 
mesothelial cells that is highly expressed in many human tumors including 
virtually all mesothelioma and pancreatic cancers, 55% to 71% of ovarian cancers 
and 41% to 55% of lung adenocarcinomas.13-19  The limited distribution of 
mesothelin in normal human tissues and high expression in many cancers makes it 
an attractive candidate for antibody-targeted immunotherapy and clinical trials of 
anti-mesothelin antibodies are currently ongoing.20,21  Studies by Dr. Raffit 
Hassan, the Principal Investigator of the proposed trial, and his colleagues as well 

 
 
 
 
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as other groups have shown mesothelin to be also an attractive antigen for active 
cancer immunotherapy.  Dr. Hassan and colleagues have previously shown that a 
mesothelin-specific IgG antibody response is present in 39% and 42% of patients 
with mesothelioma and ovarian cancer respectively, suggesting that immune 
tolerance to mesothelin can be overcome.22  In addition, studies by Dr. Elizabeth 
Jaffee and colleagues have demonstrated that in patients with pancreatic 
carcinoma, positive clinical outcomes following vaccination with an irradiated 
allogeneic 
whole 
cell 
vaccine 
encoding 
granulocyte/macrophage-colony 
stimulating factor (GM-CSF; GVAX) correlated with induction of mesothelin-
specific cellular immunity.23,24  In a Phase 1 study, a vaccine with two allogeneic, 
GM-CSF-secreting pancreatic cell lines induced a dose-dependent delayed type 
hypersensitivity (DTH) response and CD8+ T cell response to multiple human 
leukocyte antigen (HLA)-A2, -A3, and –A24 restricted mesothelin epitopes 
exclusively in 3 of 14 patients.  Patients with DTH and CD8+ T cell responses 
had increased disease-free survival, remaining disease-free at least 25 months 
after diagnosis.  Additionally, Dr. Hassan in collaboration with Dr. Jeff Schlom at 
the National Cancer Institute (NCI) elucidated the immunogenic epitopes of 
mesothelin and showed that mesothelin-specific T cells cause lysis of 
mesothelioma tumor cells.25  The mesothelin-targeting therapeutic cancer vaccine 
furthest along in clinical development is CRS-207, a live-attenuated strain of the 
bacterium Listeria monocytogenes (Lm) encoding human mesothelin (hMeso).26,27 
1.1.3  
Listeria monocytogenes (Lm)-Based Vaccine Therapy  
Lm is an attractive platform for presentation of tumor-associated antigens and 
activation of immune response directed against cancer cells.  Lm provides both a 
potent stimulation of innate immunity and also stimulates an adaptive immune 
response through recruitment and activation of CD4+ and CD8+ T-cell immunity 
specific for encoded heterologous antigens.28-31  Aduro Biotech, Inc. (Aduro) 
developed a live-attenuated Lm platform strain (Lm ∆actA/∆inlB), known as 
ANZ-100 (previously CRS-100), which has deletions of two genes, actA and inlB, 
that encode the virulence-determinant proteins ActA and Internalin B, 
respectively27.  These two proteins facilitate cell-to-cell spread and invasion of 
nonphagocytic cells, and deletion of actA and inlB in ANZ-100 results in 
1,000-fold attenuation of these processes in mice as compared with wild-type 
Lm.32, 29  Uptake of ANZ-100 by macrophages and other phagocytic cells in the 
liver and spleen is still retained and results in a local inflammatory response as 
well as activation and recruitment of natural killer cells and T cells to the liver.  
ANZ-100 underwent clinical evaluation in a Phase 1 dose-escalation study in 

 
 
 
 
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adults with carcinoma and liver metastases and was found to be safe and well 
tolerated in 9 subjects given intravenous doses up to 3 × 108 colony-forming units 
(CFU).  Additionally, no shedding of ANZ-100 in urine, stools, or sputum was 
observed at any dose. 
ANZ-100 has additionally been engineered to express mesothelin and the 
resulting strain has been termed CRS-207.  After uptake of CRS-207 by dendritic 
cells and macrophages, mesothelin is expressed and released into the cytosolic 
compartment and subsequently processed through the endogenous MHC Class I 
presentation pathway, resulting in activation of mesothelin-specific T cell-
mediated immunity.  Other mechanisms to activate mesothelin-specific, cell-
mediated immunity may include uptake and cross-presentation of antigens by 
dendritic cells and other cells after infection by CRS-207 and apoptosis.   
Nonclinical studies have shown that CRS-207 elicits mesothelin-specific cellular 
immunity in mice and nonhuman primates and demonstrates therapeutic efficacy 
in tumor-bearing mice (refer to the Investigator’s Brochure [IB] for details).  
Findings in a Good Laboratory Practice repeated-dose study in cynomolgus 
monkeys showed that treatment with up to 3 × 1010 CFU of CRS-207 resulted in 
no changes related to body weight, food consumption or body temperature and in 
no findings related to ocular or functional cardiovascular evaluations.  CRS-207 
was detected in the blood at 24 hours after administration, but was undetectable at 
72 hours.  There were transient and dose-dependent decreases in red blood cell, 
platelet and white blood cell (WBC) counts.  Hepatic and renal function changes 
were transient and generally less than two-fold from that at baseline status.  A 
Phase 1 study (VAC07001; NCT00585845) has been completed with CRS-207 to 
determine the maximum tolerated dose and to explore the safety profile in 
subjects with advanced mesothelioma, non–small-cell lung cancer, ovarian cancer 
or pancreatic adenocarcinoma who had failed standard therapy.26  CRS-207 was 
found to be well tolerated at doses up to 1 × 109 CFU.  Adverse events (AEs) such 
as fevers, chills, and nausea reported as the most common, immediate, transient, 
mild, and temporally related to CRS-207 administration were self-correcting and 
were resolved by the time of the subjects’ discharge.  Lymphopenia was observed 
in all doses (1 × 108, 3 × 108, 1 × 109 and 1 × 1010 CFU), and transaminase 
elevations were observed at doses of 3 × 108, 1 × 109 and 1 × 1010 CFU.  Both 
were dose-dependent, although transient and not considered clinically significant.  
Two CRS-207-related serious adverse events (SAEs) were reported.  One SAE of 
moderate constipation occurred in one subject after the second dose of CRS-207 
at 1 × 108 CFU.  The second SAE, a significant decrease in blood pressure (BP) 

 
 
 
 
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after infusion, occurred in another subject after one dose of CRS-207 at 1 × 1010 
CFU.  This subject required aggressive fluid management and recovered to 
baseline status within 24 hours.  This dose level was subsequently discontinued 
and confirmed the maximum tolerated dose (MTD) as 1 × 109 CFU.  No shedding 
of CRS-207 in urine or stools was observed at any dose.   
While the VAC07001 study enrolled subjects with multiple disease types and was 
not powered to assess survival, 6 of 17 subjects survived for ≥ 15 months.  Of 
these 6 “long-term” survivors, 3 had pancreatic cancer, 2 had non-small-cell lung 
cancer, and 1 had mesothelioma.  All 6 subjects had prior immunotherapy or 
subsequent local radiation.  Five of 6 subjects received all 4 doses of CRS-207 
and all 5 evaluable subjects demonstrated vaccine-induced Lm-specific responses.  
In addition, 4 of the 5 evaluable subjects among the long-term survivors had 
stable disease by RECIST at day 91 (end of study).    
As 3 of the 6 “long-term” survivors were pancreatic cancer patients had 
previously received GVAX pancreas vaccine in separate clinical studies, CRS-
207 
in 
combination 
with 
GVAX 
pancreas 
vaccine 
(with 
low-dose 
cyclophosphamide [Cy]) is currently being evaluated in a Phase 2 study in 
metastatic pancreatic cancer patients who have received or refused chemotherapy 
(Protocol ADU-CL-01; NCT01417000).  Enrollment has been completed in this 
study and a recent interim analysis showed a significant improvement in median 
overall survival in subjects who received GVAX pancreas vaccine and CRS-207 
compared to subjects who received GVAX pancreas vaccine alone (6.0 months 
vs. 3.4 months; one-sided p=0.0.0057).  These interim data were reviewed by an 
independent data monitoring committee who recommended that the study be 
stopped for efficacy and subjects on the GVAX pancreas vaccine arm offered 
rollover treatment with GVAX pancreas vaccine and CRS-207.  FDA concurred 
with this decision.  Subjects in the study continue to receive treatment and all 
subjects are being followed for survival, safety and clinical and immune 
responses.  Safety findings have been consistent with prior clinical experience.  
The most frequent Grade 3/4 related toxicities were fever, lymphopenia, 
hypophosphatemia, elevated liver enzymes and fatigue following CRS-207 in 
<5% of subjects.  To date, there have been no treatment-related SAEs, significant 
laboratory abnormalities or safety signals.  
Another Phase 2 study for pancreatic cancer, ADU-CL-04, was initiated in 2014.  
This study enrolls subjects with previously-treated metastatic pancreatic cancer 
for evaluation of GVAX pancreas vaccine (with low-dose Cy) and CRS-207 

 
 
 
 
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compared to CRS-207 alone or single-agent chemotherapy alone.  As of February 
2015, over 200 subjects have been enrolled and there have been three SAEs 
reported as unexpected and related to CRS-207: Grade 3 confusion, Grade 3 
hypoxia and Grade 3 hypertension.  A second Phase 2 study in previously-treated 
metastatic pancreatic cancer was initiated in January 2015 which is evaluating 
GVAX pancreas vaccine (with low-dose Cy) and CRS-207 with and without anti-
PD-1 antibody (nivolumab) in 88 subjects.  Six patients have been treated with no 
significant toxicities or SAEs reported. 
1.2 
RATIONALE FOR COMBINATION OF CRS-207 AND 
CHEMOTHERAPY 
The combination of vaccines with chemotherapy has traditionally not been used 
due to the possibility of post-chemotherapy leukopenia eliminating antitumor 
directed lymphocytes.  Emerging data, however, suggest that vaccines and 
chemotherapies may be synergistic by augmenting anti-tumor effectiveness of 
subsequent chemotherapies.33,34  Proposed mechanisms of synergy for activating 
relatively dormant T cells include chemotherapy-induced alterations in tumor 
microenvironment, up-regulation of MHC class I and numerous tumor-associated 
antigens on the surface of tumor cells, reduction of suppressor cell populations 
and tumor lysis followed by cross priming.35-37  
Synergistic activity of combinations of immunotherapy and chemotherapy is also 
supported by clinical studies.  High chemotherapy response rates were observed 
in patients with small-cell lung cancer who developed an immunologic response 
to an Ad.p53-dendritic cell vaccine.38  Advanced-stage cancer patients who 
developed immunity to cytochrome P4501B1 following administration of a 
plasmid/microparticle vaccine showed marked response to a subsequent 
chemotherapy regimen.39  Patients with metastatic androgen independent prostate 
cancer who received recombinant viral vectors containing the PSA and B7.1 
genes followed by docetaxel had a longer time to progression than patients who 
received docetaxel alone40.  Glioblastoma patients vaccinated with autologous 
tumor-pulsed dendritic cell vaccine who received subsequent chemotherapy 
exhibited significantly longer times to tumor recurrence after chemotherapy 
relative to their own previous recurrence times, as well as significantly longer 
post-chemotherapy recurrence times and survival relative to patients receiving 
isolated vaccination or chemotherapy.41,42  In mesothelioma patients, three 
vaccinations at two week intervals with autologous tumor lysate-pulsed dendritic 

 
 
 
 
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cells following chemotherapy with cisplatin/pemetrexed induced tumor specific 
CD8+ T lymphocyte activity in four of the six patients.43   
CRS-207 has been shown to be safe and well-tolerated at the proposed route of 
administration and dose for this study.26  Five subjects with mesothelioma were 
enrolled in the Phase 1 study and tolerated the treatment at doses up to 1 × 109 
CFU.  One subject with mesothelioma survived for 27 months post-first dose of 
CRS-207 in the Phase 1 study.  The proposed dose level for this study (1 × 109 
CFU) is the MTD as determined in the Phase 1 study and is the dose being 
administered in the current Phase 2 pancreatic cancer study.  This dose level has 
shown an acceptable safety profile in the 12 patients treated thus far (in both 
Phase 1 and Phase 2).  In addition, 3 of 4 evaluable patients at this dose level in 
the Phase 1 study demonstrated CRS-207-induced mesothelin-specific CD8+ T 
cell responses (as compared to 1/3 and 2/3 patients at lower dose levels) and 2 of 
6 of the “long-term” survivors received CRS-207 at this dose level. 
This study will be the first to investigate the safety and immunogenicity of 
CRS-207 with or without Cy when combined with standard of care chemotherapy 
in patients with malignant mesothelioma.  
Safety data from the first 23 subjects treated on this study have shown no additive 
or synergistic toxicities when administering CRS-207 prior to or after pemetrexed 
and cisplatin.  The most frequent AEs have been mild to moderate infusion 
reactions (e.g. nausea, chills, headache, and vomiting) as well as fatigue, anemia, 
decreased appetite, night sweats and lymphocyte count decreases related to CRS-
207 and expected AEs related to chemotherapy dosing.  No treatment-related 
unexpected Grade 3 or greater AEs, SAEs or deaths have occurred.  Additionally, 
in the first 25 subjects evaluated for objective clinical responses post-study 
treatment, 15 had best overall response of partial response (PR), 7 had stable 
disease (SD), and 3 had progressive disease (PD).  No subjects have discontinued 
treatment due to AEs related to CRS-207.   
The initial safety and clinical response data warranted further evaluation in an 
expansion phase of this Phase 1B study and the original sample size was 
increased from 16 to 40.  The sample size has been further increased to 60 in 
order to evaluate the use of low-dose Cy in this patient population and treatment 
regimen.  

 
 
 
 
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1.3 
RATIONALE FOR USE OF LOW-DOSE CYCLOPHOSPHAMIDE AND 
CRS-207 
Cyclophosphamide (Cy) is currently approved as a high-dose chemotherapy 
agent, however, when administered at low-doses, it has exhibited immune-
modulatory effects, namely in the suppression of regulatory T cells (Tregs).44  In 
the context of cancer vaccines, the preferential inhibition of Tregs may enhance 
vaccine-induced tumor-specific immunity, thereby improving vaccine efficacy.    
Data suggest that immune-modulating doses of Cy may enhance vaccine-induced 
antitumor immune responses by inhibiting CD4+ CD25+ regulatory T cell activity.  
Several studies have demonstrated this concept and shown prolonged survival of 
patients receiving low-doses of Cy 24-72 hours prior to vaccination with minimal 
side effects.1,2,45,46  
Increased vaccine-induced T cell responses and improved survival has been 
demonstrated in nonclinical studies of CRS-207 administered with immune-
modulatory doses of Cy.  In mice administered 50 mg/kg Cy (equivalent to 140 
mg/m2 human dose), immune responses measured seven days after administration 
of CRS-207 demonstrated that the combination of Cy and CRS-207 increased 
mesothelin-specific T cell responses compared to saline and CRS-207 alone.  In a 
lung tumor model, tumor-bearing mice received 50 or 100 mg/kg Cy 
(corresponding to 140 to 280 mg/m2 of the human dose equivalent, respectively) 
followed one day later with 2×106 CFU CRS-207 or ANZ-100 (the empty LADD 
platform strain, also named Lm11) and were monitored for survival over 90 days.  
The combination of low-dose Cy and CRS-207 increased the rate of survival to 
100% compared to CRS-207 alone (60% survival) or Cy alone (0%, mOS = 33.5 
days) (Figure 1).  The combination of Cy and LADD-based vaccines has been 
shown to improve anti-tumor efficacy compared to LADD-vaccine alone in 
several models. 
 
 
 

 
 
 
 
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Figure 1.  
Cyclophosphamide Followed by CRS-207 Improves Vaccine 
Potency. 
Female Balb/c mice (n=10) were implanted i.v. with 2×105 CT26 tumor cells expressing 
mesothelin.  Two days later, mice were administered 50 or 100 mg/kg Cy.  One day later, 
mice were vaccinated i.v. with 2×106 CFU CRS-207 or Lm11 (empty LADD platform).  Mice 
that received only saline (HBSS) were included as controls.  Animals were monitored for 
survival.  mOS = median overall survival. 
 
100~--- -~---------
90 
80 
70 
60 
50 
40 
30 
20 
10 
0-+---.... -------,.--- -"T"""----r------. 
0 
20 
40 
60 
80 
100 
Days post tumor challenge 
mOS (dalr'.s) 
...,_HBSS 
1S.S 
-+- Cy (100) 
33.S 
-+- Lmll 
17 
-+- Cy (100) + Lmll 
30 
...,_ CRS-207 
undefined 
-+- Cy (SO) + CRS-207 
undefined 
-+- Cy (100) + CRS-207 
undefined 

 
 
 
 
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2.0 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To determine the safety of CRS-207 (with or without Cy) when administered in 
combination with pemetrexed and cisplatin and to evaluate the induction of 
immune response to mesothelin as measured by IFN-γ enzyme-linked 
immunosorbent spot (ELISPOT) assay prior to treatment and at time points 
during and after treatment.    
2.2 
SECONDARY OBJECTIVES 
To evaluate objective tumor response, progression free survival, time to 
progression, overall survival and the predictive value of serum mesothelin for 
therapeutic response for each treatment regimen. 
2.3 
EXPLORATORY OBJECTIVES 
i) to conduct immune subset analysis (e.g. CD4, CD8, Treg) and gene expression 
profiling of tumor tissue pre- and post-vaccination; ii) to assess induction of anti-
mesothelin humoral immune response; iii) to measure tumor marker kinetics as 
biomarkers of tumor response; iv) evaluate the association between improvement 
in pulmonary function and tumor response; v) evaluate the relationship of tumor 
response to overall survival.                      

 
 
 
 
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3.0 
STUDY DESIGN 
3.1 
BASIC DESIGN CHARACTERISTICS 
This is a phase 1B study to evaluate the safety and induction of immune response 
of CRS-207 with or without low-dose Cy in combination with pemetrexed and 
cisplatin in front-line therapy in subjects with MPM.  
Up to 16 subjects were originally planned to be enrolled in this study.  Up to an 
additional 44 subjects will be enrolled in an expansion phase of this study (for a 
total of up to 60 subjects) to obtain additional safety, immune and efficacy data.  
Subjects will be enrolled into 2 mutually exclusive cohorts described below.   
Cohort 1: At least 32 subjects will receive 2 prime vaccinations (PV) of CRS-207 
(1 × 109 CFU given i.v. over approximately 1 hour) 2 weeks apart followed 2 
weeks later by up to 6 cycles of pemetrexed and cisplatin 3 weeks apart.  Three 
weeks after completion of chemotherapy, subjects will receive an additional 2 
infusions (boost vaccinations; BV) of CRS-207 3 weeks apart (Figure 1). Subjects 
enrolled in Cohort 1 include the 16 subjects originally planned plus a minimum of 
the first 16 subjects enrolled into the expansion phase. 
Cohort 2: The remaining subjects enrolled in the expansion phase (up to 28 total) 
will receive CRS-207 in combination with chemotherapy at the dose and schedule 
described above, however, these subjects will also receive low-dose Cy (200 
mg/m2) over 30 minutes one day prior to each CRS-207 infusion (i.e. prior to each 
PV and BV infusion).   
All subjects will return to the clinic 4 weeks after their 2nd boost vaccination for 
an End of Course (EOC) visit.  Subjects will have follow-up visits 4 weeks after 
the EOC visit and every 8 weeks thereafter until treatment discontinuation.  
Subjects will continue to receive maintenance vaccinations (MV) with (Cohort 2) 
or without Cy (Cohort 1) following their original schedule at each follow-up visit 
if they are clinically stable and continue to meet dosing eligibility.  Subjects may 
continue on treatment with radiographic disease progression if subject is clinically 
stable and investigator believes the treatment may be providing benefit. 
The study will consist of a screening period (within 28 days of the first 
administration of study drug), followed by administration of test treatments per 
Figure 2.  Tumor assessment by computed tomography (CT) with optional 
fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic 

 
 
 
 
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resonance imaging (MRI) will be performed every 6-8 weeks until subject comes 
off study.  Tumor biopsies, which are optional, will be performed pre-treatment, 
before start of chemotherapy (i.e. after initial 2 infusions of CRS-207), after 
completion of chemotherapy, and after CRS-207 to evaluate tumor lymphocytic 
(e.g. CD4, CD8, Treg) infiltrate.  A seven-day course of antibiotics will be 
administered to eliminate any residual CRS-207 beginning 7 days following the 
second infusion of CRS-207 during the induction phase, and after the final study 
dose of CRS-207. 
 
Figure 2.  
Study Treatment Timeline, Doses Scheduled and Follow-up  
 
 
 
*Or investigator believes subject is no longer receiving benefit if treatment continued beyond radiographic progression 
 
To monitor initial safety of the sequential vaccine regimen, no more than 1 
subject per week will be enrolled for the first 6 subjects.  Dose-limiting toxicities 
are defined in Section 3.6.  If >33% of subjects (i.e. 1 out of 3 subjects) 
experience a dose-limiting toxicity during the study, the dose will be lowered to 3 
× 108 CFU for all subsequent dosing with CRS-207.  Blood will be collected at 
EOS to assess the clearance of CRS-207.  
Safety will be assessed by collection of data on AEs, vital signs, physical 
examination, clinical hematology, serum chemistry, and deaths.  Induction of 
CRS-207
q 2 weeks
x 2 infusions
4
3
14
Weeks
5
8
11
17
20
23
26
Pemetrexed plus Cisplatin
q 3 weeks x up to 6 cycles
CRS-207
q 3 weeks 
x 2 infusions
q8wks
-
Screening
30
Immune Analysis
Follow-up
(beginning 
Week 34)
Until Disease
Progression*
1
Prime Vaccination 
(PV)
Chemotherapy Treatment
(CY)
Boost Vaccination 
(BV)
Maintenance 
Vaccinations (MV) 
CRS-207 (with or without 
CY given one day prior) 
q 8 weeks (eligible 
subjects)
(with or without CY 
given one day prior)
(with or without CY 
given one day prior)
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immune response to mesothelin will be evaluated by ELISPOT assay prior to 
treatment and at time points during and after treatment.  Objective tumor 
response, progression free survival and time to progression will be measured 
using modified RECIST for assessment of response in MPM (Appendix A) and 
immune-related response criteria. 47  Other evaluations will include overall 
survival, immune subset analysis (e.g. CD4, CD8, Treg) and gene expression 
profiling of tumor tissue pre and post vaccination by immunohistochemistry, 
evaluating induction of anti-mesothelin humoral immune response by ELISA, 
assessing tumor marker kinetics by measuring serum levels of mesothelin and 
CA-125 and plasma osteopontin. 
3.2 
STUDY POPULATION 
3.2.1 
Inclusion Criteria 
To be considered eligible to participate in this study, subjects must meet the 
inclusion criteria listed below: 
(1) 
Subjects must have histologically-confirmed epithelial or biphasic pleural 
mesothelioma not amenable to potentially curative surgical resection at the 
time of study entry (subjects with biphasic tumors that have a 
predominantly (≥50%) sarcomatoid component will be excluded) 
(2) 
Measurable disease, as defined by modified RECIST for MPM 4 
(3) 
ECOG Performance Status of 0 or 1 
(4) 
Normal organ and marrow function, as defined by: 
• 
Absolute neutrophil count (ANC) ≥ 1,500/µl 
• 
Platelet count ≥ 100,000/µl 
• 
Bilirubin ≤ 1.5 × upper limit of normal (ULN), or bilirubin ≤ 3× ULN 
if due to Gilbert’s disease 
• 
AST and ALT ≤ 2.5× ULN  
• 
Albumin ≥ 2.5 g/dL 
• 
Creatinine clearance ≥ 50 mL/min per Cockcroft-Gault formula 
(Creatinine clearance = {[(140-age) x weight in kilograms] x [0.85 if 
female]}/[72 x creatinine in mg/dL]) 
• 
CD4 ≥ 0.2×109/L 
• 
Hemoglobin ≥9.0 g/dL 

 
 
 
 
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(5) 
Age 18 years and over 
(6) 
Must have pulmonary function testing with documented values for vital 
capacity (VC) and forced expiratory volume in 1 second (FEV1) > 45% of 
predicted value and oxygen saturation ≥ 90% on room air, as measured by 
pulse oximeter 
(7) 
Anticipated life expectancy greater than 6 months 
(8) 
Female subjects of childbearing potential must consent to use a medically 
acceptable method of highly effective contraception (oral hormonal 
contraceptive, condom plus spermicide, or hormone implants) throughout 
the study period and for 28 days after their final study drug administration 
(A barrier method of contraception must be employed by all subjects 
(male and female), regardless of other methods.) 
(9) 
Subject provides informed consent and is willing and able to comply with 
all study procedures 
3.2.2 Exclusion Criteria 
To be eligible for entry into the study, subjects must not meet any of the exclusion 
criteria listed below: 
(1) 
Be a candidate for curative surgery at the time of study entry 
(2) 
Have had surgery or pleurodesis within 2 weeks prior to dosing 
(3) 
Have had prior radiotherapy (except palliative extra-thoracic localized 
radiotherapy) or biologic therapy for MPM within 3 weeks prior to dosing 
(4) 
Have had prior systemic chemotherapy for MPM (Prior intracavitary 
cytotoxic drugs or immunomodulators are not permitted, unless given for 
the purpose of pleurodesis.) 
(5) 
Have an active malignancy with the exception of any of the following:  
• adequately treated basal cell carcinoma  
• squamous cell carcinoma of the skin, or in situ cervical cancer 

 
 
 
 
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• adequately treated Stage I cancer from which the subject is 
currently in remission and has been in remission for ≥ 3 years 
• Stage I prostate cancer that does not require treatment 
• any other cancer from which the subject has been disease-free for 
≥ 2 years 
(6) 
Have documented and ongoing central nervous system (CNS) involvement 
with their malignant disease (history of CNS involvement is not an 
exclusion criterion but the CNS metastases should have been adequately 
treated [radiation or surgical resection] and subjects are neurologically 
stable for 3 months off steroids)   
(7) 
Have any evidence of clinically significant ascites   
(8) 
Have clinically significant pleural effusion 
(9) 
Have clinically significant heart disease (such as uncontrolled angina, 
myocardial infarction within 3 months, congestive heart failure of New 
York Heart Association III or IV) 
(10) 
Have valvular heart disease that requires antibiotic prophylaxis for 
prevention of endocarditis, consistent with American Heart Association 
(AHA) guidelines  
(11) 
History of any autoimmune disease, including patients with a history of 
inflammatory bowel disease, (including ulcerative colitis and Crohn’s 
Disease), patients with a history of symptomatic disease (e.g. rheumatoid 
arthritis, systemic progressive sclerosis [scleroderma], systemic lupus 
erythematosus, autoimmune vasculitis [e.g. Wegener’s granulomatosis]); 
central nervous system or motor neuropathy considered of autoimmune 
origin (e.g. Guillain-Barre Syndrome, Myasthenia gravis, multiple 
sclerosis). Patients with Graves’, Hashimoto’s Disease, vitiligo, and 
diabetes type 1 will be allowed 
(12) 
Have any immunodeficiency disease or immune-compromised state (e.g. 
use of immunosuppressive agents) within 14 days prior to study 
enrollment 
(13) 
Have baseline coagulopathy > Grade 3 unless due to anticoagulant therapy 

 
 
 
 
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(14) 
Have peripheral neuropathy ≥ Grade 2   
(15) 
Use of systemically-active steroids within 14 days prior to enrollment in 
the study 
(16) 
Use of more than 3 grams per day of acetaminophen 
(17) 
Use of aspirin or other nonsteroidal anti-inflammatory drugs for 2 days 
before, during, and for 2 days after each administration of pemetrexed 
disodium (5 days before, during, and 2 days after each administration of 
pemetrexed disodium for piroxicam, naproxen, diflunisal, or nabumetone) 
(18) 
Have received treatment with an investigational product within 28 days of 
study treatment or planned to receive within 28 days after vaccine 
administration. 
(19) 
Have known allergy to both penicillin and sulfa drugs 
(20) 
Have known or suspected allergy or hypersensitivity to yeast or any other 
component of CRS-207 (e.g. glycerol), Platinol or platinum-containing 
compounds, or pemetrexed 
(21) 
Have received a diagnosis of human immunodeficiency virus (HIV), 
hepatitis B, or hepatitis C (exception: clear evidence of natural immunity, 
immunity subsequent to vaccination, or successful eradication of the virus 
following antiviral therapy) 
(22) 
Be a woman who is pregnant or breastfeeding 
(23) 
Have prosthetic heart valves; major implant(s) or device(s) (e.g. artificial 
joints and prosthetics) placed within 12 months of study screening; or 
current or prior history of infection or clinically significant AEs associated 
with an exogenous implant(s) or device(s) that cannot be easily removed 
(24) 
Have had major surgery or significant traumatic injury occurring within 28 
days prior to CRS-207 administration or anticipated surgery or procedure 
requiring general anesthesia or deep sedation during study participation 
(including 28 days after last dose of CRS-207) (Minor procedures [dental 
work, skin biopsy, etc.], celiac plexus block, and biliary stents are 
allowed.) 

 
 
 
 
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(25) 
Have an unhealed wound which increases risk for bacterial infection 
(26) 
Be unable to avoid intimate contact with another individual known to be at 
high risk of listeriosis (e.g. newborn infant, pregnant female, etc.) for at 
least 7 days after receiving a CRS-207 infusion 
(27) 
Have an intercurrent illness that is either life-threatening or of clinical 
significance such that it might limit compliance with study requirements 
(including, but not limited to, ongoing or active infection, metabolic [e.g. 
diabetes] or neurologic disease, peripheral vascular disease, or psychiatric 
illness/social situations) 
(28) 
Have insufficient peripheral venous access to permit completion of the 
study dosing and compliance with study phlebotomy regimen 
(29) 
Have a history of alcohol dependence or use of illicit drugs that could 
potentially interfere with adherence to study procedures or requirements 
(e.g. opioids, cocaine, amphetamines, hallucinogens, etc.) 
3.2.3 
Dosing Eligibility 
Subjects must have adequate organ function as defined by the laboratory values in 
Table 1 before each dose of CRS-207 in Cohort 1 or Cy in Cohort 2.  Laboratory 
tests may be done up to 3 days prior to CRS-207 dosing (Cohort 1) or 2 days prior 
to Cy dosing for subjects receiving Cy (Cohort 2).  Subjects who do not meet the 
dosing-eligibility requirements will be monitored.  Delayed doses will be 
discussed with the medical monitor. 
Table 1. 
Dosing-Eligibility Requirements 
Hematologic 
Renal 
Hepatic 
ANC ≥1,500/µL 
Platelets ≥100,000/µl 
Hemoglobin ≥9 g/dL 
CD4 ≥ 0.2×109/L prior to 1st post-
chemotherapy CRS-207 boost 
vaccination  
Creatinine ≤2.0 × ULN 
AST/ALT ≤2.5× ULN 
Bilirubin ≤1.5× ULN or  
Bilirubin ≤3.0 × 
ULN if due to 
Gilbert’s disease  
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; ULN = upper limit of normal; WBC = white blood cell. 
* Cockcroft-Gault formula: Creatinine Clearance = {[(140-age) x weight in kilograms] x [0.85 if 
female]}/[72 x creatinine in mg/dL] 
 
 

 
 
 
 
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3.3 
ENDPOINTS 
3.3.1 
Primary Endpoint 
The primary endpoints are as follows:  
• The induction of mesothelin-specific T cell responses as measured by IFN-γ 
ELISPOT assay prior to treatment and at different time points during 
treatment.  T cell responses to mesothelin will be considered positive when 
the frequency of specific responses are > 1 in 105 CD8+ peripheral blood 
lymphocytes (PBL) above the control sample and increased by at least 2-fold 
compared to baseline.   
• Safety assessed by evaluation of AEs and deaths, vital signs, physical 
examination findings, clinical chemistry and hematology laboratory findings 
in subjects treated with CRS-207 (with or without Cy) combined with 
pemetrexed and cisplatin 
3.3.2 
Secondary Endpoints 
The secondary endpoints are as follows: 
• Objective tumor response, progression free survival and time to progression 
assessed by modified RECIST for assessment of response in MPM4 and 
irRC47 
• Overall survival 
• Measure of serum mesothelin to assess predictive value for therapeutic 
response 
3.3.3 
Exploratory Endpoints 
Exploratory endpoints are as follows: 
• Immune subset analysis (e.g. CD4, CD8, Treg) by immunohistochemistry and 
gene expression profiling of tumor tissue pre and post vaccination  
• Induction of anti-mesothelin humoral immune response by ELISA 
• Tumor marker kinetics measured by serum levels of mesothelin and CA-125 
and plasma osteopontin; other markers may also be evaluated  

 
 
 
 
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• Pulmonary function tests (PFTs) measured by forced vital capacity (FVC), 
forced expiratory volume in 1 second (FEV1) and vital capacity (VC)  
3.4 
RANDOMIZATION AND BLINDING 
No randomization or blinding is planned.  
3.5 
REPLACEMENT OF DROPOUTS 
Subjects who withdraw consent or are removed from the study before completing 
at least 4 cycles of chemotherapy will be considered dropouts and may be 
replaced at the discretion of the lead investigator, sponsor and medical monitor.   
3.6 
DOSE-LIMITING TOXICITIES  
Dose-limiting toxicities (DLTs) are defined as events that are determined by the 
investigator as related to CRS-207 that meet one of the following criteria: 
• A fever of >40°C that lasts for greater than 24 hours and does not respond to 
antipyretics  
• Clinically significant hypotension unresponsive to intravenous fluids (e.g. 
systolic BP <90 mm Hg or mean arterial pressure <55 mm Hg as measured on 
two separate occasions at least 10 minutes apart)  
• Grade 3 or greater decreases in leukocytes, ANC, or platelets that persist for 
more than 4 days 
• Hemoglobin ≤7.0 g/dL  
• ALT, AST, or alkaline phosphatase elevations >5 times the ULN (Grade 3) 
that persist for more than 7 days  
• Initiation of antibiotic therapy, coincident with simultaneous isolation of 
CRS-207 from a normally sterile body site, other than blood (e.g. 
cerebrospinal fluid, joint fluid)  
• Unexpected Grade 3 laboratory abnormalities lasting >48 hours 
• Grade 3 or greater hypophosphatemia or lymphopenia that persist for more 
than 7 days 

 
 
 
 
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• Any other Grade 3 or greater event according to National Cancer Institute’s 
Common Terminology Criteria for AEs (CTCAE) Version 4.03 
All unexpected Grade 3 events will be reviewed by the lead investigator, sponsor 
and medical monitor.  If the event is determined to be related to CRS-207 dosing 
and clinically meaningful, it will be considered a dose-limiting toxicity.  Grade 3 
laboratory abnormalities should be repeated within 24-72 hours if clinically 
indicated and monitored as necessary to determine if event meets DLT criteria. 
DLTs will be continuously monitored per cohort and across cohorts.  If more than 
33% of subjects (i.e. 1 in 3 subjects) experience a DLT at the starting dose of 1 × 
109 CFU, the dose will be lowered to 3 × 108 CFU for all subsequent dosing with 
CRS-207.  Subjects currently receiving treatment may continue to receive CRS-
207 dosing at the lower dose and all subsequent subjects will receive CRS-207 at 
the lower dose.  DLTs will continue to be monitored  at the lower dose. 

 
 
 
 
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4.0 
DRUGS AND DOSAGES 
4.1 
IDENTIFICATION AND DESCRIPTION OF CLINICAL TRIAL 
MATERIAL (CTM) 
4.1.1 
CTM 
CRS-207 is a formulated live-attenuated strain hMeso38 of Lm, derived by 
deletion of actA and inlB coding sequences from a Streptomycin-resistant, 
wild-type strain and insertion of the hMeso coding sequence.  The CRS-207 drug 
product consists of attenuated Lm (1 × 109 CFU total) suspended in 1.0 mL of 
Dulbecco’s phosphate buffered saline and 9% vol/vol glycerol, filled into a 
single-use 3-mL glass vial with a gray butyl stopper and aluminum crimp seal 
with a flip-off cap, and stored frozen at –60ºC or colder until intravenous 
administration.  CRS-207 is supplied by Aduro. 
ALIMTA®, pemetrexed for injection, is an antifolate antineoplastic agent that 
exerts its action by disrupting folate-dependent metabolic processes essential for 
cell replication.  Pemetrexed disodium heptahydrate has the chemical name L-
Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-
5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate.  It is a white to almost-white 
solid with a molecular formula of C20H19N5Na2O6•7H2O and a molecular weight 
of 597.49.  Pemetrexed is supplied as a sterile lyophilized powder for i.v. infusion 
available in single-dose vials.  The product is a white to either light yellow or 
green-yellow lyophilized solid.  Each 500-mg vial contains pemetrexed disodium 
equivalent to 500 mg pemetrexed and 500 mg of mannitol.  Pemetrexed will be 
supplied by the institutional pharmacy. 
Cisplatin, USP (cis-diamminedichloroplatinum) is a heavy metal complex 
containing a central atom of platinum surrounded by two chloride atoms and two 
ammonia molecules in the cis position.  It is a white powder with the molecular 
formula PtCl2H6N2, and a molecular weight of 300.1.  Cisplatin injection is a 
sterile aqueous solution for intravenous use, each mL containing 1 mg cisplatin 
and 9 mg sodium chloride.  Cisplatin will be supplied by the institutional 
pharmacy. 
Cyclophosphamide (Cy; active ingredient cyclophosphamide monohydrate) is a 
synthetic antineoplastic drug chemically related to the nitrogen mustards.  It is 
commercially available in a sterile powder formulation for use in i.v. 

 
 
 
 
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administration.  Cyclophosphamide will be supplied by the institutional 
pharmacy. 
4.1.2 
Labeling 
Because the study is not blinded, the labeling will be that used on commercial 
vials of Cy, ALIMTA®, pemetrexed for injection, and cisplatin.  The vials for 
CRS-207 will be labeled with the following: product name; volume; storage 
conditions; product lot number; sponsor name and address; fill date; and a caution 
statement (“Caution: New drug limited by Federal law to investigational use”).  
CRS-207 drug product is packaged in kit boxes that are also labeled with product 
name, number of vials, concentration, storage condition, a caution statement, 
sponsor name and address, expiration date, and kit lot number. 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE 
4.2.1  
Cyclophosphamide 
Cohort 2 only: Cy will be administered to subjects by i.v. infusion at the 
immunomodulating dose of 200 mg/m2 in 100 mL normal saline over 30 minutes 
one day prior to each CRS-207 dose. 
For complete product information on dosage and administration, 
contraindications, warnings/precautions, adverse reactions, and drug 
interactions, see package insert for cyclophosphamide (Appendix E). 
4.2.2 
CRS-207  
CRS-207 will be administered by IV infusion (1 × 109 CFU in 100 mL sterile 
saline, USP, over approximately 1 hour). CRS-207 is prepared by thawing one 
vial of drug product at room temperature. A total of 1 mL of product is drawn 
with a syringe and inserted into 1 bag of 100 mL saline solution for IV injection. 
Additional details for storage and preparation of CRS-207 are provided in the 
study Pharmacy Manual. 
CRS-207 will be administered to subjects by i.v. infusion on Day 1 of Weeks 1 
and 3 for Cohort 1 or Day 2 of Weeks 1 and 3 for Cohort 2 prior to chemotherapy 
(prime vaccinations) and 3 and 6 weeks after the final chemotherapy cycle (boost 
vaccinations).  Subjects who continue to meet dosing eligibility will receive 

 
 
 
 
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additional CRS-207 maintenance vaccinations at each follow-up visit.  CRS-207 
must not be administered via central venous catheters or infusion ports. 
Before each CRS-207 infusion, subjects will be premedicated with 650 mg 
acetaminophen.  Subjects will receive a minimum of 500 mL of normal saline 
immediately before CRS-207 infusion and at least 500 mL after infusion (1 L is 
recommended for patients who can tolerate it, to mitigate infusion reactions).  
Additional fluids may be given for persistent tachycardia, fever or hypotension 
based on investigator’s discretion.  Subjects will be observed in the clinic for at 
least 4 hours after each infusion.  Subjects who are not stable to be released at 4 
hours after infusion should continue to be monitored until stable.  Hospital 
admissions for overnight monitoring will not be considered an SAE unless the 
event meets criteria for seriousness other than hospitalization.   
Accumulating subject experience during and after CRS-207 infusions at 1 × 109 
CFU have further demonstrated the following clinical observations which are to 
be expected: 
• 
Fevers. Despite the acetaminophen premedication, subjects can spike fevers 
up to 40°C starting at the end of the CRS-207 infusion generally through the 
next 24 hours. Oral Ibuprofen (400 to 800 mg) and acetaminophen (650 to 
1000 mg) can be used in alternate sequence every 4 hours.  
• 
Rigors. Rigors (generally once or twice) have been observed starting during 
or at the end of the CRS-207 infusion through 24 hours. Intravenous 
narcotics such as morphine or meperidine can be administered per 
institutional policy. Oral morphine or non-steroidal anti-inflammatory drugs 
(NSAIDs) may be used as home treatment. 
• 
Blood pressure. Decreases in blood pressure have been observed 
necessitating additional IV fluids during the 4 hour observation period (up to 
1 or 2 L).  This may be the result of fever, compartmental shifts of fluid 
resulting from the CRS-207 infusion, and the use of narcotics. Some 
subjects have also been slightly hypotensive at 24 hours. Subjects are 
encouraged to hydrate themselves liberally at home with oral fluids. 

 
 
 
 
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CRS-207 with Pemetrexed and Cisplatin 
 
 
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• 
Nausea and vomiting. Nausea and vomiting have been reported and 
observed within 24 hours after CRS-207 infusion.  Subjects may be given 
anti-emetics as needed. 
 
4.2.3 
Pemetrexed  
The recommended dose of pemetrexed is 500 mg/m2 body surface area (BSA) in 
100 mL 0.9% sodium chloride administered over 10 minutes as an intravenous 
infusion on Day 1 of a 21-day cycle.  Dose reductions may be required for 
subjects with hepatic or renal impairment or history of hematologic or non-
hematologic toxicity to pemetrexed/cisplatin (see Appendix C, prescribing 
information for Alimta®).  Subjects may receive pre-medications (e.g. folic acid 
and cyanocobalamin) and pre- and post-infusion hydration per standard of care 
and investigator’s practice.   
For complete product information on dosage and administration, 
contraindications, warnings/precautions, adverse reactions, and drug 
interactions, see package insert for ALIMTA®, pemetrexed for injection 
(Appendix C). 
4.2.4 
Cisplatin 
The recommended dose of cisplatin is 75 mg/m2 BSA in 1L 0.9% sodium chloride 
with mannitol 30g/L infused over 2 hours, beginning approximately 30 minutes 
after the end of pemetrexed administration on Day 1 of each 21 day cycle.   
Subjects may receive anti-emetics, e.g. dexamethasone, prior to cisplatin infusion 
per standard of care and investigator’s practice.   
Dose reductions may be required for subjects with hepatic or renal impairment or 
history of hematologic or non-hematologic toxicity to pemetrexed/cisplatin (see 
Appendix D, prescribing information for cisplatin).  If a subject is determined to 
be intolerant to cisplatin after at least one dose, carboplatin may be substituted to 
be administered with pemetrexed per standard of care with the approval of the 
Sponsor. 

 
 
 
 
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CRS-207 with Pemetrexed and Cisplatin 
 
 
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For complete product information on dosage and administration, 
contraindications, warnings/precautions, adverse reactions, and drug 
interactions, see the package insert for cisplatin (Appendix D). 
4.2.5 
Delayed Dosing  
Dosing of CRS-207 with or without Cy (prime vaccination 2 [PV2], boost 
vaccination 1 [BV1], boost vaccination 2 [BV2] or maintenance vaccinations 
[MVs]) may be delayed up to 2 weeks.  The medical monitor should be contacted 
for further instruction on continued dosing for any delay greater than 2 weeks.  
The total delay time during the prime vaccination period may not exceed 2 weeks, 
i.e. the first cycle of chemotherapy treatment should be administered no later than 
Week 7, after which the medical monitor should be contacted to discuss continued 
dosing.  For subjects enrolled in Cohort 2, if CRS-207 dosing is delayed more 
than 72 hours after administration of Cy for a particular dose, the dose will be 
delayed and Cy re-administered a minimum of 1 week after the original Cy 
dosing and CRS-207 administered according to schedule thereafter. 
Delayed chemotherapy dosing or missed chemotherapy doses due to the subject’s 
clinical status are at the discretion of the investigator, but the medical monitor 
may be contacted to discuss plans for continued dosing.  The Sponsor should be 
notified of all modifications to the planned study schedule during the 
chemotherapy dosing period.  
If administration of CRS-207 doses (with or without Cy) or chemotherapy cycles 
are delayed, the subsequent dosing schedule will be adjusted according to the 
delayed dose(s). 
4.3 
STORAGE AND HANDLING OF CLINICAL TRIAL MATERIAL 
4.3.1 
Cyclophosphamide 
Cyclophosphamide powder should be kept at or below 25ºC.  Cy reconstituted in 
normal saline is chemically and physically stable for 24 hours at room 
temperature and for 6 days when refrigerated.  Guidelines outlining the 
procedures for proper handling and disposal of anticancer drugs should be 
followed when handling Cy (OSHA 1996).  Protective gloves should be worn 
when handling Cy in both powder and reconstituted forms. 

 
 
 
 
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4.3.2 
CRS-207 
CRS-207 must be stored at –60ºC or colder until just before use.  The 
investigational site(s), per institutional guidelines, will destroy used CRS-207 
vials after formulation for administration.  The formulation of CRS-207 for 
administration and the destruction of each used vial will be carefully documented 
in the study Pharmacy Manual.  The principal investigator is responsible for CRS-
207 accountability during on-site monitoring visits.  Unused CRS-207 will be 
destroyed at the study site after final investigational product accountability and 
notification by Sponsor, unless otherwise directed by Sponsor.   
Wild-type Lm is classified by the Centers for Disease Control and Prevention for 
handling in the laboratory according to Biosafety Level 2 practices.  Since CRS-
207 is attenuated by greater than 1,000-fold compared to wild-type Lm, 
individuals who prepare CRS 207 for injection should take appropriate 
precautions to avoid contamination or direct contact with the agent.  Once it is 
prepared for infusion, CRS-207 can be handled with BSL 1 practices, including 
use of protective gloves, eye and face protection when handling and thorough 
hand washing after handling as the chance for direct exposure to CRS-207 by 
study personnel should be greatly diminished.  Study personnel and staff should 
also adhere to the institutional guidelines for standard precautions.  
4.3.3 
Environmental Precautions  
Wild-type Lm is a common pathogen that is widely distributed in the environment 
and contaminates a variety of ready-to-eat foods.  Despite the presence of Lm in 
diverse locations, clinically apparent human infection is not commonly reported 
in immunocompetent, normal individuals.  Direct human-to-human spread of Lm 
is believed to be limited mainly to vertical transmission from mother to neonate.  
Standard isolation precautions are usually recommended for subjects infected 
with wild-type Lm.  CRS-207 is a live-attenuated construct originating from wild-
type Lm which contains deletion of 2 virulence genes that render it greater than 
1,000-times less toxic than wild-type Lm.  Preclinical studies demonstrated that 
virtually all CRS-207 was cleared from the body within 4 days of infusion and 
clinical studies with CRS-207 and similar live-attenuated Lm strains showed no 
shedding of the bacterium in urine or feces post-infusion.  While the risk of 
infection with CRS-207 is unknown and expected to be low or none based on 
these data, precautions should be exercised to avoid intimate contact between 
subjects and individuals who are at high risk of listeriosis (e.g. newborn infants, 

 
 
 
 
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CRS-207 with Pemetrexed and Cisplatin 
 
 
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Page 26 
pregnant women, HIV-positive individuals) for at least 7 days after each CRS-207 
infusion. 
4.4 
PRODUCT ACCOUNTABILITY 
The investigator is responsible for the control of the investigational agent under 
study.  An investigational agent dispensing log must be kept current and should 
contain the following information: 
• The subject number and initials of each subject to whom the investigational 
agent is administered 
• The date(s) and quantity of the investigational agent administered to the 
subject 
• Documentation of proper disposal of used investigational drug vials 
• Documentation of proper disposal (or return, at sponsor’s request) of unused 
investigational drug vials 
All records and unused supplies of the investigational agent must be available for 
inspection at every monitoring visit. 
4.5 
PRIOR, CONCOMITANT, AND EXCLUDED THERAPY 
During the course of the clinical study, subjects are anticipated to continue the use 
of prescribed medications identified during the screening procedures, consistent 
with study inclusion and exclusion criteria.  Concomitant medications used in this 
study include: 
• 7-day antibiotic regimen scheduled 7 days after the last dose of CRS-207 prior 
to chemotherapy (2nd prime vaccination) and after final dose of CRS-207 
when treatment is discontinued 
• Acetaminophen prior to each CRS-207 infusion 
• Folic acid and cyanocobalamin administered with pemetrexed 
• Anti-emetics (per investigator’s standard practice), including dexamethasone, 
administered with cisplatin 
• Medications to treat any treatment-emergent AEs 

 
 
 
 
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Medications to treat treatment-emergent AEs should not interfere with the study 
and can be used at the investigator’s discretion.  Antipyretics may be used to treat 
fever or to prevent recurrence of fever.  The details of any concomitant 
medications must be recorded in the case report form (CRF).  The generic name, 
dosage, duration, and reason for the concomitant medication should be included 
in this report.  
The following therapies are not permitted during the study (if administered, the 
subject may be removed from the study): 
• 
Non-study chemotherapy or immunotherapy (approved or investigational) 
• 
TNF pathway inhibitors or PI3 kinase inhibitors 
• 
Systemically active steroids for more than 3 days or use of any systemic 
steroids within 14 days before or after dosing, with exception of study-
prescribed steroids 
• 
Any other investigational product 
• 
Filgrastim (Neupogen or G-CSF) or Sargramostin (Leukine or GM-CSF) 
should not be administered 14 days prior to or 14 days after any CRS-207 
dose.  Approval must be obtained from the medical monitor for a subject to 
continue dosing if administered within this timeframe. 
• 
Prophylactic vaccines (e.g. pneumococcal vaccine, influenza vaccine) 
should not be administered 28 days prior to or 28 days after any CRS-207 
dose.  Approval must be obtained from the medical monitor for a subject to 
continue dosing if a prophylactic vaccine is administered within this 
timeframe. 
In addition, the following therapies should not be administered during the study 
unless medically necessary and approval must be obtained from the medical 
monitor for a subject to continue dosing if therapy is given concurrently with 
study participation: 
• 
General anesthesia or deep sedation 
• 
Aspirin >325 mg/d (chronic daily use of aspirin ≤325 mg/d and heparin 
flushes for central lines are allowed) 
• 
More than 4 g/d of acetaminophen 

 
 
 
 
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CRS-207 with Pemetrexed and Cisplatin 
 
 
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• 
Systemic antibiotics 
If subjects receive immunosuppressive medications on or after study, prophylactic 
antibiotics to prevent CRS-207 infection are strongly recommended for the 
duration of the treatment with the immunosuppressant (recommended oral 80 mg 
trimethoprim / 400 mg sulfamethoxazole once daily or 160 mg trimethoprim / 800 
mg sulfamethoxazole (DS) three days a week). 

 
 
 
 
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CRS-207 with Pemetrexed and Cisplatin 
 
 
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5.0 
EXPERIMENTAL PROCEDURES 
5.1 
OVERVIEW: SCHEDULE OF TIME AND EVENTS 
An overview of study time and events for Cohort 1 is presented in Table 2a and 
for Cohort 2 in Table 2b. 

 
 
 
 
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Table 2a. CRS-207 and Pemetrexed/Cisplatin [Cohort 1] 
Nominal Weeks (Wk)a 
Screening 
Wk 
1 
Wk  
3 
Wk 
5 
Wk 
8 
Wk  
11 
Wk 
14 
Wk 
17 
Wk 
20 
Wk  
23 
Wk  
26 
Wk 
30 
Follow-up: 4 wks 
after EOC then 
every 8 wksb  
Visit ID 
SCR 
PV1 
PV2 
CY
1 
CY
2 
CY
3 
CY
4 
CY
5 
CY
6 
BV1 
BV2 
EOC 
FU/EOS 
Cycle Study Day 
(-28) 
1 
2 
8 
1 
2 
8 
1 
1 
1 
1 
1 
1 
1 
2 
8 
1 
2 
8 
1 
1 
Visit Windows (days) 
  
- 
- 
±1 
- 
- 
±1 
 - 
- 
-  
 - 
 - 
 - 
- 
- 
±1 
- 
- 
±1 
+7 
±7 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history, medication history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cancer-related treatment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Baseline signs/symptoms 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Virology screen
 c 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation panel, UA
 d 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pulmonary Function Test 
e 
X 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram, 12-lead 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
CT, tumor assess.; optional FDG-PET
 f 
X 
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
X 
 
Physical examination
 g 
X 
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
ECOG performance status 
X 
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
Vital signs, pulse oximetry, weight, height 
h 
X 
X 
X 
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
  
X 
X 
Pregnancy test
 i 
X 
X 
  
  
X 
  
  
 
 
 
 
 
 
X 
  
  
X 
  
  
 
 X 
CD4 count
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
Creatinine clearance
 j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical hematology, serum chemistry
 k,l 
X 
X 
X 
 
X 
X 
 
X
 l 
X
 l 
X
 l 
X
 l 
X
 l 
X
 l 
X
  
X 
 
X 
X 
 
X 
X 
Tumor marker(s)
 m 
X 
X 
  
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
 
Concomitant medications, AEs
 n 
  
X 
X 
Xn  
X 
X 
Xn  
X 
X 
X 
X 
X 
X 
X 
X 
Xn  
X 
X 
Xn 
X 
X 
PBMC 
o 
  
X 
  
  
X 
  
  
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
 
Serum for Lm/mesothelin immunity
p 
  
X 
X 
  
X 
X 
  
X 
  
  
  
  
  
X 
X 
  
X 
X 
  
X 
 
HLA-typing
 q 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Archival tissue 
 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy (optional)
 s 
 
X 
  
  
  
  
  
X  
  
  
  
  
  
 X 
  
  
  
  
  
X 
  
Antibiotics
 t 
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
 
  
 X
u 
Blood sample for CRS-207 testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRS-207
 w,x 
  
X 
  
  
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
  
  
  
 X
u 
Pemetrexed/cisplatin
 y, z  
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  

 
 
 
 
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Footnotes: 
a    Study schedule and timing displayed is based on the subject completing the full treatment regimen of 6 chemotherapy cycles.  However, subjects may receive CRS-207 boost vaccinations if they complete 
between 4-6 cycles in which case the visit timing will be modified. If CRS-207 doses or chemotherapy cycles are delayed, subsequent dosing schedule will be adjusted according to the delayed dose(s). 
b Follow-up visit to occur 4 weeks after EOC then every 8 weeks until treatment discontinuation.  EOS Visit will occur within 4 weeks after the last dose of study drug or prior to commencing the new 
therapy. If the EOS visit occurs earlier than 4 weeks, a safety follow-up telephone call on Day 28 (+/- 7 days) is required; document contact in the study records.   
c    Virology screen will be performed if one has not been done within 14 days before screening: HIV antibody, hepatitis B surface antigen, and hepatitis C antibody (exception: clear evidence of natural immunity, 
immunity subsequent to vaccination, or successful eradication of the virus following antiviral therapy); additional virology may also be evaluated. 
d   Coagulation panel includes the following: prothrombin time (PT), international normalized ratio of prothrombin time (INR), activated partial thromboplastin time (APTT); UA includes the following: bilirubin, 
blood, glucose, ketones, leukocytes, nitrite, pH, protein, specific gravity. 
e  Pulmonary function tests (PFTs) to include VC, FVC and FEV1. 
f   A spiral CT of the thorax and abdomen will be performed.  If a subject cannot have a CT scan (e.g. allergy to contrast dye) an MRI should be performed.  CT scans may be done within 1 week prior to or after 
scheduled visit.  Optional FDG-PET may be done.  A clinical assessment of tumor status using modified RECIST will be completed. 
g  Complete physical examinations will be conducted at baseline and EOS; symptom-directed physical examinations to be conducted on Day 1 of dosing weeks. 
h   Blood pressure, pulse, respiratory rate, temperature and pulse oximetry are required as indicated.  Weight will be taken on Day 1 of dosing weeks.  Height required at screening only.  Pre-dose blood pressure 
should be performed in a supine position after the subject has been resting for at least 5 minutes 
i   Pregnancy tests will be administered to women of childbearing potential: serum pregnancy test is required at screening, and pregnancy tests (urine or serum) are required before doses on Day 1 of CRS-207-
dosing weeks.  Pregnancy tests (urine or serum) only required at follow-up visits at which maintenance vaccinations will be administered. 
j 
Creatinine clearance calculated by Cockcroft-Gault formula = {[(140-age) x weight in kilograms] x [0.85 if female]}/[72 x creatinine in mg/dL] 
k   Clinical hematology: CBC with differential ANC, platelet count; serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, LDH, ALT, AST, alkaline phosphatase, bilirubin (total, 
direct, and indirect), total protein, albumin, calcium, magnesium, uric acid and phosphate.  Blood draws may be taken up to 3 days prior to dosing with CRS-207.   
l   Clinical hematology and chemistry tests to be taken prior to each chemotherapy treatment.   
m   Tumor markers to be assessed include Mesothelin, CA-125, and plasma osteopontin; other markers may also be assessed. 
n 
Adverse Events (AEs) and concomitant medications review.  A phone call follow-up for AEs and concomitant medications will be conducted on day 2 ± 1 days after each CRS-207 infusion. 
o  Up to 200 mL of whole blood to be processed within 6 hours into peripheral blood mononuclear cells (PBMCs) and stored frozen in liquid nitrogen. 
p  Whole blood (10 mL) will be collected between 20 and 26 hours after start of dosing for assessment of Lm and mesothelin immunity. 
q  The HLA-typing should include type A and B of class I antigens, low resolution. 
r  Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the sample is obtained or documentation that the sample cannot be obtained. Detailed instructions for tissue 
collection, processing and shipment are provided in the Laboratory Manual. 
s   An optional CT or an ultrasound-guided core needle biopsy should be performed at the site presented for mesothelioma for consenting subjects.  
t  
A 7-day course of antibiotics will be taken starting 7 days after the 2nd dose of CRS-207 (PV2) and after final dose of CRS-207 when treatment is discontinued.  A 7-day course of antibiotics will be initiated at 
the EOS visit after blood has been collected for CRS-207 culture.  Antibiotic regimens must be completed prior to initiation of any other cancer-related therapy.  Subjects with a central line port will receive 1 
dose of IV antibiotics followed by 6 days of oral antibiotics; all other subjects will receive 7 days of oral antibiotics (refer to Section 5.2.2.5). Site personnel will contact the subject by telephone to facilitate 
compliance with antibiotic treatment; subjects required to record self-administration of antibiotics in a diary. 
u   Subjects who are clinically stable and meet dosing eligibility, will continue to receive maintenance vaccinations beginning at the first follow-up visit 4 weeks after EOC and every 8 weeks thereafter.  Subjects 
may continue on treatment with radiographic disease progression if they are clinically stable and the Investigator believes the treatment may be providing benefit. A 7-day course of antibiotics starting 7 days after 
vaccination will be administered following the second dose of CRS-207 (PV2) and after final dose of CRS-207. 
v   Blood for CRS-207 culture will be collected at EOS to assess clearance of CRS-207.   At EOS, blood will be collected prior to initiation of antibiotics (if applicable, blood should also be collected from the central 
line port).   
w CRS-207 will be administered via i.v. injection (1 × 109 CFU in approximately 100 mL 0.9% sodium chloride).  Vital signs (BP, pulse, respiratory rate, temperature) will be measured every 30 minutes during the 
CRS-207 infusion and every hour during post-infusion follow-up.  Subjects will be observed for at least 2 hours after each infusion.  Subjects who are not stable enough to be released at 2 hours after infusion 
should continue to be monitored until subject is considered clinically stable. 
x      CRS-207 premedications include the following: 650 mg of acetaminophen to be administered orally prior to each dose of CRS-207.  Subjects will receive a minimum of 500 mL of normal saline immediately 
before CRS-207 infusion and at least 500 mL after infusion.  Additional fluids may be given for persistent tachycardia, fever or hypotension based on investigator’s discretion.   
y    Subjects may receive folic acid, cyanocobalamin, and anti-emetics premedication for chemotherapy per standard of care and investigator’s practice. 
z 
The recommended dose of pemetrexed is 500 mg/m2 BSA in 100 mL 0.9% sodium chloride administered over 10 minutes as an i.v. infusion on Day 1 of 21-day cycle.  The recommended dose of cisplatin is 75 
mg/m2 BSA in 1 L 0.9% sodium chloride with mannitol 30 g/L infused over 2 hours beginning approximately 30 minutes after end of pemetrexed administration on day 1 of 21-day cycle.  Dose reductions may 
be required for subjects with hepatic or renal impairment or history of toxicity to pemetrexed or cisplatin.  If a subject is determined to be intolerant to cisplatin after at least one dose, carboplatin may be 
substituted to be administered with pemetrexed per standard of care with the approval of the Sponsor. 
 

 
 
 
 
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CRS-207 with Pemetrexed and Cisplatin 
 
 
Version 8, 08 March 2018 
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Abbreviations: 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; BV = boost 
vaccine; CBC = complete blood count; CT  =computed tomography; EOS = End of Study; FDG-PET = positron emission tomography with fluorodeoxyglucose; FEV1 = forced expiratory volume in 1 second; HIV = 
human immunodeficiency virus; HLA = human leukocyte antigen; LDH = lactate dehydrogenase; Lm = Listeria monocytogenes; MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cells; 
PD = progressive disease; i.v. = intravenous; p.o. = per oral; PV = prime vaccination; UA = urinalysis; VC = vital capacity. 
 
 

 
 
 
 
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Protocol ADU-CL-02-v8 
CRS-207 with Pemetrexed and Cisplatin 
 
 
Version 8, 08 March 2018 
Page 33 
Table 2b. Schedule of Procedures – Low-dose Cy/CRS-207 and Pemetrexed/Cisplatin [Cohort 2] 
Nominal Weeks (Wk)a 
 
Wk  
1 
Wk  
3 
Wk 
5 
Wk 
8 
Wk  
11 
Wk 
14 
Wk 
17 
Wk 
20 
Wk  
23 
Wk  
26 
Wk 
30 
Follow-up: 4 
wks after 
EOC then 
every 8 wks  
Visit ID 
SCR 
XP1 
PV1 
XP2 
PV2 
CY1 
CY2 
CY3 
CY4 
CY5 
CY6 
XB1 
BV1 
XB2 
BV2 
EOC 
FU/EOS 
Cycle Study Days 
(-28) 
1 
2 
3 
9 
1 
2 
3 
9 
1 
1 
1 
1 
1 
1 
1 
2 
3 
9 
1 
2 
3 
9 
1 
1 
Visit Windows (days) 
 
- 
- 
- 
±1 
- 
- 
- 
±1 
- 
- 
- 
- 
- 
- 
- 
- 
- 
±1 
- 
- 
- 
±1 
+7 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer-related treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline signs/symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology screen
 c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel, UA
 d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Test 
e 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Electrocardiogram, 12-lead 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CT, tumor assessment; optional 
FDG-PET
f 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Physical examination
 g 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
ECOG performance status 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs, pulse oximetry, 
weight, and height 
h 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Pregnancy test
 i 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
CD4 count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Creatinine clearance
 j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical hematology, serum 
chemistry
 k,l 
X 
X 
 
X 
 
X 
 
X 
 
X
 l 
X
 l 
X
 l 
X
 l 
X
 l 
X
 l 
X
  
 
X 
 
X 
 
X 
 
X 
X 
Tumor marker(s)
 m 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
Concomitant medications, AEs
 n 
 
X 
X 
X 
X
 n 
X 
X 
X 
X
 n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
 n 
X 
X 
X 
X
 n 
X 
X 
PBMC 
o 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Serum for Lm/mesothelin 
immunity
 p 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HLA-typing
 q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue
  
 
X
 r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy (optional)
 s 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Antibiotics
 t 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood for CRS-207 testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamidew 
 
X  
 
 
 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Xw 
CRS-207
 x, y 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Xw 
Pemetrexed/cisplatin
 z, aa 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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a    Study schedule and timing displayed is based on the subject completing the full treatment regimen of 6 chemotherapy cycles.  However, subjects may receive Cy/CRS-207 boost vaccinations if they complete 
between 4-6 cycles in which case the visit timing will be modified. If CRS-207 doses or chemotherapy cycles are delayed, subsequent dosing schedule will be adjusted according to the delayed dose(s). 
b 
Follow-up visit to occur 4 weeks after EOC then every 8 weeks until treatment discontinuation.    EOS Visit will occur within 4 weeks after the last dose of study drug or prior to commencing the new therapy. If 
the EOT visit occurs earlier than 4 weeks, a safety follow-up telephone call on Day 28 (+/-7 days) is required; document contact in the study records.   
c    Virology screen will be performed if one has not been done within 14 days before screening: HIV antibody, hepatitis B surface antigen, and hepatitis C antibody (exception: clear evidence of natural immunity, 
immunity subsequent to vaccination, or successful eradication of the virus following antiviral therapy); additional virology may also be evaluated.  
d   Coagulation panel includes the following: prothrombin time (PT), international normalized ratio of prothrombin time (INR), activated partial thromboplastin time (APTT); UA includes the following: bilirubin, 
blood, glucose, ketones, leukocytes, nitrite, pH, protein, specific gravity. 
e 
Pulmonary function tests to include VC, FVC and FEV1. 
f   A spiral CT scan of the thorax and abdomen will be performed. If a subject cannot have a CT scan (eg, due to an allergy to contrast dye), an MRI should be performed. CT scans may be done within 1 week prior 
to or after scheduled visit, and must also be done prior to initiation of chemotherapy up to the start of chemotherapy. Optional FDG-PET may be done.  A clinical assessment of tumor status using modified 
RECIST will be completed. 
g 
Complete physical examinations will be conducted at baseline and EOC; symptom-directed physical examinations to be conducted on Day 1 of dosing weeks. 
h   Blood pressure, pulse, respiratory rate, temperature and pulse oximetry are required as indicated. Weight will be recorded on Day 1 of dosing weeks.  Height is required at screening only. Pre-dose blood pressure 
should be measured in a supine position after the subject has been resting for at least 5 minutes. 
i   Pregnancy tests will be administered to women of childbearing potential: serum pregnancy test is required at screening, and pregnancy tests (urine or serum) are required before doses on Day 1 of CRS-207 
dosing weeks.  
j 
Creatinine clearance is to be calculated by Cockcroft-Gault formula = {[(140-age) x weight in kilograms] x [0.85 if female]}/[72 x creatinine in mg/dL] 
k  Clinical hematology: CBC with differential ANC, platelet count; serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, LDH, ALT, AST, alkaline phosphatase, bilirubin (total, 
direct, and indirect), total protein, albumin, calcium, magnesium, uric acid and phosphate.  Blood draws may be taken up to 3 days prior to dosing with CRS-207 or 2 days prior to Cy.  Clinical hematology and 
chemistry tests should be measured prior to each chemotherapy treatment.   
l 
Clinical hematology and chemistry tests to be taken prior to each chemotherapy treatment 
m  Tumor markers to be assessed include mesothelin, CA-125, and plasma osteopontin; other markers may also be assessed. 
n 
AEs and concomitant medications review. A phone call follow-up for AEs and concomitant medications will be conducted on day 3 ± 1 days after CRS-207 vaccination.  
o   Up to 200 mL of whole blood should be processed within 6 hours into PBMCs and stored frozen in liquid nitrogen. 
p  Whole blood (10 mL) will be collected between 20 and 26 hours after start of dosing for assessment of Lm and mesothelin immunity. 
q 
The HLA-typing should include type A and B of class I antigens, low resolution. 
r 
Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the sample is obtained or documentation that the sample cannot be obtained. Detailed instructions for tissue 
collection, processing and shipment are provided in the Laboratory Manual. 
s 
An optional CT or an ultrasound-guided core needle biopsy should be performed at the site presented for mesothelioma for consenting subjects. 
t 
A 7-day course of antibiotics will be taken starting 7 days after the second dose of CRS-207 (PV2) and after final dose of CRS-207 when treatment is discontinued.  A 7-day course of antibiotics will be initiated 
at the EOS visit after blood has been collected for CRS-207 culture.  Antibiotic regimens must be completed prior to initiation of any other cancer-related therapy.  Subjects with a central line port will receive 1 
dose of IV antibiotics followed by 6 days of oral antibiotics; all other subjects will receive 7 days of oral antibiotics (refer to Section 7.3.6). Site personnel will contact the subject by telephone to facilitate 
compliance with antibiotic treatment; subjects required to record self-administration of antibiotics in a diary. 
u 
Cy will be administered one day prior to each CRS-207 dose by i.v. infusion at the dose of 200 mg/m2 in 100 ml normal saline over 30 minutes. 
v   Blood for CRS-207 culture will be collected at EOS to assess clearance of CRS-207.   At EOS, blood will be collected prior to initiation of antibiotics (if applicable, blood should also be collected from the central 
line port).   
w Subjects who are clinically stable and meet dosing eligibility will continue to receive maintenance vaccinations with Cy (dosing day 1) and CRS-207 (dosing day 2) beginning at the first follow-up visit 4 weeks 
after EOC and every 8 weeks thereafter.  Subjects may continue on treatment with radiographic disease progression if they are clinically stable and the Investigator believes the treatment may be providing 
benefit. A 7-day course of antibiotics starting 7 days following the second dose of CRS-207 (PV2) and after final dose of CRS-207. 
x 
CRS-207 will be administered via i.v. injection (1 × 109 CFU in 100 mL 0.9% sodium chloride). Vital signs (BP, pulse, respiratory rate, temperature) will be measured every 30 minutes during the CRS-207 
infusion and every hour during post-infusion follow-up. Subjects will be observed for at least 2 hours after each infusion. Subjects who are not stable enough to be released at 2 hours after infusion should 
continue to be monitored until subject is considered clinically stable.  
y 
CRS-207 premedications include the following: 650 mg of acetaminophen should be administered orally prior to each dose of CRS-207.  Subjects will receive a minimum of 500 mL of normal saline immediately 
before CRS-207 infusion and at least 500 mL after infusion. Additional fluids may be given for persistent tachycardia, fever or hypotension based on investigator’s discretion. 
z 
Subjects may receive folic acid, cyanocobalamin, and anti-emetics premedication for chemotherapy per standard of care and investigator’s practice. 
aa The recommended dose of pemetrexed is 500 mg/m2 BSA in 100 mL 0.9% sodium chloride administered over 10 minutes as an i.v. infusion on Day 1 of the 21-day cycle. The recommended dose of cisplatin is 
75 mg/m2 BSA in 1 L 0.9% sodium chloride with mannitol 30 g/L infused over 2 hours beginning approximately 30 minutes after the end of pemetrexed administration on Day 1 of the 21-day cycle.  Dose 

 
 
 
 
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reductions may be required for subjects with hepatic or renal impairment or history of toxicity to pemetrexed or cisplatin.  If a subject is determined to be intolerant to cisplatin after at least one dose, carboplatin 
may be substituted to be administered with pemetrexed per standard of care with the approval of the Sponsor.  
Abbreviations: 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; BV = boost 
vaccine; CBC = complete blood count; CT = computed tomography; CY = cycle; EOC = end of cycle; EOS = End of Study; FDG-PET = positron emission tomography with fluorodeoxyglucose; FEV1 = forced 
expiratory volume in 1 second; FVC = forced vital capacity; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; LDH = lactate dehydrogenase; Lm = Listeria monocytogenes; MRI = magnetic 
resonance imaging; PBMC = peripheral blood mononuclear cells; PD = progressive disease; PT = prothrombin time; PV = prime vaccine; INR = international normalized ratio of prothrombin time; i.v. = intravenous; 
p.o. = per oral; UA = urinalysis; SCR = screening; VC = vital capacity. 

 
 
 
 
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5.2 
STUDY PROCEDURES 
5.2.1 
Screening Period (28 days prior to first study dose) 
Before screening assessments are conducted, the subject must be given a complete 
explanation of the purpose and evaluations of the study.  Subsequently, the 
subject must sign and receive a copy of an informed consent form (ICF) that was 
approved by the institutional review board (IRB) and an authorization for use and 
disclosure of protected health information (PHI) before any study-specific 
procedure is performed.  An original signed consent form will be retained in the 
subject’s source documentation at the site, and a copy will be provided for the 
subject to take home.  Screening will occur within 28 days before treatment 
administration.  Potential subjects will be evaluated for entry into the study 
according to the stated inclusion and exclusion criteria.  Individuals who are 
identified during this screening as not eligible for study enrollment need not 
complete all screening procedures.  The reason for ineligible status will be 
documented. 
The following evaluations will be performed to assess the subject’s eligibility for 
the study: 
• 
Medical history, including history of carcinoma treatment 
• 
Medication history over the past 28 days, including prescription and 
over-the-counter medications, herbs, vitamins, minerals, and prophylactic 
vaccines 
• 
Baseline signs and symptoms 
• 
Physical examination 
• 
ECOG performance status 
• 
Vital signs (BP, pulse, respiratory rate, temperature), height, weight, and 
pulse oxygen saturation 
• 
Resting 12-lead electrocardiogram 
• 
Pulmonary function tests: VC, FVC and FEV1 

 
 
 
 
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• 
Clinical hematology: complete blood count (CBC) with differential ANC 
and platelet count  
• 
Serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, lactate dehydrogenase (LDH), ALT, AST, alkaline phosphatase, 
bilirubin (total, direct, indirect), total protein, albumin, calcium, magnesium, 
uric acid, and phosphate 
• 
Coagulation panel: prothrombin time (PT), international normalized ratio of 
prothrombin time (INR), and activated partial thromboplastin time (APTT) 
• 
Virology screen if one has not been done within 14 days before screening: 
HIV antibody, hepatitis B surface antigen, and hepatitis C antibody  
• 
Urinalysis (UA): bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, 
protein, and specific gravity 
• 
Creatinine clearance calculated by Cockcroft-Gault formula = {[(140-age) x 
weight in kilograms] x [0.85 if female]}/[72 x creatinine in mg/dL] 
• 
CD4 count 
• 
Tumor markers: mesothelin, CA-125 and plasma osteopontin.  Other 
markers may also be evaluated. (See Section 5.3) 
• 
Serum pregnancy test (for women of childbearing potential only)  
• 
Spiral CT scan of thorax and abdomen if one has not been done within 14 
days before screening.  If a subject cannot have a CT scan [e.g. allergy to 
contrast dye], a magnetic resonance imaging [MRI] should be performed.).  
CT with FDG-PET scan may be done (optional). 
• 
Clinical assessment of tumor status using modified RECIST for assessment 
of response in MPM4 and irRC47. 
The investigator may use clinical judgment when determining the clinical 
significance of laboratory parameter findings throughout the study.  The medical 
monitor may, depending on study criteria, be consulted before enrollment about a 
potential subject with abnormal laboratory values that are not considered 
clinically significant. 

 
 
 
 
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5.2.2 
Treatment Period 
5.2.2.1 
CRS-207 Prime Vaccinations (PV1, PV2) (with or without low-dose Cy) 
All subjects will be administered CRS-207 during Weeks 1 and 3 (Day 1 for 
Cohort 1 and Day 2 for Cohort 2).  Cohort 2 only will receive a low-dose Cy 
administration one day prior to each CRS-207 prime vaccination by i.v. infusion 
at the dose of 200 mg/m2 in 100 mL normal saline over 30 minutes.   
CRS-207 will be administered by i.v. infusion at 1 × 109 CFU in 100 mL 0.9% 
sodium chloride over approximately 1 hour.  Prior to CRS-207 administration, 
subjects will be premedicated with 650 mg of acetaminophen before drug 
administration.  Subjects will receive a minimum of 500 mL of normal saline 
immediately before CRS-207 infusion and at least 500 mL after infusion (1 L is 
recommended for subjects who can tolerate it, to mitigate infusion reactions).  
Additional fluids may be given for persistent tachycardia, fever or hypotension 
based on investigator’s discretion.  Investigators will not make dose adjustments 
or changes to administration schedule or rate without prior approval from sponsor.  
CRS-207 must not be administered via central venous catheter or infusion port.   
Vital signs (BP, pulse, respiratory rate, temperature) will be obtained every 30 
minutes during the CRS-207 infusion and every hour during post infusion follow-
up.  Subjects will be observed for at least 4 hours after each infusion.  Subjects 
who are not stable enough to be released at 4 hours after infusion should continue 
to be monitored until stable.  Presence of fever alone does not indicate subject is 
not clinically stable. 
Because results for clinical hematology and serum chemistry need to be obtained 
before each CRS-207 administration, subjects may have blood drawn for these 
evaluations up to 3 days prior to receiving CRS-207 in Cohort 1 or 2 days prior to 
Cy for subjects in Cohort 2.  Blood samples must not be collected from a central 
line after infusion of CRS-207 for at least 4 days.     
Prior to receiving any study drug on Day 1 of Weeks 1 (PV1 for Cohort 1 or XP1 
for Cohort 2) and 3 (PV2 for Cohort 1 or XP2 for Cohort 2), the following 
evaluations will be performed:  
• 
Symptom-directed physical examination (May be done up to 3 days prior to 
CRS-207 dosing (Cohort 1) or 2 days prior to Cy for subjects receiving Cy 
(Cohort 2)). 

 
 
 
 
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• 
ECOG performance status 
• 
Vital signs (BP, pulse, respiratory rate, temperature, pulse oximetry) and 
weight taken prior to CRS-207 dosing for on Day 1 for Cohort 1 and prior to 
Cy dosing on Day 1 and CRS-207 dosing on Day 2 for Cohort 2; blood 
pressure taken prior to CRS-207 administration (pre-dose) should be taken 
in supine position after subject has been resting for at least 5 minutes 
• 
Urine or serum pregnancy test (for women of childbearing potential only) 
• 
Blood draws for clinical hematology, serum chemistry.  Blood draw may be 
done up to 3 days prior to CRS-207 dosing (Cohort 1) or 2 days prior to Cy 
for subjects receiving Cy (Cohort 2). 
• 
Blood draw (serum and plasma) for tumor marker(s).  Blood draw may be 
done up to 3 days prior to CRS-207 dosing (Cohort 1) or 2 days prior to Cy 
for subjects receiving Cy (Cohort 2).  (See Section 5.3) 
• 
AEs and concomitant medications review 
• 
Blood draw for isolation of PBMC (up to 200 mL). Blood draw may be 
done up to 3 days prior to CRS-207 dosing (Cohort 1) or 2 days prior to Cy 
for subjects receiving Cy (Cohort 2).  (See Section 5.3) 
• 
Blood draw for Lm- and mesothelin-specific immunity assays (10 mL). 
Blood draw may be done up to 3 days prior to CRS-207 dosing (Cohort 1) 
or 2 days prior to Cy for subjects receiving Cy (Cohort 2).  (See Section 5.3) 
• 
Blood draw for Class I HLA-typing (A and B, low resolution); at Week 1 
(PV1) only.  Blood draw may be done up to 3 days prior to CRS-207 dosing 
(Cohort 1) or 2 days prior to Cy for subjects receiving Cy (Cohort 2).   (see 
Section 5.3) 
• 
Optional core needle biopsy; may be done anytime between screening and 
prior to dosing at Week 1 (PV1) only (see Section 5.3) 
Note: Urine pregnancy test and blood draws for hematology, chemistry and 
tumor markers are not required at Week 1 (PV1) if Screening Visit is 
conducted within 3 days prior to PV1 Visit. 

 
 
 
 
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5.2.2.2 
CRS-207 Prime Vaccinations Follow-up  
One day after CRS-207 infusion (Day 2 for Cohort 1 or Day 3 for Cohort 2), the 
following evaluations will be performed: 
• 
Vital signs (BP, pulse, respiratory rate, temperature, pulse oximetry)  
• 
Blood draws for clinical hematology, serum chemistry.  Any unexpected 
Grade 3 laboratory abnormalities should be repeated within 24-72 hours. 
• 
AEs and concomitant medications review 
• 
Blood draw for Lm- and mesothelin-specific immunity assays (10 mL).  
Blood should be drawn within 20-26 hours after start of CRS-207 dosing.  
(See Section 5.3) 
One week (7 ± 1 days) after each CRS-207 infusion, subjects will be contacted by 
phone to assess AEs and concomitant medications and to confirm initiation of 7-
day course of antibiotics (after 2nd prime vaccination [PV2] only). 
5.2.2.3 
Chemotherapy Treatment: Pemetrexed and Cisplatin Administration 
(CY1 to CY6) 
On Day 1 of Weeks 5 (CY1), 8 (CY2), 11 (CY3), 14 (CY4), 17 (CY5) and 20 
(CY6), pemetrexed and cisplatin treatment will be administered.  Pemetrexed will 
be administered at 500 mg/m2 BSA in 100 mL 0.9% sodium chloride 
administered over 10 minutes as an intravenous infusion.  Cisplatin will be 
administered at 75 mg/m2 BSA in 1L 0.9% sodium chloride with mannitol 30g/L 
infused over 2 hours, beginning approximately 30 minutes after the end of 
pemetrexed administration.  Subjects may receive pre-medications (e.g. folic acid, 
cyanocobalamin, and anti-emetics) and pre- and post-infusion hydration per 
standard of care and investigator’s practice.  Dose reductions may be required for 
subjects with hepatic or renal impairment or history of toxicity to pemetrexed or 
cisplatin.   
If a subject is determined to be intolerant to cisplatin after at least one dose, 
carboplatin may be substituted to be administered with pemetrexed per standard 
of care with the approval of the Sponsor.   
Subjects who complete at least 2 cycles of pemetrexed/cisplatin may go on to 
receive CRS-207 3 weeks after their final cycle of pemetrexed/cisplatin.  Subjects 

 
 
 
 
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who receive less than 2 cycles will be discontinued from treatment and continued 
to be followed for safety and clinical and immune responses. 
Prior to pemetrexed/cisplatin treatment, the following procedures will be 
performed: 
• 
Symptom-directed physical examination (May be done up to 3 days prior to 
dosing) 
• 
ECOG performance status 
• 
Vital signs (BP, pulse, respiratory rate, temperature, pulse oximetry) and 
weight 
• 
Blood draws for clinical hematology, serum chemistry.  Blood draw may be 
done up to 3 days prior to dosing. 
• 
Blood draw (serum and plasma) for tumor marker(s).  Blood draw may be 
done up to 3 days prior to dosing.  (See Section 5.3)  
• 
AEs and concomitant medications review 
• 
Spiral CT scan of thorax and abdomen with optional FDG-PET scan; at 
Weeks 5 (CY1), 11 (CY3), 17 (CY5).  If a subject cannot have a CT scan 
[e.g. allergy to contrast dye], an MRI should be performed.  CT scan may be 
done within ±7 days of scheduled timepoint. 
• 
Clinical assessment of tumor status using modified RECIST for assessment 
of response in MPM4 and irRC47; at Weeks 5 (CY1), 11 (CY3), 17 (CY5) 
• 
Pulmonary function tests: VC, FVC and FEV1; at Weeks 5 (CY1), 11 
(CY3), 17 (CY5) for Cohort 2 only 
• 
Blood draw for isolation of PBMC (up to 200 mL); at Week 5 (CY1) only.  
Blood draw may be done up to 3 days prior to dosing. (See Section 5.3)  
• 
Blood draw for Lm- and mesothelin-specific immunity assays (10 mL); at 
Week 5 (CY1) only.  Blood draw may be done up to 3 days prior to dosing. 
(See Section 5.3)   

 
 
 
 
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• 
Optional core needle biopsy; may be done anytime between PV2 and prior 
to dosing at Week 5 (CY1) only (See Section 5.3)  
5.2.2.4 
CRS-207 Post-chemotherapy Boost Vaccination (BV1, BV2) 
During the post-chemotherapy boost vaccination (BV) period, all subjects 
(Cohorts 1 and 2) will be administered two infusions of CRS-207 3 weeks apart at 
least 3 weeks after the last chemotherapy cycle.   
Cohort 2 only will receive a low-dose Cy administration one day prior to each 
CRS-207 boost vaccination by i.v. infusion at the dose of 200 mg/m2 in 100 mL 
normal saline over 30 minutes.  Subjects must receive at least 2 cycles of 
pemetrexed and cisplatin to continue to receive CRS-207 (with or without Cy) 
after chemotherapy.   
CRS-207 will be administered and monitored and the same procedures conducted 
as on Day 1 in Section 5.2.2.1 and Day 2 in Section 5.2.2.2.   One week (7 ± 1 
days) after each CRS-207 infusion, subjects will be contacted by phone to assess 
AEs and concomitant medications. 
In addition to those procedures listed in Section 5.2.2.1, prior to the first study 
drug dosing (Cy or CRS-207) at boost vaccination (BV1) following 
chemotherapy, the following procedures will be conducted: 
• 
CD4 count.  Blood draw may be done up to 3 days prior to CRS-207 dosing 
(Cohort 1) or 2 days prior to Cy for subjects receiving Cy (Cohort 2). 
• 
Spiral CT scan of thorax and abdomen with optional FDG-PET scan.  If a 
subject cannot have a CT scan [e.g. allergy to contrast dye], an MRI should 
be performed.  CT scan may be done within ±7 days of BV2. 
• 
Clinical assessment of tumor status using modified RECIST for assessment 
of response in MPM4 and irRC47 
• 
Pulmonary function tests: VC, FVC and FEV1 for Cohort 2 only 
• 
Optional core needle biopsy; may be done anytime between CY6 (or final 
chemotherapy cycle) and prior to dosing at BV1 (See Section 5.3) 

 
 
 
 
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5.2.2.5 
Antibiotic Administration  
To eliminate any potentially residual CRS-207, subjects will be administered 
antibiotics after PV2 (and prior to receiving pemetrexed/cisplatin) and at the EOT 
visit and prior to receiving subsequent cancer-related (non-study) therapy.   
Subjects with a central line port will receive 1 dose [2 mg ampicillin or 3-5 mg/kg 
trimethoprim/ sulfamethoxazole (in penicillin-allergic subjects)] of IV antibiotics 
through the port, followed by 6 days of oral antibiotics [amoxicillin or 
trimethoprim/sulfamethoxazole (in penicillin-allergic subjects)]; all other subjects 
will receive a 7-day course of oral amoxicillin or trimethoprim/sulfamethoxazole 
(in penicillin-allergic subjects).  
Site personnel will contact the subject by telephone to facilitate compliance with 
antibiotic treatment; subjects will be required to record self-administration of 
antibiotics in a diary. 
If infection with CRS-207 is confirmed or suspected after more than 7 days post-
infusion, IV antibiotics (see below) should be initiated as soon as possible and 
follow-up cultures obtained periodically to confirm absence/clearance of any 
CRS-207 infection. The Medical Monitor should be consulted regarding 
continuation of study drug treatment and treatment of suspected or confirmed 
infection. 
Consult the package inserts for amoxicillin, trimethoprim, and sulfamethoxazole 
for product information on dosage and administration, contraindications, 
warnings/precautions, adverse reactions, and drug interactions. 
5.2.2.5.1  Antibiotic Treatment for CRS-207 Infection 
The recommended antibiotic regimen for suspected or confirmed CRS-207 
infection after more than 7 days post-infusion is IV administration of ampicillin 
(or 
trimethoprim/sulfamethoxazole 
in 
penicillin-allergic 
subjects) 
plus 
gentamicin. Initial doses of ampicillin should be approximately 12 g/day (or per 
drug label) divided (3-4 grams per dose every 3 to 4 hours), with gentamicin 3 
mg/kg (or per drug label) daily in divided doses every 8 hours (with adjustments 
according to renal function and serum levels of gentamicin). In penicillin-allergic 
subjects, initial IV doses of trimethoprim/sulfamethoxazole should be 15 to 20 
mg/kg/day (or per drug label) (based on trimethoprim component) divided 4 times 

 
 
 
 
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per day, with gentamicin 3 mg/kg daily in divided doses every 8 hours (with 
adjustments according to renal function and serum levels of gentamicin). For 
those individuals who receive IV antibiotics, the course of therapy is anticipated 
to be greater than or equal to 14 days, depending on clinical course. Antibiotic 
treatment may be completed with use of oral antibiotics, if clinically indicated. 
5.2.2.6 
End of Course (EOC) Follow-up  
Subjects will return to the clinic for follow-up approximately 4 weeks after their 
2nd boost vaccination.  The following evaluations will be performed: 
• 
Spiral CT scan of thorax and abdomen with optional FDG-PET scan.  If a 
subject cannot have a CT scan [e.g. allergy to contrast dye], an MRI should 
be performed.  CT scan may be done within ±7 days of EOC. 
• 
Clinical assessment of tumor status using modified RECIST for assessment 
of response in MPM4 and irRC47 
• 
Pulmonary function tests: VC, FVC and FEV1 for Cohort 2 only 
• 
Physical examination 
• 
ECOG performance status 
• 
Resting 12-lead electrocardiogram 
• 
Vital signs (BP, pulse, respiratory rate, temperature, pulse oximetry) and 
weight 
• 
Blood draws for clinical hematology, serum chemistry 
• 
Blood draw (serum and plasma) for tumor marker(s) (See Section 5.3) 
• 
AEs and concomitant medications review 
• 
Blood draw for isolation of PBMC (up to 200 mL) (See Section 5.3) 
• 
Blood draw for Lm- and mesothelin-specific immunity assays (10 mL) (See 
Section 5.3) 
• 
Optional core needle biopsy; may be done any time after final dose in course 
(see Section 5.3) 

 
 
 
 
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5.2.3 
Study Follow-up Period/End of Study (EOS) 
Subjects will return to the clinic for follow-up approximately 4 weeks after their 
EOC visit and every 8 weeks thereafter until disease progression or investigator 
determines subject is no longer receiving benefit from treatment (if subject 
continues treatment beyond progression).  Subjects who are clinically stable and 
continue to meet dosing eligibility will receive maintenance vaccinations (with or 
without Cy) at every follow-up visit. Subjects may continue on treatment with 
radiographic disease progression if subject is clinically stable and investigator 
believes the treatment is providing benefit. All subjects will complete an EOS 
visit no more than four weeks following the final dose of study medication or 
prior to receipt of other cancer-related treatment. If the EOS visit occurs earlier 
than 4 weeks, a safety follow-up telephone call on Day 28 (+/- 7 days) is required; 
document contact in the study records.   
The following evaluations will be done at each follow-up (FU) visit and at the end 
of study (EOS) visit: 
• 
Symptom-directed physical examination 
• 
ECOG performance status 
• 
Vital signs (BP, pulse, respiratory rate, temperature, pulse oximetry) and 
weight (day 1 only) 
• 
Blood draws for clinical hematology, serum chemistry 
• 
AEs and concomitant medications review 
• 
For eligible subjects receiving maintenance vaccinations (MVs), CRS-207 
(without Cy [Cohort 1] or with Cy [Cohort 2]) will be administered at every 
follow-up visit.  CRS-207 and Cy will be administered following the same 
procedures stated in Section 5.2.2.1. Subjects will be monitored for at least 2 
hours after each infusion or until they are considered clinically stable.   
Blood draws for clinical labs may be done up to 3 days prior to CRS-207 
dosing (Cohort 1) or 2 days prior to Cy for subjects receiving Cy (Cohort 2).  
Subjects will be contacted by phone to assess AEs and concomitant 
medications 1 day after CRS-207 infusion.   

 
 
 
 
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• 
Blood will be collected to assess clearance of CRS-207 at EOS Visit.  For 
subjects with a central line port, a blood sample will also be taken through 
the port.  This blood collection must be taken prior to administration of the 
EOS antibiotics. 
• 
To eliminate any potentially residual CRS-207, subjects will initiate a 7-day 
course of antibiotics at the EOS visit and prior to receiving any subsequent 
cancer-related therapy (refer to Section 5.2.2.5).   
In accordance with good medical practice, any ongoing AE present at end of the 
study, including a clinically significant laboratory test abnormality, which is 
determined by the investigator as possibly or probably related to the study 
investigational agents, will be followed until resolved, until the event stabilizes 
and the overall clinical outcome has been ascertained, or until the subject is lost to 
follow-up.  
5.3 
LABORATORY EVALUATIONS 
5.3.1 
Immune Monitoring Assessments 
Peripheral blood mononuclear cells and serum 
Peripheral blood mononuclear cells (PBMCs) and serum will be collected at 
various time points as listed in Table 2, prior, during and post treatment to assess 
Lm- and mesothelin-specific immunity.  T cell responses to mesothelin will be 
considered positive when the frequency of specific responses are ≥ 1 in 105 CD8+ 
peripheral blood lymphocytes (PBL) above the control sample and increased by at 
least 2-fold compared to baseline.  T cell responses to Lm (LLO) will be 
considered positive when specific T cell frequencies were ≥ 1 in 105 PBMCs and 
increased by at least 2-fold compared to baseline. 
Collection 
Briefly, up to 200 mL of whole blood will be collected in green top tubes (heparin 
sulfate) or heparinized syringes.  At NCI site, please page 102-11964 (Gareth 
Peters or alternate technician from Dr. Figg’s laboratory) for immediate pick-up.  
At other sites, please refer to laboratory manual for storage and shipping 
instructions.  

 
 
 
 
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Processing and Storage 
• PBMCs will be processed within 6 hours post-collection using Ficoll-
Hypaque centrifugation.  Isolated PBMCs will be stored in liquid nitrogen.  
Plasma collected from the PBMC process will be aliquoted and stored at -
70°C or colder. 
• Serum will be processed within 6 hours post-blood draw from a 10 mL serum 
tube.  The serum samples will be stored at -70°C or colder.   
• The detailed procedures for PBMC and serum processing will be provided in a 
laboratory manual.  Training will also be provided and only trained, qualified 
personnel will process samples. 
• Samples will be processed and stored at each site locally.  At NCI, samples 
will be processed and stored by the Molecular Pharmacology Program 
(Building 10, Room 5A01; William Figg, Pharm.D.) 
Testing Sites 
• Cellular mesothelin- and Lm-specific immunity will be assessed by IFN-γ 
ELISPOT analysis as previously described 
26.  Additionally, serum 
cytokines/chemokines will be assessed 20 to 26 hours following each CRS-
207 infusion.  Samples for ELISPOT and cytokine/chemokine analysis will be 
stored locally and batch-shipped in liquid nitrogen to Aduro for testing. 
• Antibody specific to mesothelin will be tested by ELISA as previously 
described 22.  Antibody testing will be conducted at NCI at the laboratory of 
Dr. Raffit Hassan, M.D (Building 37, Room 5108).    
5.3.2 
Tumor Markers 
Tumor markers such as mesothelin, CA-125 and osteopontin will be monitored 
before, during and after the treatment course.  Serum will be collected to 
determine circulating levels of mesothelin and CA-125, two tumor markers that 
have been demonstrated to be elevated in subjects with pleural mesothelioma.  
Systemic levels of osteopontin will be determined from plasma by a 
commercially-available ELISA.   
CA-125 will be collected as per local laboratory standards. 
Mesothelin and Osteopontin Sample Collection 

 
 
 
 
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Samples for mesothelin testing will be drawn in a 5 mL red top tube and samples 
for osteopontin testing will be drawn in a 5 mL green top tube before during and 
after treatment as indicated in the study calendar.   
At NCI site, please page 102-11964 (Gareth Peters or alternate technician from 
Dr. Figg’s laboratory) for immediate pick-up.  At other sites, please refer to 
laboratory manual for storage and shipping instructions. 
Mesothelin and Osteopontin Processing and Storage 
Serum and plasma specimens will be stored by the Molecular Pharmacology 
Program (Building 10, Room 5A01; William Figg, Pharm.D.) at -70°C or colder. 
Mesothelin and Osteopontin Testing Sites 
The analyses will be performed in batch at NCI in the laboratory of Dr. Raffit 
Hassan, M.D. (Building 37, Room 5108).   
5.3.3 
Tumor Biopsy 
Collection 
Tissue biopsies will be encouraged but done strictly on a voluntary 
basis.  Standard techniques will be used for pre-treatment and post-treatment 
percutaneous biopsies which may include CT, cone beam CT, ultrasound, or 
fusion guided biopsy.  When clinically feasible and judged minimal risk by 
Interventional Radiology, the same total number biopsies will be prospectively 
acquired from areas of tumor that may exhibit imaging features of higher or lower 
cellularity, such as higher PET scan activity, or evidence solid features or viability 
on CT scan. This will allow biopsy specimens to be marked as “high imaging 
cellularity” or “low imaging cellularity”, which could enhance the ability to 
obtain quality tissue biomarkers, immunohistochemistry or mRNA, and could 
facilitate the identification of reliable biomarkers for response. 
Biopsies will be obtained from primary tumor sites and metastatic sites (if 
applicable).  No more than 4 cores may be obtained per site.  Half of the biopsy 
specimen will be used for immunohistochemistry (IHC) analysis.  The other half 
will be used for gene expression analysis. 
Archival tissue from all subjects will be obtained if possible, with exception for 
subjects who agree to the optional tumor biopsy at screening do will not need 
archival tissue obtained. 

 
 
 
 
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Processing and Storage 
The fixed tissue samples that will be used for IHC analysis will be processed and 
embedded in paraffin.  Tissue blocks will be made from the paraffin-embedded 
tissue.  Tissue blocks will be stored at room temperature.   
The tissue that will be used for gene expression analysis will be stored 
immediately after collection in at least 5 volumes of RNAlater® solution.  The 
samples will be stored overnight at 4°C and transferred to -70°C or colder for 
long-term storage until RNA isolation.  Samples obtained at NCI will be stored by 
the Molecular Pharmacology Program (Building 10, Room 5A01; William Figg, 
Pharm.D) 
Please consult laboratory manual for shipping instructions.   
Testing Sites 
IHC analysis will be performed at the Laboratory of Pathology at NCI to 
determine mesothelin expression within the tumor.  Furthermore, collected tumor 
tissue will be assessed for CD4+ and CD8+ T cell infiltration as well as the 
presence of regulatory T cells (FoxP3+).  Additional markers might be assessed.  
Tumor expression analysis will be performed on the isolated RNA from tumor 
biopsy tissue as previously described.48 
Gene expression profiling of tumor tissue samples will be conducted by Aduro.  
5.3.4  
Blood Cultures for CRS-207 Surveillance 
Blood samples from subject’s peripheral vein will be obtained at EOS to monitor 
for presence of CRS-207.  For subjects with a central line port, a blood sample 
will also be taken through the port.  Subjects with samples positive for the 
presence of CRS-207 will initiate IV antibiotics per Section 5.2.2.5 and be re-
tested until negative cultures are confirmed.  See Section 6.8.1 for additional 
information on suspected CRS-207 or Listeria infection. 

 
 
 
 
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6.0 
PROCEDURES FOR HANDLING AES AND SAES 
6.1 
DEFINITION OF AN ADVERSE EVENT 
The following definition of an AE will be used for this study: 
Any untoward medical occurrence in a subject administered an 
investigational product and which does not necessarily have to have 
a causal relationship with this treatment.  An adverse event can 
therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to medicinal (investigational) product.  
Examples of AEs include the following: 
• 
Significant or unexpected worsening or exacerbation of the indication under 
study 
• 
Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in frequency or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product 
administration, even if they were present before the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction with 
another medical product 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication 
An overdose should not be reported as an AE or SAE; instead the symptoms 
resulting from the overdose should be reported as the AE or SAE. 
Examples of AEs do not include the following: 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy) (Instead, 
the medical condition that led to the procedure is an AE.) 
• 
Situations that are unwanted but in which an untoward medical occurrence 
did not occur, for example social inconvenience after admission to a hospital 

 
 
 
 
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• 
Anticipated day-to-day fluctuations of a preexisting disease or condition 
(present or detected before enrollment) that does not worsen overall 
• 
Expected progression of the disease being studied, including signs or 
symptoms of the disease being studied, unless progression is more severe 
than expected for the subject’s condition 
It is the responsibility of the investigator to perform periodic and special 
assessments for AEs.  The investigator and clinical staff will note all AEs offered 
by the subject at baseline, during administration of the CTM, and at the follow-up 
visit.  All clinical complaints volunteered by, or elicited from, the subject during 
the study will be recorded on the appropriate page of the CRF for the study period 
indicated.  If any AE occurs, the subject will receive appropriate treatment and 
medical supervision.  
All AEs judged to be clinically significant, including clinically significant 
laboratory abnormalities, will be followed until resolution.  All AEs will be 
summarized in the annual report or more frequently, if requested by the regulatory 
agency.  SAEs require special reporting in addition to documentation in the CRF 
as described below. 
6.2 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) 
In this study, the definition of an SAE is an AE that meets any of the following 
criteria: 
• 
Results in death 
• 
Is life-threatening 
Note: The term life-threatening in the definition of serious refers to an event 
in which the subject was at risk of death at the time of the event.  It does not 
refer to an event that hypothetically might have caused death if it were more 
severe. 
• 
Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the subject has been detained 
at the hospital or emergency ward for observation or treatment that would 
not have been appropriate in the physician’s office or out-patient setting.  
Complications that occur during hospitalization are AEs but not necessarily 

 
 
 
 
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SAEs.  An occurrence or complication that prolongs hospitalization is an 
SAE.  When there is doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered an SAE.  Hospitalization for 
elective treatment of a preexisting condition that did not worsen from its 
original baseline severity is not considered an SAE. 
Hospital admissions for overnight monitoring following CRS-207 infusion 
will not be considered an SAE unless the event meets criteria for seriousness 
other than hospitalization.   
• 
A persistent or significant disability or incapacity 
Note: The term disability means a substantial disruption of a person’s ability 
to conduct normal life functions.  This definition is not intended to include 
AEs of relatively minor medical significance, such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g. 
sprained ankle), that may interfere or prevent everyday life functions, but do 
not constitute a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
A congenital anomaly or birth defect 
• 
Other important medical event 
Note: Medical or scientific judgment should be exercised in deciding 
whether reporting is appropriate for other important medical events that may 
not result in death, be life-threatening, or require hospitalization but still 
may jeopardize the subject or may require medical intervention to prevent 
one of the outcomes listed in this definition.  These events should also be 
considered serious.  
An SAE requires additional detailed reports and follow-up.  The content of these 
detailed reports must address the investigator’s estimate of causality. 
6.3 
RECORDING AEs AND SAEs 
All AEs will be reported from the time study treatment is first administered to the 
subject (PV1 for Cohort 1 or XP1 for Cohort 2) through 28 days after receipt of 
final dose of investigational product. 

 
 
 
 
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All preexisting medical conditions will be recorded on the baseline physical 
examination page of the CRF.  Starting with the first administration of first 
investigational product, any new event or experience that was not present at 
screening, or worsening of an event present at screening, is considered to be an 
AE.  Unchanged, chronic conditions are not AEs and should not be recorded on 
the AE page of the CRF. 
When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (e.g. hospital progress notes, laboratory and diagnostic reports) 
relative to the event.  The investigator is to record all relevant information about 
any AE (including SAEs) on the AE page of the CRF.  It is not acceptable for the 
investigator to send photocopies of the subject’s medical records in lieu of the 
proper completion of the appropriate AE (or SAE) CRF pages.  However, there 
may be instances where copies of medical records for certain cases are requested.  
In such instances, all subject identifiers and PHI will be blinded on the copies of 
the medical records before submission to the appropriate authorities. 
The investigator will also attempt to establish a diagnosis of the event on the basis 
of signs, symptoms, or other clinical information.  In such cases, the diagnosis, 
not the individual signs and symptoms, should be documented on the appropriate 
CRF as the AE or SAE.  In addition, SAEs need to be reported on the SAE report 
form provided in the study procedures manual (SPM). The SPM provides 
additional guidelines. 
6.4 
ASSESSMENT OF GRADE 
The investigator will make an assessment of grade for each AE and SAE reported 
during the study, which will be recorded in the CRF.  The assessment will be 
based on the National Cancer Institute’s CTCAE, Version 4.03, and graded as 
shown below: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activities of daily living 

 
 
 
 
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• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
Any AE that changes in grade during its course will be recorded in the CRF at the 
highest level experience by the subject. 
6.5 
ASSESSMENT OF CAUSALITY 
The investigator is obligated to estimate the relationship between the 
investigational products and the occurrence of each AE or SAE by using his or 
her best clinical judgment.  Other causes, such as the history of the underlying 
disease, concomitant therapy, other risk factors, and the temporal relationship of 
the event to the investigational products will be considered and investigated.  The 
investigator will also consult the IB or product labeling information for marketed 
products in the determination of the assessment. 
There may be situations when an SAE has occurred and the investigator has 
minimal information to include in the initial report.  However, it is very important 
that the investigator always assess causality for every event before the 
transmission of the SAE.  The investigator may change his or her opinion of the 
causality in light of follow-up information, amending the SAE report.  The 
causality assessment (Table 3) is one of the criteria used to determine regulatory 
reporting requirements and should not be left blank. 

 
 
 
 
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Table 3. 
Assessment of Causality/Relatedness of AEs  
Term 
Definition 
Definitely related 
The AE is clearly related to the investigational agent(s) or research 
intervention: the AE has a temporal relationship to the administration 
of the investigational agent(s) or research intervention, follows a 
known pattern of response, and no alternative cause is present.  
Probably related  
The AE is likely related to the investigational agent(s) or intervention: 
the AE has a temporal relationship to the administration of the 
investigational agent(s) or research intervention and follows a known 
or suspected pattern of response, but an alternative cause may be 
present.  
Possibly related 
The AE may be related to the investigational agent(s) or intervention: 
the AE has a temporal relationship to the administration of the 
investigational agent(s) or research intervention, follows a suspected 
pattern of response, but an alternative cause is present. 
Unlikely to be related  
The AE is doubtfully related to the investigational agent(s) or 
intervention: the AE has a temporal relationship to the administration 
of the investigational agent(s) or research intervention but follows no 
known or suspected pattern of response, and an alternative cause is 
present.  
Unrelated (or not 
related) 
The AE is clearly NOT related to the investigational agent(s) or 
intervention: the AE has no temporal relationship to the 
administration of the investigational agent(s) or research intervention 
and follows no known or suspected pattern of response, and an 
alternative cause is present.  
AE = adverse event. 
6.6 
REPORTING OF SAEs 
Reporting of SAEs will begin at the time study treatment is first administered to 
the subject (PV1 for Cohort 1 or XP1 for Cohort 2) and will continue through 28 
days after receipt of final dose of investigational product.   
SAEs will be reported to the sponsor by phone, fax, or e-mail within 24 hours of 
the time the investigator becomes aware of the event.   
SAE Reporting Fax Number: 510-295-2666 
The Medical Monitor may also be contacted to discuss a safety event: 
Jackie Walling, MBChB, PhD: mobile: 650-483-9726 
The urgency for reporting SAE(s) is fourfold: 
1. 
To enable the safety department to fulfill the reporting requirements to the 
appropriate regulatory authority 

 
 
 
 
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2. 
To facilitate discussion (and implementation, if necessary) between the 
safety department and the investigator of appropriate follow-up measures in 
the event an expedited report is required 
3. 
To facilitate Aduro’s rapid dissemination of information about AEs to other 
investigators or sites in a multicenter study by using expediting reporting 
4. 
To facilitate investigator reporting of unanticipated problems involving risk 
to human subjects to the IRB and institutional biosafety committee 
In the event an SAE is observed, the SAE report will be completed as thoroughly 
as possible including the following: 
• 
All available details about the event 
• 
Signature of the investigator 
The SAE report will be forwarded to the sponsor or designee within the 
designated time frames.  If the investigator does not have all information about an 
SAE, the investigator will not wait to receive additional information before 
notifying the sponsor of the event and completing the form.  The form will be 
updated when additional information is received.  
Aduro will report all SAEs that are unexpected and considered possibly or 
probably related to the administration of the investigational agents to the Food 
and Drug Administration in the form of an expedited safety report within 
15 calendar days after receiving information on the SAE.  Aduro will also report 
to the United States Food and Drug Administration (FDA) and National Institutes 
of Health Office of Biotechnology Activities (NIH OBA) by fax or phone within 
7 days of receiving the information, any unexpected life-threatening or fatal SAEs 
that are considered at least possibly associated with the investigational agents.  
Aduro, or designee, will also notify all participating investigators of expedited 
safety reports within 15 calendar days after receiving information.  The 
investigators will notify their reviewing IRB and institutional biosafety committee 
(IBC) as required by institutional policies.  

 
 
 
 
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6.7 
FOLLOW-UP OF AEs AND SAEs 
After the initial AE or SAE report, the investigator is required to proactively 
follow each subject and provide further information to the safety department in 
regards to the subject’s condition. 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
Once the event is resolved, the appropriate AE or SAE report page will be 
updated.  The investigator will also ensure that the follow-up includes any 
supplemental information that may explain the causality of the event(s). 
New or updated information will be recorded on the originally completed AE or 
SAE report, with all changes signed and dated by the investigator or designee.  
The updated AE or SAE report will then be signed by the investigator and 
resubmitted to the safety department. 
6.8 
ADVERSE EVENTS OF SPECIAL INTEREST 
6.8.1 
Suspected Infection with CRS-207 or Listeria 
Suspected infection with CRS-207 and/or Listeria are considered adverse events 
of special interest (AESI) and should be reported following SAE reporting 
procedures irrespective of temporal relationship to study drug administration. In 
the event a subject has a positive Listeria or CRS-207 culture at any time during 
or after study participation, the event should be reported to the Sponsor within 24 
hours of the event. 
All AESIs must be reported for the duration of the study regardless of causality. 
In the case of a suspected persistent CRS-207 or Listeria infection that has not 
been confirmed by culture, collection of blood, urine and stool samples in 
duplicate is recommended. One set of samples should be cultured locally for 

 
 
 
 
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Listeria per institutional guidelines. Culture of cerebrospinal fluid should be 
obtained for subjects with suspected central nervous system infection. In such 
instances, analysis of cerebrospinal fluid should also include cell count, protein, 
glucose, and Gram stain. If samples are positive for Listeria, the Sponsor must be 
notified immediately, and the duplicate samples and Listeria isolate must be sent 
to Sponsor or designee for testing to confirm CRS-207. Instructions on collection, 
storage and shipping of samples for CRS-207 testing are provided in the Central 
Laboratory Manual.  
If Listeria has been confirmed at the clinical site or an external laboratory, all 
efforts should be made to obtain a sample of the bacterial isolate from the original 
positive culture and submit to the Sponsor for strain confirmation; records on all 
samples cultured during this period must be obtained and provided to the Sponsor.  
Refer to the Central Laboratory Manual for sample collection and shipping 
instructions. 
If infection with CRS-207 is confirmed or suspected, IV antibiotics (Section 
5.2.2.5) should be initiated as soon as possible and follow-up cultures obtained 
periodically to confirm absence/clearance of any CRS-207 infection.  

 
 
 
 
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7.0 
STUDY OR STUDY SITE TERMINATION AND SUBJECT 
DISCONTINUATION 
7.1 
PREMATURE STUDY OR STUDY SITE TERMINATION 
If Aduro, the investigator, the medical monitor, the study monitor, or appropriate 
regulatory officials discover conditions arising during the study that indicate that 
the study should be halted or that the study center should be terminated, this 
action may be taken after appropriate consultation among Aduro, the investigator, 
the medical monitor, and the study monitor.  Conditions that may warrant 
termination of the study include, but are not limited to the following: 
• 
The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study 
• 
A decision on the part of Aduro to suspend or discontinue testing, 
evaluation, or development of the product for any reason          
A study conducted at a single study site in a multicenter study may also warrant 
termination under the following conditions: 
• 
Failure of the investigator to enroll subjects into the study at an acceptable 
rate 
• 
Failure of the investigator to comply with pertinent regulations of 
appropriate regulatory authorities 
• 
Submission of knowingly false information from the research facility to 
Aduro, the study monitor, or appropriate regulatory authority 
• 
Insufficient adherence to protocol requirements  
Study termination and follow-up will be performed in compliance with the 
conditions set forth in the International Conference on Harmonisation (ICH) E6, 
Guideline for Good Clinical Practice, Sections 4.12, 4.13, 5.20, and 5.21. 
7.2 
SUBJECT DISCONTINUATION 
Subjects will be encouraged to complete the study; however, they may voluntarily 
withdraw at any time.  The investigator will provide a written explanation 
describing the reason for discontinuation in a source document, which will be 

 
 
 
 
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transcribed to the appropriate CRF page.  Subjects who wish to withdraw from the 
study will be encouraged to complete the planned administration of antibiotics, 
complete EOS assessments, post-treatment monitoring for CRS-207, and to 
complete assessments scheduled during the follow-up visit.  
Subjects who withdraw consent or discontinue treatment before completing at 
least 2 cycles of chemotherapy will be considered dropouts and may be replaced 
at the discretion of the lead investigator, sponsor and medical monitor.  A subject 
may be removed from treatment for the reasons listed in Sections 7.2.1 through 
7.2.4.   
7.2.1 
Adverse Event 
If a subject suffers an AE that, in the judgment of the investigator, Aduro, or the 
medical monitor, presents an unacceptable consequence or risk to the subject, the 
subject may be discontinued from further participation in the study. 
7.2.2 
Intercurrent Illness 
A subject may be discontinued from the study if, in the judgment of the 
investigator, the subject develops an intercurrent illness or complication 
(including progressive disease) that, in any way, justifies withdrawal from the 
study.  
7.2.3 
Noncompliance 
After consultation between the investigator, the medical monitor, or study 
monitor, and Aduro when appropriate, a subject may be discontinued from the 
study for the following administrative reasons: 
• 
Failure to receive study medication or treatment as mandated by the protocol  
• 
Failure to comply with protocol requirements 
• 
Unauthorized, subject-initiated changes in dosing regimen 

 
 
 
 
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7.2.4 
Refusal of CTM Administration 
If, for any reason, the subject refuses CTM administration during the study, the 
subject may be discontinued from the study, and the reason(s) for refusal will be 
documented on the appropriate CRF page.  Reasonable efforts should be made to 
monitor the subject for AEs and to complete follow-up assessments.  These 
efforts should be documented on the appropriate CRF page. 

 
 
 
 
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8.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL 
ANALYSIS 
8.1 
DATA COLLECTION AND PROCESSING 
CRFs will be used to capture study results and data.  The study coordinator or 
other authorized study personnel will transcribe data from source documents onto 
paper or electronic CRFs.  All CRFs will be reviewed and source verified by the 
study monitor during periodic site visits, and the study monitor will ensure that all 
data in the CRF are correct and complete.  Before or between visits, the medical 
monitor or study monitor may request copies of the CRFs for preliminary medical 
review.  Once the CRFs are complete and source-verified, the investigator must 
sign and date all required pages, verifying the accuracy of all data contained 
within the CRF.  Training will be provided on proper completion of CRFs. 
If electronic CRFs are used, training will be provided for the electronic data 
capture (EDC) system.  All personnel using the EDC system must have 
appropriate education, training, and experience.  The investigator will be provided 
with standard operating procedures (SOPs) (contained in the SPM or a 
vendor-specific SOP) on the use of the EDC system.  The investigator will be 
responsible for documenting employee education, training, and previous 
experience that pertains to the EDC system.  
The investigator must maintain adequate security of the EDC system, including 
documentation that all users have been trained on the appropriate SOPs and a list 
of authorized users.  To ensure attributability, all personnel responsible for data 
entry must obtain a unique electronic signature before any data can be entered in 
the CRFs.  The system must be configured to ensure that the signer cannot readily 
repudiate the signed record as not genuine.  Authorized study personnel will be 
assigned a unique password and associated electronic signature after receiving 
SOP training.  
If EDC systems other than those provided and maintained by the sponsor are used 
for documentation and data capture, the investigator must ensure that the systems 
are validated and ensure data backup as described in Section 9.2. 

 
 
 
 
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8.2 
STATISTICAL ANALYSIS 
8.2.1 
General Overview 
The data will be summarized in tables listing the mean, standard deviation, 
median, minimum, maximum and number of subjects in a group for continuous 
data; in tables listing count and percentage for categorical data; and median and 
standard error for time-to-event data.  Data will be listed for each subject.  All 
statistical analyses will be performed and data appendices will be created by using 
SAS.  The effects of noncompliance, dropouts, and covariates will be assessed to 
determine the impact on the general applicability of results from this study.  
Unless specified otherwise, summaries will be reported by treatment regimen 
(Cohort) and overall.  This corresponds to Cohort 1 (CRS-207 without Cy), 
Cohort 2 (CRS-207 with Cy), and overall.  For select summaries of disposition, 
baseline data, and key efficacy endpoints, summaries of Cohort 1 will be further 
broken out by subjects enrolled in the original and expansion phase.  No formal 
comparisons across enrollment phase (original vs. expansion) or treatment 
regimen (Cohort 1 vs. Cohort 2) will be performed.  
Further details of the analysis, including the handling of missing data 
transformations, assessing impact of the expansion cohort, impact of changes to 
the planned chemotherapy regimen and further modifications to populations of 
analysis will be provided in a separate statistical analysis plan. 
8.2.2 
Populations of Interest 
The full analysis (FAS) population is all subjects enrolled who receive at least one 
dose of study treatment. 
The per protocol population is defined as subjects who receive two doses of CRS-
207 (with or without Cy) followed by at least 4 cycles of pemetrexed and 
cisplatin. 
Subjects with major protocol violations will be excluded from the per protocol 
population.  The precise reasons for excluding subjects from the per protocol set 
will be fully defined and documented before database lock. 
8.2.3 
Baseline Comparability 
Demographics and baseline clinical variables for subjects will be summarized 
using descriptive statistics.  Relationship to efficacy and safety endpoints may be 

 
 
 
 
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assessed via scatter plots for pairs of continuous endpoints and summary statistics 
within categories for categorical / continuous pairs, and contingency tables (N, 
percent) for pairs of categorical endpoints.  Differences in baseline variables 
across enrollment phase (original vs. expansion) will be evaluated descriptively 
and may be used as covariates in sensitivity analyses of efficacy endpoints. 
8.2.4 
Efficacy Analysis 
Efficacy analysis will be conducted on full analysis and per protocol populations.  
Standard adjustments to analyses for pre-specified or baseline-suggested clinical 
covariates will be performed; these covariate-adjusted analyses will be considered 
secondary analyses.  The primary endpoint is the change in IFN-γ production of 
mesothelin-specific T cells by ELISPOT assay from baseline to (1) immediately 
after CRS-207 (with or without Cy), (2) after receiving chemotherapy, and (3) 
after receiving two subsequent doses of CRS-207 (with or without Cy) following 
chemotherapy.  Change from baseline will be compared via paired t-test of log-
transformed post/pre ELISPOT values and assessed for statistical significance via 
Hochberg multiplicity alpha adjustment.  T cell responses to mesothelin will be 
considered positive when the frequency of specific responses are ≥ 1 in 105 CD8+ 
peripheral blood lymphocytes (PBL) above the control sample and increased by at 
least 2-fold compared to baseline.  T cell responses to Lm (LLO) will be 
considered positive when specific T cell frequencies were ≥ 1 in 105 PBMCs and 
increased by at least 2-fold compared to baseline.  In addition, if change from 
baseline in the logarithmic scale is not normally distributed (that is, if p<0.05 by a 
Shapiro-Wilks test) then a Wilcoxon signed rank test will be performed instead. 
Analyses of other efficacy endpoints including changes in PFTs, objective tumor 
response, progression free survival, time to progression and overall survival will 
be conducted on the full analysis and per protocol populations.  Time to event 
data will be analyzed using Kaplan-Meier methods and will be calculated from 
date of first dose of study treatment.  Further details on the analyses including 
censoring strategies will be described in a statistical analysis plan. 
Exploratory analyses will be conducted to evaluate the relationship between PFT 
improvement and tumor response, as well as to evaluate the relationship between 
overall survival and tumor response.   

 
 
 
 
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8.2.5 
Safety Analysis 
AE data will be listed individually and incidence of AEs summarized by system 
organ class and preferred terms within a system organ class for each treatment 
group.  When calculating the incidence of AEs, each AE (based on preferred 
terminology defined by Medical Dictionary for Regulatory Activities, 
Version 13.1, or the most current version) will be counted only once for a given 
subject.  In analyses of grade and causality, if the same AE occurs on multiple 
occasions, the highest grade and strongest relationship to study drug will be 
assumed.  If two or more AEs are reported as a unit, the individual terms will be 
reported as separate experiences.   
Changes in vital signs, hematology, and clinical chemistry parameters from 
baseline to the end of the study will be examined.  Treatment-emergent changes 
from normal to abnormal values in key laboratory parameters will be identified. 
8.2.6 
Pharmacokinetic Analysis 
No formal pharmacokinetic or pharmacodynamic analyses are planned for the 
investigational agents used in this study.   
8.2.7 
Interim Analysis 
Safety data will be reviewed on an ongoing basis by Aduro, the investigator(s), 
and medical monitor. 
No formal interim analysis for this phase 1B study is planned. 
8.2.8 
Sample Size 
Up to 60 subjects in total may be enrolled, based on the original planned cohort of 
16 subjects and an expansion cohort that may enroll up to an additional 44 
subjects.  At least 32 subjects will receive CRS-207 in combination with 
chemotherapy (Cohort 1).  Additional subjects (up to 28) will receive Cy one day 
prior to each CRS-207 administration combined with chemotherapy (Cohort 2). 
The originally planned sample size calculation was based on the primary endpoint 
of change in mesothelin-specific T cell responses as measured from ELISPOT. 
With one primary parameter (ELISPOT) to be measured with respect to a change 
from baseline at three post-baseline time points, the sample size will be selected 
to allow each test to be performed using a 0.017 two-tailed significance level, in 

 
 
 
 
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order to allow the overall set of three tests to be very conservatively performed as 
if at an overall 0.05 level using a Bonferroni adjustment. Assuming 14 subjects 
with complete measurements of the main parameter at baseline and the three 
subsequent time points, there would be 80% power to detect a change from 
baseline to each time point equal to 1.0 standard deviations of the change (1.0 
effect size) using a two-tailed 0.017 level paired t-test.  This stringent multiplicity 
adjustment is for power computation only.  In practice, for analysis purposes, 
instead of requiring that each test achieve a 0.017 level in order to be declared 
significant, a less overly stringent Hochberg adjustment may be used.  In order to 
allow for a small number of inevaluable subjects, up to 16 subjects could be 
enrolled. 
The expansion cohort of up to 44 additional subjects, including subjects receiving 
Cy one day prior to CRS-207 (Cohort 2) is intended to obtain additional safety, 
immune and efficacy data for future study planning.  The expansion sample size is 
based on practical rather than statistical considerations.   

 
 
 
 
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9.0 
CLINICAL STUDY ADMINISTRATION 
9.1 
INFORMED CONSENT AND AUTHORIZATION FOR USE AND 
DISCLOSURE OF PHI  
Written informed consent and authorization of use and disclosure of PHI must be 
obtained from each subject (or the subject’s legally authorized representative) 
before performing any study-specific screening/baseline period evaluations.  One 
copy of the signed ICF and authorization for use and disclosure of the PHI form 
will be given to the subject, and the investigator will retain the original.  The ICF 
and authorization for use and disclosure of PHI, which is prepared by the 
investigator or the site, must be reviewed and approved by Aduro, the study 
monitor (if applicable), and the site’s IRB before the initiation of the study.  The 
ICF must contain the 20 elements of informed consent described in ICH E6, 
Section 4.8.  The authorization for use and disclosure of PHI must contain the 
elements required by Title 45 of the CFR, Section 164.508(b), for valid 
authorizations.   
9.2 
STUDY DOCUMENTATION 
9.2.1 
Investigator Information 
Investigator information is included in the SPM, which is updated as needed. 
9.2.2 
Investigator Study Files 
Documentation about the investigator and study staff, the IRB, and the institution, 
is required by the sponsor before study site initiation.  Copies of these documents 
as well as supplemental information, such as the investigator’s obligations, IB, 
clinical study protocol and amendments, safety information, CTM, biological 
samples, 
laboratory, 
SPM 
and 
study 
logs, 
monitoring 
activities, 
sponsor/investigator/study monitor correspondence, will be kept on-site in study 
site-specific binders. 
Aduro will be responsible for maintaining backup of all CRF data.  The 
investigator is responsible for maintaining backup of all electronic data systems 
used for primary documentation or source documentation.  Backup of electronic 
data will be performed periodically as described in the site-specific SOPs.  
Backup records must be stored at a secure location on site, and backup and 
recovery logs must be maintained to facilitate data recovery.  Finally, if an 

 
 
 
 
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electronic medical records system that is not supported by the sponsor (or is 
discontinued or decommissioned) is used, the investigator must maintain a system 
to retrieve these records or arrange for the transfer of these records to an alternate 
electronic format or to paper. 
Changes to any electronic records requires an audit trail, in accordance with 
21 CFR 11.10(e), and should include who made the changes and when and why 
the changes were made.  An audit trail is defined as a secure, computer-generated, 
time-stamped electronic record that will allow reconstruction of the course of 
events relating to the creation, modification, and deletion of an electronic record.  
Audit trails must be created incrementally, in chronological order, and in a 
manner that does not allow new audit trail information to overwrite existing data.  
Finally, audit trails should be in a readable format and readily available at the 
study site and any other location where electronic study records are maintained. 
Audit trails are generated automatically for electronic CRFs.  The investigator is 
responsible for maintaining audit trails of all electronic data systems used for 
primary documentation or source documentation. 
9.2.3 
CRFs and Source Documentation 
The investigator must make study data accessible to the site monitor, to other 
authorized representatives of Aduro, and to the appropriate regulatory authority 
inspectors.  The original CRF for each subject will be checked against source 
documents at the study site by the site monitor.   
9.2.4 
Retention of Study Documents 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and 
electronic documentation and administrative records, must be retained by the 
investigator for a minimum of 2 years after notification that the appropriate 
regulatory authority has approved the product for the indication under study, 
notification that the entire clinical investigation will not be used in support of a 
marketing application, or notification that the marketing application was not 
approved.  No study documents will be destroyed or moved to a new location 
without prior written approval from Aduro.  If the investigator relocates, retires, 
or withdraws from the clinical study for any reason, all records required to be 
maintained for the study should be transferred to an agreed-upon designee, such 
as another investigator at the institution where the study was conducted. 

 
 
 
 
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Audit trails for electronic documents must be retained for a period at least as long 
as that required for the subject electronic records to which they pertain.  The 
investigator must retain either the original or a certified copy of audit trails. 
9.3 
CONFIDENTIALITY 
9.3.1 
Data 
All information about the nature of the proposed investigation provided by Aduro 
or the study monitor to the investigator (with the exception of information 
required by law or regulations to be disclosed to the IRB, the subject, or the 
appropriate regulatory authority) must be kept in confidence by the investigator. 
9.3.2 
Subject Anonymity 
The anonymity of participating subjects must be maintained.  Subjects will be 
identified by their initials and an assigned subject number on CRFs and other 
documents retrieved from the site or sent to the study monitor, Aduro, regulatory 
agencies, or central laboratories/reviewers.  Documents that identify the subject 
(e.g. the signed ICF) must be maintained in strict confidence by the investigator, 
except to the extent necessary to allow auditing by the appropriate regulatory 
authority, the study monitor, or Aduro representatives. 
9.4 
PROTOCOL COMPLIANCE 
Substantive changes in the protocol include changes that affect the safety of 
subjects or changes that alter the scope of the investigation, the scientific quality 
of the study, the experimental design, dosages, assessment variable(s), the number 
of subjects treated, or the subject selection criteria.  Such changes must be 
prepared as a protocol amendment by Aduro only upon joint approval of the 
changes by Aduro and the investigator.  A protocol amendment must receive IRB 
approval before implementation.  In parallel with the IRB approval process, the 
protocol amendment will be submitted to the appropriate regulatory authority as 
an amendment to the regulatory submission under which the study is being 
conducted.  If a protocol amendment requires changes in the ICF, the revised ICF 
prepared by the investigator must also be approved by Aduro, the study monitor, 
and the IRB before implementation. 
Emergency departures from the protocol that eliminate an apparent immediate 
hazard to a particular subject and that are deemed crucial for the safety and 

 
 
 
 
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well-being of that subject may be instituted for that subject only.  The investigator 
or the attending physician also will contact the medical monitor as soon as 
possible in the case of such a departure.  These departures do not require 
preapproval by the IRB; however, the IRB and the medical monitor must be 
notified in writing as soon as possible after the departure has been made.  In 
addition, the investigator will document in the subject’s CRF the reasons for the 
protocol deviation and the ensuing events.  
9.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY 
The study monitor, in accordance with Aduro’s requirements, will ensure that the 
study is conducted and documented properly by carrying out the relevant 
activities outlined in ICH E6, Section 5.18.4. 
9.6 
GENERAL INFORMATION 
The investigator should refer to the IB, product labels, and the SPM, any other 
information provided during the study initiation visit or by the study monitor, and 
the appendices of this protocol for further information about this investigational 
new product or details of the procedures to be followed during the course of this 
study. 
 

 
 
 
 
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10.0 
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Florell SR, Coffin CM, Holden JA, et al. Preservation of RNA for functional 
genomic studies: a multidisciplinary tumor bank protocol. Modern pathology : an official 
journal of the United States and Canadian Academy of Pathology, Inc 2001;14:116-28. 
 
 

 
 
 
 
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APPENDICES 

 
 
 
 
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APPENDIX A 
Modified RECIST for Assessment of Response in MPM 
 
 
 
 
Page 76

Annals of Oncology 15: 257–260, 2004
Original article
DOI: 10.1093/annonc/mdh059
© 2004 European Society for Medical Oncology
Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma
M. J. Byrne1* & A. K. Nowak1,2
*Correspondence to: Dr M. J. Byrne, Department of Medical Oncology, 
Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia. 
Tel: +61-8-93463841; Fax: +61-8-93463390; 
E-mail: mjbyrne@cyllene.uwa.edu.au
1Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA 6009; 2Department of Medicine, University of Western Australia, Nedlands, 
WA 6009, Australia
Received 29 May 2003; revised 5 August 2003; accepted 30 September 2003
Background: The growth pattern of malignant pleural mesothelioma makes the use of RECIST (response
evaluation criteria in solid tumours) response criteria difficult. We have developed and validated Modified
RECIST criteria adapted to the growth pattern of malignant pleural mesothelioma.
Patients and methods: We evaluated 73 patients from two clinical trials of cisplatin/gemcitabine chemo-
therapy in malignant pleural mesothelioma. Tumour thickness perpendicular to the chest wall or mediastinum
was measured in two positions at three separate levels on thoracic CT scans. The sum of the six measurements
defined a pleural unidimensional measure. Bidimensionally measureable lesions were measured unidimension-
ally as for RECIST. All measurements were added to obtain the total tumour measurement. A reduction of
at least 30% on two occasions 4 weeks apart defined a partial response; an increase of 20% over the nadir
measurement, progressive disease. The validity of the modified criteria was gauged by evaluating survival and
pulmonary function.
Results: Response according to these criteria predicted for superior survival (15.1 versus 8.9 months; P = 0.03)
and forced vital capacity (FVC) increase during treatment (P <0.0001). A significant correlation between
change in linear tumour measurement and FVC was seen (R = 0.63; P = 0.0001).
Conclusion: These Modified RECIST criteria for tumour response correlate with survival and lung function
and can be used to measure outcome in pleural mesothelioma.
Key words: chemotherapy, clinical trials, mesothelioma, RECIST, response criteria, validation
Introduction
The ability to measure reproducibly tumour response to treatment
is vital in the development of new drugs and therapeutic combina-
tions, particularly for the conducting of phase II studies. Con-
ventional response criteria have always been difficult to apply to
malignant mesothelioma due to its unique pattern of growth.
Malignant mesothelioma most commonly grows as a ‘rind’
around the pleural surface, and on computed tomography (CT)
scan may not produce spherical lesions with bidimensionally
measurable diameters. The WHO criteria [1] are poorly suited to
evaluating response in mesothelioma, as they were developed
principally to assess bidimensionally measurable disease. When
used for unidimensional measurement, these criteria require a 50%
decrease in the sum of unidimensional measurements to define a
partial response (PR). This equates to a 75% decrease in the sum
of the products of perpendicular diameters rather than the 50%
decrease required to define response in bidimensionally measur-
able lesions.
The recently developed RECIST (response evaluation criteria
in solid tumours) criteria [2] are more suited to tumour assessment
in mesothelioma, as they specify the use of unidimensional measure-
ments, with PR defined as a 30% decrease in the sum of the
longest diameter for all target lesions. However, the selection of
measurement sites in mesothelioma is difficult, and without fur-
ther definition of the method of measurement, the RECIST criteria
could be applied differently by different investigators (Figure
1A). Early experience suggests that modification of the criteria
may be required in the special case of mesothelioma [3].
We have developed a modification of the RECIST criteria
specifically to address the difficulties of measurement inherent in
assessing changes in tumour bulk in pleural mesothelioma. We
have previously performed two phase II clinical trials of the use of
cisplatin and gemcitabine in patients with measurable pleural
mesothelioma; a single centre study [4] and a subsequent confirm-
atory multicentre study [5]. In these studies, response rates of
47.6% [4] and 33% [5] were seen. Response criteria that incor-
porated both unidimensional and bidimensional measurements
had been developed and used to assess response in these two trials
(‘original response criteria’). Using Modified RECIST criteria,
we have now reassessed the response to treatment for a total of
73 patients who entered these two studies. To validate these new
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criteria we have related response to survival and to serial changes
in pulmonary function on treatment.
Patients and methods
Patient population
Data on the 73 patients entered in the two previous clinical trials of cisplatin
and gemcitabine in malignant pleural mesothelioma were obtained. All patients
had measurable disease, defined as pleural tumour thickness of at least 1.5 cm
on spiral CT scan, and histologically or cytologically confirmed mesothelioma.
CT scans had been performed in all patients prior to the first cycle of chemo-
therapy, and then before the second, fourth and sixth cycles. Further CT scans
were performed after the final cycle of chemotherapy, and then twice a month
until disease progression. Forced vital capacity (FVC) had been measured
prior to study entry and on day 1 of each chemotherapy cycle in 52 patients
entered on the second study.
The original response criteria used in both trials were as follows. Tumour
measurements were performed on transverse cuts on thoracic CT scans at three
separate anatomically reproducible levels on the study entry CT scan and at the
same levels on subsequent scans. Where possible, bidimensional lesions were
measured. If there were no bidimensionally measurable lesions, unidimen-
sional measurements of pleural tumour thickness were performed. Bidimen-
sionally measurable lesions were measured using the longest dimension and
the length perpendicular to the longest measurement. For unidimensionally
measurable lesions, thickness of pleural tumour was measured at two separate
sites on each of the three levels and the six measurements summated to pro-
duce a total measurement. Palpable masses were measured clinically on day 1
of each cycle as for bidimensionally measurable lesions. A pleural effusion
was not considered a measurable lesion.
Tumour response was defined as: (i) complete response (CR): disappear-
ance of all known disease, determined by two observations not less than 4 weeks
apart; (ii) PR: a ≥50% decrease in the sum of the products of perpendicular
diameters of bidimensionally measured lesions on two occasions not less than
4 weeks apart, or a ≥30% decrease in the sum of linear tumour measurements
on two observations not less than 4 weeks apart; (iii) no change: a decrease in
bidimensional tumour area of <50% or an increase of <25%, or a decrease in
the sum of unidimensional measurements of <30% or an increase of <25%,
provided no new lesions have appeared; (iv) progressive disease: a ≥25%
increase in the size of the tumour being measured (unidimensional or bidimen-
sional) or the appearance of new lesions.
Where response at sites measured bidimensionally differed from that at
sites measured unidimensionally, the overall patient response was assessed by
an audit group. The sites with dominant tumour bulk were favoured.
The protocols for each study were approved by the Committee for Human
Rights of the University of Western Australia and the Sir Charles Gairdner
Hospital Clinical Drug Trials Committee. Written informed consent was
obtained from each patient before entry.
Modified RECIST criteria
Modified RECIST criteria were developed. The major problems in applying
the RECIST criteria to malignant pleural mesothelioma are in the interpreta-
tion of the meaning and placement of the ‘longest unidimensional diameter’ of
the target tumour mass to be measured. The longest diameter of a tumour mass
is frequently that which follows the inner curve of the chest wall. Defining the
limits of such a diameter is often problematical. When the tumour regresses
with treatment the line may cross an area outside the tumour margin because of
the curve of the chest wall. This may produce difficulty with reproducibility of
measurement. Furthermore, the longest tumour diameter may be between two
fixed structures, such as the thoracic vertebrae and the carina, and measure-
ment in these areas may not fully reflect tumour response.
The Modified RECIST criteria we have developed were as follows. Tumour
thickness perpendicular to the chest wall or mediastinum was measured in two
positions at three separate levels on transverse cuts of CT scan (Figure 1B).
The sum of the six measurements defined a pleural unidimensional measure.
Transverse cuts at least 1 cm apart and related to anatomical landmarks in the
thorax were chosen to allow reproducible assessment at later time points. If
measureable tumour was present, transverse cuts in the upper thorax, above the
level of division of the main bronchi were preferred. At reassessment, pleural
thickness was measured at the same position at the same level and by the same
observer. This was not necessarily the greatest tumour thickness at that level.
Nodal, subcutaneous and other bidimensionally measurable lesions were
measured unidimensionally as per the RECIST criteria. Unidimensional
measurements were added to obtain the total tumour measurement.
CR was defined as the disappearance of all target lesions with no evidence
of tumour elsewhere, and PR was defined as at least a 30% reduction in the
total tumour measurement. A confirmed response required a repeat obser-
vation on two occasions 4 weeks apart. Progressive disease (PD) was defined
as an increase of at least 20% in the total tumour measurement over the nadir
measurement, or the appearance of one or more new lesions. Patients with
stable disease (SD) were those who fulfilled the criteria for neither PR nor PD.
Figure 1. Example of measurement of a single computed tomography scan 
slice. (A) Lines represent possible interpretations of ‘longest tumour 
diameter’ according to current RECIST criteria. (B) Lines represent 
suggested measurement sites perpendicular to fixed structures, chest wall 
and vertebral column, according to Modified RECIST criteria.
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B 

259
Validation of modified criteria
The response status of all 73 patients was re-assessed at each trial time point
according to these Modified RECIST criteria. Patients were assigned to one of
two groups: responding patients (‘responders’) and patients with SD or PD
(‘non-responders’). Overall survival from the start of treatment and serial
changes in FVC were analysed for these two groups as a surrogate measure of
patient benefit.
Results
Tumour measurements from a total of 236 CT scans from 73
patients were reassessed for response status at each time point in
the trials according to the modified criteria. In general there was a
close correlation between the original response criteria and the
Modified RECIST. Of 81 time points originally showing PR, 72
remained classified as PR, five became SD and four became PD.
Of 105 time points originally showing SD, 93 remained as SD, 11
became PR and one became PD. Of 50 time points originally
showing PD, 47 remained PD, two became SD and one became
PR (Table 1). The overall confirmed response rate as assessed by
the two systems did not differ, as two patients classified as SD
became PR and two patients classified as PR became SD (Table 2).
Median survival was plotted as a Kaplan–Meier curve for the
responding and non-responding patients (Figure 2). There was
a statistically significant difference in survival between the
two patient groups (log rank test P = 0.03). Median survival was
15.1 months for responding patients and 8.9 months for non-
responding patients.
FVC was plotted as a percentage of starting FVC for the
responding and non-responding patients (Figure 3). FVC improved
significantly over the course of treatment for responding patients
as compared with non-responding patients (P = 0.0001).
The change in FVC against change in linear tumour measure-
ment was plotted for each patient (Figure 4); a significant cor-
relation was seen (R = 0.63, P = 0.001).
Discussion
The response criteria used in our previous two trials of chemo-
therapy in mesothelioma incorporated bidimensional measure-
ments, as the WHO response criteria were widely used when the
first of these trials began accrual. These response criteria were
not altered for the second trial, which sought to broaden the
applicability of our findings in the first single-centre study into a
Table 1. Comparison of response at individual time point observations 
between original response criteria and Modified RECIST criteria
RECIST, response evaluation criteria in solid tumours; CR, complete 
response; PR, partial response; SD, stable disease; PD, progressive disease.
Original response criteria
Modified RECIST criteria
CR
PR
SD
PD
Total
CR
0
0
0
0
0
PR
0
72
5
4
81
SD
0
11
93
1
105
PD
0
1
2
47
50
Total
0
84
100
52
236
Table 2. Comparison of response rates for original response criteria versus 
Modified RECIST criteria
RECIST, response evaluation criteria in solid tumours; CR, complete 
response; PR, partial response; SD, stable disease; PD, progressive disease.
CR
PR
SD
PD
Overall response (%)
Original response 
criteria
0
27
40
6
37
Modified RECIST 
criteria
0
27
40
6
37
Figure 2. Kaplan–Meier survival curve of overall survival (days) from start 
of treatment for 73 patients treated with cisplatin and gemcitabine. 
Responding (dashed line) versus non-responding (solid line) patients as per 
Modified RECIST criteria. P value represents results of log rank test.
Figure 3. Forced vital capacity (FVC) as percentage of individual baseline 
FVC for all 73 patients treated with cisplatin and gemcitabine. Responding 
(filled squares) versus non-responding (open squares) patients as per 
Modified RECIST criteria. P value represents results ANOVA.
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l100 
... L_ Responding patients 
__J_ Non-responding patients 
Cl) -
c,s ... 
iv 
> 
·s: ... 
:::, 
en 
=i ... 
Cl) > 
0 
80 
60 
40 
20 
p=0.03 
0 
0 
250 
500 
750 
1000 
1250 
Overall survival tiITB (days) 
170 
S 160 
p<0.0001 
] 
,= 
150 
&a, 140 
T 
t -------·• I 
!j:: _/v-'f---t--
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2 
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··• ·- Responding patients 
-o- Non-responding patients 
5 
6 

260
multicentre setting, adding prospective evaluation of quality of
life and lung function end points. In order to make the response
rates of the two trials directly comparable, it was important that
the measurement criteria used in the two studies were the same.
Subsequently, the RECIST criteria have been developed and
become widely accepted and used in clinical trials. The applica-
tion of RECIST criteria could, however, be variably interpreted by
different investigators in mesothelioma, and this may lead to
unsatisfactory results [3]. We have developed Modified RECIST
criteria that are specifically designed to address the unique growth
pattern of pleural malignant mesothelioma. Use of these modified
response criteria did not materially alter the response rates in our
two previous trials. However, the modified criteria avoided diffi-
cult and ambiguous situations that arose in response interpretation
in the two previous trials; for example, how to evaluate response
when discordance between unidimensional and bidimensional
lesions occurred.
Whilst tumour response and progression directly reflect changes
in tumour bulk, they are most clinically useful when they relate
closely to other measures of a patient’s condition. Response is a
surrogate for patient benefit in the evaluation of new drugs and
combinations. Patient benefit in pleural mesothelioma may include
an improvement in survival or lung function, and improvement in
symptom control or quality of life. Thus, it is important that any
valid measurement of response should reflect changes in these
parameters. We have demonstrated that these Modified RECIST
criteria successfully distinguish between responders and non-
responders for the parameters of survival and change in FVC, thus
demonstrating their validity.
Further evaluation of these modified criteria should be per-
formed before they can be incorporated routinely into future clin-
ical trials. The development of an automated measurement format
may enhance the speed and reproducibility of the measurements
[6] and go some way to overcoming the potential problem of inter-
observer variability. We have avoided this issue by using the same
observer or an audit group to undertake the measurements. Tests
of inter-observer variability are important, however, as has been
demonstrated in the assessment of response in lung cancer [7]. To
confirm the practicality of the criteria they should be applied to a
group of clinicians who lack extensive experience in the measure-
ment of mesothelioma in clinical trials.
Acknowledgements
A.K.N. was the recipient of an Eva K. A. Nelson scholarship.
References
1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of
cancer treatment. Cancer 1981; 47: 207–214.
2. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate
the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:
205–216.
3. van Klaveren RJ, Aerts JGJV, de Bruin HG et al. Inadequacy of the
RECIST criteria for the evaluation of response in patients with malignant
pleural mesothelioma (MPM). Proc Am Soc Clin Oncol 2002; 21: 310a.
4. Byrne MJ, Davidson JA, Musk AW et al. Cisplatin and gemcitabine treat-
ment for malignant mesothelioma: a phase II study. J Clin Oncol 1999;
17: 25–30.
5. Nowak AK, Byrne MJ, Williamson R et al. A multicentre phase II study
of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer
2002; 87: 491–496.
6. Armato SG, Oxnard GR, Macmahon H et al. A computer interface for the
semi-automated measurement of mesothelioma on CT scans. Proc Am
Soc Clin Oncol 2003; 22: 668.
7. Erasmus JJ, Gladish GW, Broemeling L et al. Interobserver and intra-
observer variability in measurement of non-small-cell carcinoma lung
lesions: implications for assessment of tumor response. J Clin Oncol
2003; 21: 2574–2582.
Figure 4. Forced vital capacity (FVC) versus total tumour measurement 
standardised as percentage of individual baseline on day 1 of cycle 1.      
R = 0.6304, the result of linear regression analysis; P <0.0001, significance 
of deviation from 0 of the line of regression.
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-300 
.... 
Cl) g_ 
C, 
+ 
.... 200 
>. 
ns 
'tJ 
0 
100 
:... 
LI. 
+ 
+ + 
+ 
R=0.6304 
p<0.0001 
0 
50 
100 
150 
200 
Total tumor measurement (% of day 
1 cycle 1) 

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APPENDIX B 
Immune-related Response Criteria (irRC) Quick Reference 
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Comparison between RECIST 1.1 criteria and the irRC* 
RECIST 1.1 
irRC RECIST 1.1 
New, measurable 
lesions 
Always represent PD 
Incorporated into tumor 
burden 
New, non-
measurable 
lesions  
Always represent PD 
Does not define 
progression (but precludes 
irCR) 
Non-index 
lesions 
Changes contribute to defining best 
overall response (BOR) of CR, PR, SD, 
and PD 
Contribute to defining 
irCR (complete 
disappearance required) 
CR 
Disappearance of all lesions in two 
consecutive observations not less than 4 
week apart 
Disappearance of all 
lesions in two consecutive 
observations not less than 
4 week apart if single arm 
trial and primary endpoint 
only 
PR 
> 30% decrease in the sum of the
diameters of all index lesions compared
with baseline in two observations at least
4 week apart, in absence of new lesions
or unequivocal progression of non-index
lesions
≥ 30% decrease in tumor 
burden compared with 
baseline in two 
observations at least 4 
week apart if single arm 
trial and primary endpoint 
only 
SD 
< 30% decrease in sum of longest 
diameters of all index lesions compared 
with baseline cannot be established nor < 
20% increase compared with nadir, in 
the absence of new lesions or 
unequivocal progression of non-index 
lesions 
< 30% decrease in tumor 
burden compared with 
baseline cannot be 
established nor < 20% 
increase compared with 
nadir 
PD 
At least 20% increase in the sum of the 
longest diameters of index lesions and/or 
unequivocal progression of non-index 
lesions 
At least 20% increase in 
tumor burden compared 
with nadir (at any single 
time point) in two 
consecutive observations 
at least 4 week apart 
Handling of 
lymph nodes 
Lymph nodes are considered 
pathologically enlarged if >10 mm in 
SAD.  To be measurable, nodal lesions 
must be ≥ 15 mm in SAD.  Nodal 
lesions with SAD >10 mm and <15 mm 
are non- measurable.  The sum of the 
diameters (LD for extranodal target 
lesions, SAD for nodal lesions) is 
followed through the course of therapy 
Not differentiated from 
other tumor measurements 
•
Based on Wolchok et al., 2009
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Derivation of irRC Overall Responses* 
(Modified for RECIST 1.1. Criteria) 
 
Measurable response 
Non-measureable response 
Overall 
response 
Index 
and 
new, 
measurable lesions 
(tumor burden)** % 
Non-index lesions 
New, non- 
measurable lesions 
Using irRC 
↓ 100 
Absent 
Absent 
irCR/\ 
↓ 100 
Stable 
Any 
irPR/\ 
↓ 100 
Unequivocal progression 
Any 
irPR/\ 
↓ ≥ 30 
Absent/ Stable 
Any 
irPR/\ 
↓ ≥ 30 
Unequivocal progression 
Any 
irPR/\ 
↓ <30 to <20↑ 
Absent/ Stable 
Any 
irSD 
↓ <30 to <20↑ 
Unequivocal progression 
Any 
irSD 
≥ 20↑ 
Any 
Any 
irPD/\ 
* Based on Wolchok et al., 2009 
**Decreases assessed relative to baseline, including measurable lesions only (>5 x 5 mm). 
/\Assuming response (irCR or irPR) and progression (irPD) are confirmed by a second consecutive 
assessment at least 4 weeks apart. 
 
 
Defining immune-related Response Criteria by RECIST 1.1 criteria at the appropriate 
radiographic assessment time points (irDCR at the second consecutive radiographic 
assessment): 
 
1. Any patient with stable disease or progressive disease at any time in the trial with "rapid 
clinical deterioration" felt to be related to disease progression is irPD 
 
2. Any patient who meets the criteria for RECIST 1.1 CR at a radiographic assessment time 
point is irCR 
 
3. Any patient who meets the criteria for RECIST 1.1 PR at a radiographic assessment time 
point is irPR 
 
4. Any patient who meets the criteria for RECIST 1.1 SD at a radiographic assessment time 
point is irSD 
 
5. A patient with RECIST 1.1 PD but no rapid clinical deterioration may stay on study if 
his/her next tumor measurement evaluation is stable disease or better. 
 
6. If patient has first time PD by RECIST 1.1 criteria, call it unconfirmed PD for irRC 
RECIST 1.1. 
 
7. A patient with unconfirmed irPD at a radiographic assessment time point whose next 
tumor measurement is SD or better will be considered to be included in the irDCR at 
the second consecutive radiographic assessment time point. 
 
8. A patient with unconfirmed irPD at a radiographic assessment time point who fails to 
qualify for RECIST 1.1 SD or unconfirmed CR or PR by next tumor measurement 
will be considered to have RECIST 1.1 PD and irPD at the initial radiographic 
assessment time point. 
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APPENDIX C 
ALIMTA Prescribing Information 
Page 84

1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use 
ALIMTA safely and effectively. See full prescribing information for 
ALIMTA.
ALIMTA (pemetrexed for injection) Lyophilized Powder, for Solution for 
Intravenous Use
Initial U.S. Approval: 2004
--------------------------- RECENT MAJOR CHANGES --------------------------
Warnings and Precautions, Third Space Fluid (5.7) --- removal
11/2011
----------------------------INDICATIONS AND USAGE ---------------------------
ALIMTA® is a folate analog metabolic inhibitor indicated for:
•
Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung 
Cancer:
•
Initial treatment in combination with cisplatin. (1.1)
•
Maintenance treatment of patients whose disease has not 
progressed after four cycles of platinum-based first-line 
chemotherapy. (1.2)
•
After prior chemotherapy as a single-agent. (1.3)
•
Mesothelioma: in combination with cisplatin. (1.4)
Limitations of Use:
•
ALIMTA is not indicated for the treatment of patients with squamous 
cell non-small cell lung cancer. (1.5)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Combination use in Non-Small Cell Lung Cancer and Mesothelioma:
Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each
21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning 
30 minutes after ALIMTA administration. (2.1)
•
Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose 
of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. (2.2)
•
Dose Reductions: Dose reductions or discontinuation may be needed 
based on toxicities from the preceding cycle of therapy. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS ---------------------
•
100 mg vial for injection (3)
•
500 mg vial for injection (3)
-------------------------------CONTRAINDICATIONS------------------------------
History of severe hypersensitivity reaction to pemetrexed. (4)
------------------------ WARNINGS AND PRECAUTIONS -----------------------
•
Premedication regimen: Instruct patients to take folic acid and 
vitamin B12. Pretreatment with dexamethasone or equivalent reduces 
cutaneous reaction. (5.1)
•
Bone marrow suppression: Reduce doses for subsequent cycles based on 
hematologic and nonhematologic toxicities. (5.2)
•
Renal function: Do not administer when CrCl <45 mL/min. (2.4, 5.3)
•
NSAIDs with renal insufficiency: Use caution in patients with mild to 
moderate renal insufficiency (CrCl 45-79 mL/min). (5.4)
•
Lab monitoring: Do not begin next cycle unless ANC ≥1500 cells/mm3, 
platelets ≥100,000 cells/mm3, and CrCl ≥45 mL/min. (5.5)
•
Pregnancy: Fetal harm can occur when administered to a pregnant 
woman. Women should be advised to use effective contraception 
measures to prevent pregnancy during treatment with ALIMTA. (5.6)
-------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions (incidence ≥20%) with single-agent use 
are fatigue, nausea, and anorexia. Additional common adverse reactions when 
used in combination with cisplatin include vomiting, neutropenia, leukopenia, 
anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and 
Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 
or www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS ------------------------------
•
NSAIDs: Use caution with NSAIDs. (7.1)
•
Nephrotoxic drugs: Concomitant use of these drugs and/or substances 
which are tubularly secreted may result in delayed clearance. (7.2)
See 17 for PATIENT COUNSELING INFORMATION and 
FDA-approved patient labeling
Revised: 12/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Nonsquamous Non-Small Cell Lung Cancer – Combination 
with Cisplatin
1.2
Nonsquamous Non-Small Cell Lung Cancer – Maintenance
1.3
Nonsquamous Non-Small Cell Lung Cancer – After Prior 
Chemotherapy
1.4
Mesothelioma
1.5
Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
Combination Use with Cisplatin
2.2
Single-Agent Use
2.3
Premedication Regimen
2.4
Laboratory Monitoring and Dose Reduction/Discontinuation 
Recommendations
2.5
Preparation and Administration Precautions
2.6
Preparation for Intravenous Infusion Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Premedication Regimen
5.2
Bone Marrow Suppression
5.3
Decreased Renal Function
5.4
Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
with Mild to Moderate Renal Insufficiency
5.5
Required Laboratory Monitoring
5.6
Pregnancy Category D
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
7.2
Nephrotoxic Drugs
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Patients with Hepatic Impairment
8.7
Patients with Renal Impairment
8.8
Gender
8.9
Race
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Non-Small Cell Lung Cancer (NSCLC) – Combination with 
Cisplatin
14.2
Non-Small Cell Lung Cancer – Maintenance
14.3
Non-Small Cell Lung Cancer – After Prior Chemotherapy
14.4
Malignant Pleural Mesothelioma
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
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17
PATIENT COUNSELING INFORMATION
17.1
Need for Folic Acid and Vitamin B12
17.2
Low Blood Cell Counts
17.3
Gastrointestinal Effects
17.4
Concomitant Medications
*Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin
ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or 
metastatic nonsquamous non-small cell lung cancer.
1.2
Nonsquamous Non-Small Cell Lung Cancer - Maintenance
ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small 
cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
1.3
Nonsquamous Non-Small Cell Lung Cancer - After Prior Chemotherapy
ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-
small cell lung cancer after prior chemotherapy.
1.4
Mesothelioma
ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose 
disease is unresectable or who are otherwise not candidates for curative surgery.
1.5
Limitations of Use
ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies 
(14.1, 14.2, 14.3)]
2
DOSAGE AND ADMINISTRATION
2.1
Combination Use with Cisplatin
Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma
The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 
21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end
of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin
package insert for more information.
2.2
Single-Agent Use
Nonsquamous Non-Small Cell Lung Cancer
The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 
21-day cycle.
2.3
Premedication Regimen
Vitamin Supplementation
To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or 
multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the 
first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. 
Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and 
every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic 
acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic 
acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].
Corticosteroid
Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone 
(or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth 
twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].
2.4
Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations
Monitoring
Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should 
be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. 
Patients should not begin a new cycle of treatment unless the ANC is ൒1500 cells/mm3, the platelet count is ൒100,000 cells/mm3, and 
creatinine clearance is ൒45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see 
Warnings and Precautions (5.5)].
Dose Reduction Recommendations
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic 
toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients 
should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with 
cisplatin.
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Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities
Nadir ANC <500/mm3 and nadir platelets ൒50,000/mm3.
75% of previous dose (pemetrexed and cisplatin).
Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.
75% of previous dose (pemetrexed and cisplatin).
Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.
50% of previous dose (pemetrexed and cisplatin).
a These criteria meet the CTC version 2.0 (NCI 1998) definition of ൒CTC Grade 2 bleeding.
If patients develop nonhematologic toxicities (excluding neurotoxicity) ൒Grade 3, treatment should be withheld until 
resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.
Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b
Dose of ALIMTA
(mg/m2)
Dose of Cisplatin
(mg/m2)
Any Grade 3 or 4 toxicities except mucositis
75% of previous dose
75% of previous dose
Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 
4 diarrhea
75% of previous dose
75% of previous dose
Grade 3 or 4 mucositis
50% of previous dose
100% of previous dose
a NCI Common Toxicity Criteria (CTC).
b Excluding neurotoxicity (see Table 3).
In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients 
should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.
Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity
Dose of ALIMTA
(mg/m2)
Dose of Cisplatin
(mg/m2)
CTC Grade
0-1
100% of previous dose
100% of previous dose
2
100% of previous dose
50% of previous dose
Discontinuation Recommendation
ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity 
after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
Renally Impaired Patients
In clinical studies, patients with creatinine clearance ൒45 mL/min required no dose adjustments other than those 
recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make 
dosage recommendations for this group of patients [see Clinical Pharmacology (12.3)]. Therefore, ALIMTA should not be 
administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR 
measured by Tc99m-DPTA serum clearance method:
Males:
[140 - Age in years] × Actual Body Weight (kg)
= mL/min
72 × Serum Creatinine (mg/dL)
Females:
Estimated creatinine clearance for males × 0.85
Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance 
is <80 mL/min [see Drug Interactions (7.1)].
2.5
Preparation and Administration Precautions
As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion 
solutions of ALIMTA. The use of gloves is recommended. If a solution of ALIMTA contacts the skin, wash the skin immediately and 
thoroughly with soap and water. If ALIMTA contacts the mucous membranes, flush thoroughly with water. Several published 
guidelines for handling and disposal of anticancer agents are available [see References (15)].
ALIMTA is not a vesicant. There is no specific antidote for extravasation of ALIMTA. To date, there have been few reported 
cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA extravasation should be managed
with local standard practice for extravasation as with other non-vesicants.
2.6
Preparation for Intravenous Infusion Administration
1.
Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration.
2.
Calculate the dose of ALIMTA and determine the number of vials needed. Vials contain either 100 mg or 500 mg of
ALIMTA. The vials contain an excess of ALIMTA to facilitate delivery of label amount.
3.
Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each
500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a
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solution containing 25 mg/mL ALIMTA. Gently swirl each vial until the powder is completely dissolved. The resulting 
solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. 
The pH of the reconstituted ALIMTA solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
4.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. If particulate matter is observed, do not administer.
5.
An appropriate quantity of the reconstituted ALIMTA solution must be further diluted into a solution of 0.9% Sodium
Chloride Injection (preservative free), so that the total volume of solution is 100 ml. ALIMTA is administered as an
intravenous infusion over 10 minutes.
6.
Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours
following initial reconstitution, when stored at refrigerated or ambient room temperature [see USP Controlled Room
Temperature] and lighting. When prepared as directed, reconstitution and infusion solutions of ALIMTA contain no
antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride 
Injection (preservative free). ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer’s 
Injection, USP and Ringer’s Injection, USP and therefore these should not be used. Coadministration of ALIMTA with other drugs 
and diluents has not been studied, and therefore is not recommended. ALIMTA is compatible with standard polyvinyl chloride (PVC) 
administration sets and intravenous solution bags.
3
DOSAGE FORMS AND STRENGTHS
ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile 
single-use vials containing 100 mg or 500 mg pemetrexed.
4
CONTRAINDICATIONS
ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other 
ingredient used in the formulation.
5
WARNINGS AND PRECAUTIONS
5.1
Premedication Regimen
Need for Folate and Vitamin B12 Supplementation
Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce 
treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and 
reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with 
Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.
Corticosteroid Supplementation
Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with 
dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].
5.2
Bone Marrow Suppression
ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) 
[see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based 
on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration 
(2.4)].
5.3
Decreased Renal Function
ALIMTA is primarily eliminated unchanged by renal excretion. 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, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage 
and Administration (2.4)].
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12
died of drug-related toxicity following administration of ALIMTA alone.
5.4
Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency
Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal 
insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].
5.5
Required Laboratory Monitoring
Patients should not begin a new cycle of treatment unless the ANC is ൒1500 cells/mm3, the platelet count is 
൒100,000 cells/mm3, and creatinine clearance is ൒45 mL/min [see Dosage and Administration (2.4)].
5.6
Pregnancy Category D
Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed 
administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 
1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this 
drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid 
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becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with
ALIMTA [see Use in Specific Populations (8.1)].
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to
rates in other clinical trials and may not reflect the rates observed in clinical practice.
In clinical trials, the most common adverse reactions (incidence ൒20%) during therapy with ALIMTA as a single-agent were 
fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ൒20%) during therapy with ALIMTA when used in 
combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and 
constipation.
Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin
Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC 
who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and 
received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC 
and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.
Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa
Reactionb
ALIMTA/cisplatin
(N=839)
Gemcitabine/cisplatin
(N=830)
All Grades 
Toxicity (%)
Grade 3-4 
Toxicity (%)
All Grades 
Toxicity (%)
Grade 3-4 
Toxicity (%)
All Adverse Reactions
90
37
91
53
Laboratory
  Hematologic
   Anemia
33
6
46
10
   Neutropenia
29
15
38
27
   Leukopenia
18
5
21
8
   Thrombocytopenia
10
4
27
13
  Renal
   Creatinine elevation
10
1
7
1
Clinical
  Constitutional Symptoms
   Fatigue
43
7
45
5
  Gastrointestinal
   Nausea
56
7
53
4
   Vomiting
40
6
36
6
   Anorexia
27
2
24
1
   Constipation
21
1
20
0
   Stomatitis/Pharyngitis
14
1
12
0
   Diarrhea
12
1
13
2
   Dyspepsia/Heartburn
5
0
6
0
  Neurology
   Neuropathy-sensory
9
0
12
1
   Taste disturbance
8
0c
9
0c
  Dermatology/Skin
   Alopecia
12
0c
21
1c
   Rash/Desquamation
7
0
8
1
a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible 
relationship to ALIMTA.
b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.
c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
No clinically relevant differences in adverse reactions were seen in patients based on histology.
In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and 
platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin 
arm.
The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to 
receive ALIMTA plus cisplatin.
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Incidence 1% to 5%
Body as a Whole — febrile neutropenia, infection, pyrexia
General Disorders — dehydration
Metabolism and Nutrition — increased AST, increased ALT
Renal — creatinine clearance decrease, renal failure
Special Senses — conjunctivitis
Incidence Less than 1%
Cardiovascular — arrhythmia
General Disorders — chest pain
Metabolism and Nutrition — increased GGT
Neurology — motor neuropathy
Non-Small Cell Lung Cancer (NSCLC) - Maintenance
Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC 
who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately 
following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully 
supplemented with folic acid and vitamin B12.
Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa
Reactionb
ALIMTA
(N=438)
Placebo
(N=218)
All Grades 
Toxicity (%)
Grade 3-4 
Toxicity (%)
All Grades 
Toxicity (%)
Grade 3-4 
Toxicity (%)
All Adverse Reactions
66
16
37
4
Laboratory
  Hematologic
    Anemia
15
3
6
1
    Neutropenia
6
3
0
0
    Leukopenia
6
2
1
1
  Hepatic
    Increased ALT
10
0
4
0
    Increased AST
8
0
4
0
Clinical
  Constitutional Symptoms
    Fatigue
25
5
11
1
  Gastrointestinal
    Nausea
19
1
6
1
    Anorexia
19
2
5
0
    Vomiting
9
0
1
0
    Mucositis/stomatitis
7
1
2
0
    Diarrhea
5
1
3
0
  Infection
5
2
2
0
  Neurology
    Neuropathy-sensory
9
1
4
0
  Dermatology/Skin
    Rash/Desquamation
10
0
3
0
a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible 
relationship to ALIMTA.
b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.
No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or 
histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 
0.6%).
Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse 
reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of 
ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences 
in Grade 3/4 adverse reactions were seen.
Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and 
erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo 
arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).
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The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA.
Incidence 1% to 5%
Dermatology/Skin — alopecia, pruritis/itching
Gastrointestinal — constipation
General Disorders — edema, fever (in the absence of neutropenia)
Hematologic — thrombocytopenia
Renal — decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate
Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation
Incidence Less than 1%
Cardiovascular — supraventricular arrhythmia
Dermatology/Skin — erythema multiforme
General Disorders — febrile neutropenia, allergic reaction/hypersensitivity
Neurology — motor neuropathy
Renal — renal failure
Non-Small Cell Lung Cancer (NSCLC) – After Prior Chemotherapy
Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly 
assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to 
receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior 
chemotherapy.
Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa
Reactionb
ALIMTA
(N=265)
Docetaxel
(N=276)
All Grades 
Toxicity (%)
Grades 3-4 
Toxicity (%)
All Grades 
Toxicity (%)
Grades 3-4 
Toxicity (%)
Laboratory
  Hematologic
   Anemia
19
4
22
4
   Leukopenia
12
4
34
27
   Neutropenia
11
5
45
40
   Thrombocytopenia
8
2
1
0
  Hepatic
   Increased ALT
8
2
1
0
   Increased AST
7
1
1
0
Clinical
  Gastrointestinal
   Nausea
31
3
17
2
   Anorexia
22
2
24
3
   Vomiting
16
2
12
1
   Stomatitis/Pharyngitis
15
1
17
1
   Diarrhea
13
0
24
3
   Constipation
6
0
4
0
  Constitutional Symptoms
   Fatigue
34
5
36
5
   Fever
8
0
8
0
  Dermatology/Skin
   Rash/Desquamation
14
0
6
0
   Pruritis
7
0
2
0
   Alopecia
6
1c
38
2c
a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible 
relationship to ALIMTA.
b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).
c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
No clinically relevant differences in adverse reactions were seen in patients based on histology.
Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that 
received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).
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The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to 
receive ALIMTA.
Incidence 1% to 5%
Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection
Dermatology/Skin — erythema multiforme
Neurology — motor neuropathy, sensory neuropathy
Renal — increased creatinine
Incidence Less than 1%
Cardiovascular — supraventricular arrhythmias
Malignant Pleural Mesothelioma (MPM)
Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with 
mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned 
to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and 
vitamin B12.
Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa
Reactionb
ALIMTA/cisplatin
(N=168)
Cisplatin
(N=163)
All Grades 
Toxicity (%)
Grade 3-4 
Toxicity (%)
All Grades 
Toxicity (%)
Grade 3-4 
Toxicity (%)
Laboratory
  Hematologic
   Neutropenia
56
23
13
3
   Leukopenia
53
15
17
1
   Anemia
26
4
10
0
   Thrombocytopenia
23
5
9
0
  Renal
   Creatinine elevation
11
1
10
1
   Creatinine clearance decreased
16
1
18
2
Clinical
  Eye Disorder
   Conjunctivitis
5
0
1
0
  Gastrointestinal
   Nausea
82
12
77
6
   Vomiting
57
11
50
4
   Stomatitis/Pharyngitis
23
3
6
0
   Anorexia
20
1
14
1
   Diarrhea
17
4
8
0
   Constipation
12
1
7
1
   Dyspepsia
5
1
1
0
  Constitutional Symptoms
   Fatigue
48
10
42
9
 Metabolism and Nutrition
   Dehydration
7
4
1
1
  Neurology
   Neuropathy-sensory
10
0
10
1
   Taste Disturbance
8
0c
6
0c
  Dermatology/Skin
   Rash
16
1
5
0
   Alopecia
11
0c
6
0c
a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible 
relationship to ALIMTA.
b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived 
from the CTC term “renal/genitourinary-other”.
c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned 
to receive ALIMTA plus cisplatin.
Incidence 1% to 5%
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Body as a Whole — febrile neutropenia, infection, pyrexia
Dermatology/Skin — urticaria
General Disorders — chest pain
Metabolism and Nutrition — increased AST, increased ALT, increased GGT
Renal — renal failure
Incidence Less than 1%
Cardiovascular — arrhythmia
Neurology — motor neuropathy
Effects of Vitamin Supplementations
Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin 
supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence 
in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.
Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the 
ALIMTA plus Cisplatin arm (% incidence)
Adverse Eventa (%)
Fully Supplemented Patients
(N=168)
Never Supplemented Patients
(N=32)
Neutropenia/granulocytopenia
23
38
Thrombocytopenia
5
9
Vomiting
11
31
Febrile neutropenia
1
9
Infection with Grade 3/4 neutropenia
0
6
Diarrhea
4
9
a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).
The following adverse events were greater in the fully supplemented group compared to the never supplemented group: 
hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).
Subpopulations
No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in 
men (24%) compared to women (16%).
Additional Clinical Trials Experience
Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.
Cases of esophagitis have been reported in clinical trials.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are 
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 
causal relationship to drug exposure.
These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.
Gastrointestinal — colitis
General Disorders and Administration Site Conditions — edema
Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously 
received radiotherapy.
Respiratory — interstitial pneumonitis
Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.
7
DRUG INTERACTIONS
7.1
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with 
ALIMTA in patients with normal renal function (creatinine clearance ൒80 mL/min). No dose adjustment of ALIMTA is needed with 
concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].
Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal 
insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin)
should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.
In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, 
nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following 
ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, 
especially myelosuppression, renal, and gastrointestinal toxicity.
7.2
Nephrotoxic Drugs
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ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant 
administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are 
also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)]
Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no 
adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in 
mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete 
ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate 
(1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal 
deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective 
contraceptive measures to prevent pregnancy during the treatment with ALIMTA.
8.3
Nursing Mothers
It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to 
discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
8.4
Pediatric Use
Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion 
over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a 
Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. 
The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for 
patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing 
sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-
brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities 
reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function 
abnormalities (increased ALT/AST), fatigue, and nausea. 
The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the 
Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax)
appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric 
patients were comparable to values reported in adults.
8.5
Geriatric Use
ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in 
patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken 
in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those 
recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].
In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were 
൒65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the 
HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ൒65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent to 
treat population.
In the maintenance non-small cell lung cancer trial 33.3% of patients treated with ALIMTA were ൒65 years and no 
differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall 
survival was 0.74 (95% CI: 0.58, 0.93) and for patients ൒65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent to treat 
population.
In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ൒65 years and 
Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 
(95% CI: 0.76, 1.19), and for patients ൒65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent to treat population.
The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were ൒65 years, and Grade 3/4 
fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the 
HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients ൒65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent 
to treat population.
8.6
Patients with Hepatic Impairment
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical 
Pharmacology (12.3)].
Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see 
Dosage and Administration (2.4)].
8.7
Patients with Renal Impairment
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ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and 
greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and 
Clinical Pharmacology (12.3)]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal 
impairment.
8.8
Gender
In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for 
overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent to treat population.
In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for 
overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent to treat population.
In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the 
HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent to treat 
population.
In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 
(95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent to treat population.
8.9
Race
In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 
9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 
(95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent to treat population.
In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For 
Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others 
the HR was 0.46 (95% CI: 0.26, 0.79) in the intent to treat population.
In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For 
Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the 
intent to treat population.
In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 
0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent to treat population.
10
OVERDOSAGE
There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, 
mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, 
thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose 
occurs, general supportive measures should be instituted as deemed necessary by the treating physician.
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 associated with Grade 3 thrombocytopenia, or Grade 3 
or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, 
intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.
The ability of ALIMTA to be dialyzed is unknown.
11
DESCRIPTION
Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-
pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula 
of C20H19N5Na2O6•7H2O and a molecular weight of 597.49. The structural formula is as follows:
ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a 
white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of ALIMTA contains pemetrexed 
disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. 
Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
ALIMTA, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent 
metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), 
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dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes 
involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as 
the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to 
polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of 
TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to 
a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in 
prolonged drug action in malignant cells.
12.2
Pharmacodynamics
Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, 
NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined 
concurrently with cisplatin.
Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA to patients not receiving folic acid and 
vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as 
measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was 
also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The 
levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed 
exposure on ANC nadir over multiple treatment cycles.
Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 
38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
12.3
Pharmacokinetics
Absorption
The pharmacokinetics of ALIMTA administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 
10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic
exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed
do not change over multiple treatment cycles.
Distribution
Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 
81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
Metabolism and Excretion
Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose 
recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as 
renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 
3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). 
The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm 
studies.
In vitro studies indicate that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that may play a 
role in active secretion of pemetrexed.
Effect of Age
No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.
Effect of Gender
The pharmacokinetics of pemetrexed were not different in male and female patients.
Effect of Race
The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are 
available to compare pharmacokinetics for other ethnic groups.
Effect of Hepatic Insufficiency
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of 
hepatically impaired patients have not been conducted [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
Effect of Renal Insufficiency
Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed 
decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 
80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with 
creatinine clearance of 100 mL/min [see Warnings and Precautions (5.4) and Dosage and Administration (2.4)].
Effect of Third Space Fluid
The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is not fully defined. A study of ALIMTA 
500 mg/m2 was performed in 31 solid tumor patients with stable third space fluid (All but 2 of the 31 patients included in study had 
mild or moderate amounts of third space fluid). Moderate pleural effusion was defined in the study as less than 1/3 the way up on one 
side with obscuring of the entire hemidiaphragm. Moderate ascites was defined as that detectable on physical exam. The pemetrexed 
plasma concentrations in these patients were comparable to those observed in previous clinical trials in patients without third space 
fluid collections. Thus, drainage of mild or moderate third space fluid collection prior to ALIMTA treatment should be considered, but 
is probably not necessary. The effect of severe third space fluid on pharmacokinetics is not known.
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Effect of Ibuprofen
Ibuprofen doses of 400 mg four times a day reduce pemetrexed’s clearance by about 20% (and increase AUC by 20%) in 
patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown [see Drug 
Interactions (7.1)].
Effect of Aspirin
Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. 
The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.
Effect of Cisplatin
Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by 
pemetrexed.
Effect of Vitamins
Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed.
Drugs Metabolized by Cytochrome P450 Enzymes
Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant 
inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus 
assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered 
at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in 
reduced fertility, hypospermia, and testicular atrophy.
14
CLINICAL STUDIES
14.1
Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin
A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to 
compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in 
combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 with cisplatin 
administered intravenously at a dose of 75 mg/m2 after ALIMTA administration, on Day 1 of each 21-day cycle. Gemcitabine was 
administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 after 
administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in 
both treatment arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.3)].
Patient demographics of the intent to treat (ITT) population are shown in Table 9. The demographics and disease 
characteristics were well balanced.
Table 9: First-Line Therapy: Summary of Patient Characteristics in Study of NSCLC 
Patient characteristic
ALIMTA plus Cisplatin (AC)
(N=862)
Gemcitabine plus Cisplatin (GC)
(N=863)
Age (yrs)
   Median (range)
61.1 (28.8-83.2)
61.0 (26.4-79.4)
Gender
   Male/Female
70.2%/29.8%
70.1%/29.9%
Origin
   Caucasian
669 (77.6%)
680 (78.8%)
   Hispanic
27 (3.1%)
23 (2.7%)
   Asian
146 (16.9%)
141 (16.3%)
   African descent
18 (2.1%)
18 (2.1%)
Stage at Entry
   IIIb/IV
23.8%/76.2%
24.3%/75.7%
Histology
   Nonsquamous NSCLCa
618 (71.7%)
634 (73.5%)
      Adenocarcinoma
436 (50.6%)
411 (47.6%)
      Large cell
76 (8.8%)
77 (8.9%)
      Otherb
106 (12.3%)
146 (16.9%)
   Squamous
244 (28.3%)
229 (26.5%)
ECOG PSc,d
   0/1
35.4%/64.6%
35.6%/64.3%
Smoking Historye
   Ever/never smoker
83.1%/16.9%
83.9%/16.1%
a Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
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b The subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as 
adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
c Eastern Cooperative Oncology Group Performance Status.
d ECOG PS was not reported for all randomized patients. Percentages are representative of N=861 for the ALIMTA plus cisplatin 
arm, and N=861 for the gemcitabine plus cisplatin arm.
e Smoking history was collected for 88% of randomized patients (N=757 for the ALIMTA plus cisplatin arm and N=759 for the 
gemcitabine plus cisplatin arm).
Patients received a median of 5 cycles of treatment in both study arms. Patients treated with ALIMTA plus cisplatin received a 
relative dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity and 95.0% of the protocol-specified cisplatin dose 
intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified 
gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.
The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the ALIMTA plus 
cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.
Table 10: First-Line Therapy: Efficacy in NSCLC - ITT Population
ALIMTA plus Cisplatin
(N=862)
Gemcitabine plus Cisplatin
(N=863)
Median overall survival (95% CI)
10.3 mos (9.8-11.2)
10.3 mos (9.6-10.9)
 Adjusted hazard ratio (HR)a,b (95% CI)
0.94 (0.84-1.05)
Median progression-free survival (95% CI)
4.8 mos (4.6-5.3)
5.1 mos (4.6-5.5)
 Adjusted hazard ratio (HR)a,b (95% CI)
1.04 (0.94-1.15)
Overall response rate (95% CI)
27.1% (24.2-30.1)
24.7% (21.8-27.6)
a Adjusted for gender, stage, basis of diagnosis, and performance status.
b A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 
1.0 indicates survival is better in the GC arm than in the AC arm.
Figure 1: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in 
NSCLC - ITT Population.
A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences 
in survival according to histology were observed and are shown in Table 11. This difference in treatment effect for ALIMTA based on 
histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the 
maintenance study [see Clinical Studies (14.2, 14.3)].
Table 11: First-Line Therapy: Overall Survival in NSCLC Histologic Subgroups
Histology Subgroup
Median Overall Survival in Months
(95% CI)
Unadjusted 
Hazard 
Adjusted Hazard 
Ratio (HR)a,b,c
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Median (95% Cl) 
0.9 
-AC 10.3 (9.8, 11 .2) 
0.8 
--GC 10.3 (9.6, 10.9) 
0.7 
ACvsGC 
Adjusted HR (95% Cl) 
:0 0.6 
0.94 (0.84, 1.05) 
cu 
.a 
0 
0.5 
... 
a. 
ca 0.4 
.ii? 
0.3 
::J 
CJ) 
0.2 
0.1 
0.0 
0 
6 
12 
18 
24 
30 
Patients at Risk 
Survival Time (months) 
AC 
862 
598 
341 
146 
45 
0 
GC 
863 
590 
327 
139 
34 
0 

15
ALIMTA plus Cisplatin
Gemcitabine plus Cisplatin
Ratio (HR)a,b
(95% CI)
(95% CI)
Nonsquamous NSCLCd
(N=1252)
11.0
(10.1-12.5)
N=618
10.1
(9.3-10.9)
N=634
0.84
(0.74-0.96)
0.84
(0.74-0.96)
   Adenocarcinoma
   (N=847)
12.6
(10.7-13.6)
N=436
10.9
(10.2-11.9)
N=411
0.84
(0.71-0.98)
0.84
(0.71-0.99)
   Large Cell
   (N=153)
10.4
(8.6-14.1)
N=76
6.7
(5.5-9.0)
N=77
0.68
(0.48-0.97)
0.67
(0.48-0.96)
   Othere
   (N=252)
8.6
(6.8-10.2)
N=106
9.2
(8.1-10.6)
N=146
1.12
(0.84-1.49)
1.08
(0.81-1.45)
Squamous Cell
(N=473)
9.4
(8.4-10.2)
N=244
10.8
(9.5-12.1)
N=229
1.22
(0.99-1.50)
1.23
(1.00-1.51)
a A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 
1.0 indicates survival is better in the GC arm than in the AC arm.
b Unadjusted for multiple comparisons.
c HRs adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
d Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
e The subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as 
adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
Figure 2: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in 
NSCLC - Nonsquamous NSCLC and Squamous Cell NSCLC.
14.2
Non-Small Cell Lung Cancer - Maintenance
A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC 
who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive 
ALIMTA or placebo immediately following platinum-based chemotherapy. ALIMTA was administered intravenously over 
10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic 
acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.3)].
The study was designed to demonstrate superior progression-free survival and overall survival of ALIMTA over placebo. 
Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are 
shown in Table 12. The demographics and baseline disease characteristics were well balanced between study arms.
Table 12: Maintenance Therapy: Summary of Patient Characteristics in Study of NSCLC
Patient characteristic
ALIMTA
(N=441)
Placebo
(N=222)
Age (yrs)
   Median (range)
60.6 (25.6-82.6)
60.4 (35.4-78.5)
Gender
   Male/Female
73.0%/27.0%
72.5%/27.5%
Ethnic Origin
   Caucasian
279 (63.3%)
149 (67.1%)
   East Asian
104 (23.6%)
50 (22.5%)
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Nonsquamous NSCLC 
Squamous Cell NSCLC 
1.0 
1.0 
0.8 
-AC 
0.8 
-AC 
:0 
--Ge :0 
--Ge 
(1S 
0.6 
(1S 
0.6 
.0 
.0 
0 
e 
.... 
a. 0.4 
a. 
0.4 
(1S 
ffl 
> 
0.2 
-~ 
0.2 
-~ 
:::, 
:::, 
Cl') 
0.0 
Cl') 
0.0 
0 
6 
12 18 24 30 
0 
6 
12 18 24 30 
Survival Time (months) 
Survival Time (months) 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 

16
   Other
58 (13.2%)
23 (10.4%)
Stage at Entrya
   IIIb/IV
18.0%/82.0%
21.2%/78.8%
Histology (%)
   Nonsquamous NSCLCb
325 (73.7%)
156 (70.3%)
        Adenocarcinoma
222 (50.3%)
106 (47.7%)
        Large cell
10 (2.3%)
10 (4.5%)
        Otherc
93 (21.1%)
40 (18.0%)
   Squamous
116 (26.3%)
66 (29.7%)
ECOG PSd
   0/1
40.1%/59.9%
38.3%/61.7%
Smoking Historye
   Ever/never smoker
74.1%/25.9%
71.5%/28.5%
Time from start of induction therapy to study randomization (months)
   Median (range)
3.25 (1.6-4.8)
3.29 (2.7-5.1)
a Stage at Entry was not reported for all randomized patients. Percentages are representative of N=440 for the ALIMTA arm and 
N=222 for the placebo arm.
b Includes patients with adenocarcinoma, large cell, and other histologic diagnoses.
c The subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as 
adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
d Eastern Cooperative Oncology Group Performance Status (ECOG PS) was not reported for all randomized patients. Percentages are 
representative of N=439 for the ALIMTA arm, and N=222 for the placebo arm.
e Smoking history was not reported for all randomized patients. Percentages are representative of N=437 for the ALIMTA arm and 
N=221 for the placebo arm.
Patients received a median of 5 cycles of ALIMTA and 3.5 cycles of placebo. Patients randomized to ALIMTA received a 
relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ൒6 cycles and a total of 98 patients (22.6%) completed 
൒10 cycles of treatment with ALIMTA.
In the overall study population, ALIMTA was statistically superior to placebo in terms of overall survival (OS) (median 
13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, 
HR=0.60 (95% CI: 0.49-0.73), p-value<0.00001). A difference in treatment outcomes was observed according to histologic 
classification. For the population of patients with nonsquamous NSCLC, ALIMTA was superior to placebo for OS (median 
15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 
0.37-0.60)). For the population of patients with squamous NSCLC, ALIMTA did not improve OS compared to placebo (median 
9.9 months versus 10.8 months, HR=1.07 (95% CI: 0.77-1.50)) or PFS (median 2.4 months versus 2.5 months, HR=1.03 (95% CI: 
0.71-1.49)). This difference in treatment effect for ALIMTA based on histology demonstrating lack of benefit in squamous cell 
histology was also observed in the first-line and second-line studies. [see Clinical Studies (14.1, 14.3)]
Efficacy results for the overall patient population are presented in Table 13 and Figure 3, and efficacy results by pre-specified 
histologic subgroups are presented in Table 14 and Figure 4, below.
Table 13: Maintenance Therapy: Efficacy of ALIMTA versus Placebo in NSCLC - ITT Population
Efficacy Parametera,b
ALIMTA
(N=441)
Placebo
(N=222)
Median overall survivalc (95% CI)
13.4 mos (11.9-15.9)
10.6 mos (8.7-12.0)
   Hazard ratio (HR)c (95% CI)
0.79 (0.65-0.95)
p-value
p=0.012
Median progression-free survival (95% CI)
4.0 mos (3.1-4.4)
2.0 mos (1.5-2.8)
   Hazard ratio (HR)c (95% CI)
0.60 (0.49-0.73)
p-value
p<0.00001
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy.
b Values for PFS given based on independent review (ALIMTA N=387, Placebo N=194).
c Unadjusted hazard ratios are provided. A HR <1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm. 
Table 14: Maintenance Therapy: Efficacy in NSCLC by Histologic Subgroupsa
Overall Survival
Progression-Free Survivalb
ALIMTA
Placebo
ALIMTA
Placebo
Median (months)
Median (months)
Median (months)
Median (months)
HRc (95% CI)
HRc (95% CI)
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17
Nonsquamous NSCLCd
15.5
10.3
4.4
1.8
N=481
0.70 (0.56-0.88)
0.47 (0.37-0.60)
   Adenocarcinoma
16.8
11.5
4.6
2.7
   N=328
0.73 (0.56-0.96)
0.51 (0.38-0.68)
   Large cell carcinoma
8.4
7.9
4.5
1.5
   N=20
0.98 (0.36-2.65)
0.40 (0.12-1.29)
   Othere
11.3
7.7
4.1
1.6
   N=133
0.61 (0.40-0.94)
0.44 (0.28-0.68)
Squamous cell
9.9
10.8
2.4
2.5
N=182
1.07 (0.77-1.50)
1.03 (0.71-1.49)
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy. 
All results unadjusted for multiple comparisons.
b Values for PFS are given based on independent review (ALIMTA N=387, Placebo N=194).
c Unadjusted hazard ratios are provided. A HR <1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm. A 
HR >1.0 indicates that the result is better in the placebo arm than in the ALIMTA arm.
d Includes patients with adenocarcinoma, large cell carcinoma, and other histology.
e The subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as 
adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
Figure 3: Kaplan-Meier Curve for Overall Survival ALIMTA (A) versus Placebo (P) in NSCLC - ITT Population.
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:c 
cu 
.c e 
a. 
co 
> -~ 
:::, 
Cl) 
1.0 
Median (95% Cl) 
0.9 
-
ALIMTA 
13.4 (11 .9, 15.9) 
0.8 
-- Placebo 
10.6 (8.7, 12.0) 
0.7 
Unadjusted HR (95% Cl) 
:0 0.6 
cu 
0.79 (0.65, 0.95) 
.0 e 0.5 
a. 
cu 
0.4 
> -~ 
0.3 
:::s 
Cl) 
0.2 
0.1 
0.0 
0 
6 
12 
18 
24 
30 
36 
42 
Patients at Risk 
Survival Time (months) 
A 
p 
1.0 
0.8 
0.6 
0.4 
0.2 
0.0 
441 
340 
221 
141 
63 
222 
160 
93 
60 
29 
29 
13 
11 
4 
0 
0 
Nonsquamous NSCLC 
Squamous Cell NSCLC 
1.0 
-AUMTA 
0.8 
-ALIMTA 
-- Placebo 
:c 
-- Placebo 
as 
0.6 
.c e 
a. 
0.4 
co 
> 
0.2 
-~ 
:::, 
Cl) 
0.0 
0 6 12 18 24 30 36 42 
0 6 12 18 24 30 36 42 
Survival Time (months) 
Survival Time (months) 

18
Figure 4: Kaplan-Meier Curves for Overall Survival ALIMTA versus Placebo in NSCLC - Nonsquamous NSCLC and 
Squamous Cell NSCLC.
14.3
Non-Small Cell Lung Cancer - After Prior Chemotherapy
A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy 
to compare the overall survival following treatment with ALIMTA versus docetaxel. ALIMTA was administered intravenously over 
10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were 
given on Day 1 of each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with folic acid and 
vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of ALIMTA to docetaxel. Patient 
demographics of the intent to treat (ITT) population are shown in Table 15.
Table 15: Second-Line Therapy: Summary of Patient Characteristics in NSCLC Study
Patient characteristic
ALIMTA
(N=283)
Docetaxel
(N=288)
Age (yrs)
   Median (range)
59 (22-81)
57 (28-87)
Gender (%)
   Male/Female
68.6/31.4
75.3/24.7
Stage at Entry (%)
   III/IV
25.1/74.9
25.3/74.7
Diagnosis/Histology (%)
   Adenocarcinoma
154 (54.4)
142 (49.3)
   Squamous
78 (27.6)
94 (32.6)
   Bronchoalveolar
4 (1.4)
1 (0.3)
   Other
47 (16.6)
51 (17.7)
Performance Status (%)a
0-1
234 (88.6)
240 (87.6)
   2
30 (11.4)
34 (12.4)
a Performance status was not reported for all randomized patients. Percentages are representative of N=264 for the ALIMTA arm and 
N=274 for the docetaxel arm.
The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the ALIMTA treatment 
arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 16). The study did not show an overall survival 
superiority of ALIMTA.
Table 16: Efficacy of ALIMTA versus Docetaxel in Non-Small Cell Lung Cancer - ITT Population
ALIMTA
(N=283)
Docetaxel
(N=288)
Median overall survival (95% CI)
8.3 mos (7.0-9.4)
7.9 mos (6.3-9.2)
   Hazard ratio (HR) (95% CI)
0.99 (0.82-1.20)
Median progression-free survival (95% CI)
2.9 mos (2.4-3.1)
2.9 mos (2.7-3.4)
   Hazard ratio (HR) (95% CI)
0.97 (0.82-1.16)
Overall response rate (95% CI)
8.5% (5.2-11.7)
8.3% (5.1-11.5)
A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences 
in survival according to histology were observed and are shown in Table 17. This difference in treatment effect for ALIMTA based on 
histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the 
maintenance study [see Clinical Studies (14.1, 14.2)].
Table 17: Second-Line Therapy: Overall Survival of ALIMTA versus Docetaxel in NSCLC by Histologic Subgroups
Histology Subgroup
Median Overall Survival in Months
(95% CI)
Unadjusted 
Hazard 
Ratio (HR)a,b
(95% CI)
Adjusted 
Hazard 
Ratio (HR)a,b,c
(95% CI)
ALIMTA
Docetaxel
Nonsquamous NSCLCd
(N=399)
9.3
(7.8-9.7)
N=205
8.0
(6.3-9.3)
N=194
0.89
(0.71-1.13)
0.78
(0.61-1.00)
   Adenocarcinoma
   (N=301)
9.0
(7.6-9.6)
N=158
9.2
(7.5-11.3)
N=143
1.09
(0.83-1.44)
0.92
(0.69-1.22)
   Large Cell
12.8
N=18
4.5
N=29
0.38
0.27
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19
   (N=47)
(5.8-14.0)
(2.3-9.1)
(0.18-0.78)
(0.11-0.63)
   Othere
   (N=51)
9.4
(6.0-10.1)
N=29
7.9
(4.0-8.9)
N=22
0.62
(0.32-1.23)
0.57
(0.27-1.20)
Squamous Cell
(N=172)
6.2
(4.9-8.0)
N=78
7.4
(5.6-9.5)
N=94
1.32
(0.93-1.86)
1.56
(1.08-2.26)
a A HR that is less than 1.0 indicates that survival is better in the ALIMTA arm than in the docetaxel arm. Alternatively, a HR that is 
greater than 1.0 indicates survival is better in the docetaxel arm than in the ALIMTA arm.
b Unadjusted for multiple comparisons.
c HRs adjusted for ECOG PS, time since prior chemotherapy, disease stage, and gender.
d Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
e The subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as 
adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
14.4
Malignant Pleural Mesothelioma
A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) 
compared survival in patients treated with ALIMTA in combination with cisplatin to survival in patients receiving cisplatin alone. 
ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 
2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of ALIMTA. Both drugs were 
given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby 
all patients were given folic acid and vitamin B12 supplementation.
The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who 
received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12
supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended [see Dosage and 
Administration (2.3)]. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 18.
Table 18: Summary of Patient Characteristics in MPM Study
Patient characteristic
Randomized and Treated Patients
Fully Supplemented Patients
ALIMTA/cis
(N=226)
Cisplatin
(N=222)
ALIMTA/cis
(N=168)
Cisplatin
(N=163)
Age (yrs)
   Median (range)
61 (29-85)
60 (19-84)
60 (29-85)
60 (19-82)
Gender (%)
   Male
184 (81.4)
181 (81.5)
136 (81.0)
134 (82.2)
   Female
42 (18.6)
41 (18.5)
32 (19.0)
29 (17.8)
Origin (%)
   Caucasian
204 (90.3)
206 (92.8)
150 (89.3)
153 (93.9)
   Hispanic
11 (4.9)
12 (5.4)
10 (6.0)
7 (4.3)
   Asian
10 (4.4)
4 (1.9)
7 (4.2)
3 (1.8)
   African descent
1 (0.4)
0
1 (0.6)
0
Stage at Entry (%)
   I
16 (7.1)
14 (6.3)
15 (8.9)
12 (7.4)
   II
35 (15.6)
33 (15.0)
27 (16.2)
27 (16.8)
   III
73 (32.4)
68 (30.6)
51 (30.5)
49 (30.4)
   IV
101 (44.9)
105 (47.2)
74 (44.3)
73 (45.3)
   Unspecified
1 (0.4)
2 (0.9)
1 (0.6)
2 (1.2)
Diagnosis/Histologya (%)
   Epithelial
154 (68.1)
152 (68.5)
117 (69.6)
113 (69.3)
   Mixed
37 (16.4)
36 (16.2)
25 (14.9)
25 (15.3)
   Sarcomatoid
18 (8.0)
25 (11.3)
14 (8.3)
17 (10.4)
   Other
17 (7.5)
9 (4.1)
12 (7.1)
8 (4.9)
Baseline KPSb (%)
70-80
109 (48.2)
97 (43.7)
83 (49.4)
69 (42.3)
90-100
117 (51.8)
125 (56.3)
85 (50.6)
94 (57.7)
a Only 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent review.
b Karnofsky Performance Scale.
Table 19 and Figure 5 summarize the survival results for all randomized and treated patients regardless of vitamin 
supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.
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Table 19: Efficacy of ALIMTA plus Cisplatin versus Cisplatin in Malignant Pleural Mesothelioma
Efficacy Parameter
Randomized and Treated Patients
Fully Supplemented Patients
ALIMTA/cis
(N=226)
Cisplatin
(N=222)
ALIMTA/cis
(N=168)
Cisplatin
(N=163)
Median overall survival
12.1 mos
9.3 mos
13.3 mos
10.0 mos
(95% CI)
(10.0-14.4)
(7.8-10.7)
(11.4-14.9)
(8.4-11.9)
Hazard ratio
0.77
0.75
Log rank p-valuea
0.020
0.051
a p-value refers to comparison between arms.
Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural 
mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 
15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 
11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.
Figure 5: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone in all Randomized and 
Treated Patients.
Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally
agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for ALIMTA plus cisplatin was 
greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) 
in the ALIMTA plus cisplatin arm compared to the control arm.
Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 
4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and 
vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin 
and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% 
of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose 
intensity. Patients treated with cisplatin alone had a dose intensity of 96%.
15
REFERENCES
1.
Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert
2004-165.
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs.
OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst
Pharm. 2006; 63:1172-1193.
4.
Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and
recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Protocol ADU-CL-02-v8
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Version 8, 08 March 2018 
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1.00 
C: 
.Q 
ti 
C: 
0.75 
Hazard Ratio 
0.77 
::::, 
... 
LL 
C: 
"I, 
Log rank p-value 
0.020 
0 
..... 
.. 0.50 
i.. 
32 
::::, 
.... ..,_ 
·;;:: 
Median Survival 
..... 
-
..,_ 
"' 
......... 
c 0.25 
= 9.3 mos 
...... _ 
<ii 
,_ 
.2: 
2: 
0.00 
::::, 
en 
0 
5 
10 
15 
20 
25 
30 
Survival Time (months) 
ALIMTA + Cisplatin (n=226) 
---
Cisplatin (n=222) 

21
ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed.
    NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton.
ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 500 mg pemetrexed.
    NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton.
16.2
Storage and Handling
ALIMTA, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP 
Controlled Room Temperature].
Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours 
following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F), or at 25°C (77°F), excursions permitted to 
15-30°C (59-86°F) [see USP Controlled Room Temperature]. When prepared as directed, reconstituted and infusion solutions of
ALIMTA contain no antimicrobial preservatives. Discard unused portion [see Dosage and Administration (2.5)].
ALIMTA is not light sensitive.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (PPI)
Patients should be instructed to read the patient package insert carefully.
17.1
Need for Folic Acid and Vitamin B12
Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce 
treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].
17.2
Low Blood Cell Counts
Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their 
physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of 
anemia occur.
17.3
Gastrointestinal Effects
Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.
17.4
Concomitant Medications
Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter 
medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].
Literature revised December 19, 2011
Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2004, 2011, Eli Lilly and Company. All rights reserved.
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APPENDIX D 
PLATINOL Prescribing Information 
Page 106

Rx only 
PLATINOL
(cisplatin for injection, USP) 
WARNING
PLATINOL (cisplatin for injection, USP) should be administered under the supervision 
of a qualified physician experienced in the use of cancer chemotherapeutic agents. 
Appropriate management of therapy and complications is possible only when adequate 
diagnostic and treatment facilities are readily available. 
Cumulative renal toxicity associated with PLATINOL is severe. Other major dose-related 
toxicities are myelosuppression, nausea, and vomiting. 
Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus, 
and/or loss of high frequency hearing and occasionally deafness, is significant. 
Anaphylactic-like reactions to PLATINOL have been reported. Facial edema, 
bronchoconstriction, tachycardia, and hypotension may occur within minutes of 
PLATINOL administration. Epinephrine, corticosteroids, and antihistamines have been 
effectively employed to alleviate symptoms (see WARNINGS and ADVERSE 
REACTIONS).
Exercise caution to prevent inadvertent PLATINOL overdose. Doses greater than 
100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid 
inadvertent PLATINOL overdose due to confusion with PARAPLATIN (carboplatin) 
or prescribing practices that fail to differentiate daily doses from total dose per cycle. 
DESCRIPTION 
PLATINOL (cisplatin for injection, USP) is a white to light yellow lyophilized powder. 
Each vial of PLATINOL contains 50 mg cisplatin, 450 mg Sodium Chloride, USP, and 
500 mg Mannitol, USP. 
The active ingredient, cisplatin, is a yellow to orange crystalline powder with the 
molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy 
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metal complex containing a central atom of platinum surrounded by two chloride atoms 
and two ammonia molecules in the cis position. It is soluble in water or saline at 
1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207q C. 
CLINICAL PHARMACOLOGY 
Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with 
a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2
doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen 
following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total body 
clearances and volumes of distribution at steady-state for cisplatin are about 15 to 
16 L/h/m2 and 11 to 12 L/m2.
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to 
chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, 
than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M 
NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis-
diammine platinum (II) in nearly equal concentrations. The latter, combined with the 
possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or 
proteins, accounts for the instability of cisplatin in biological matrices. The ratios of 
cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between 
patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins 
that is characteristic of normal drug-protein binding. However, the platinum from 
cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including 
albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two 
hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. 
The complexes between albumin and the platinum from cisplatin do not dissociate to a 
significant extent and are slowly eliminated with a minimum half-life of five days or 
more.
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Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest 
in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and 
spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is 
present in tissues for as long as 180 days after the last administration. With the exception 
of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower 
than the concentrations in the organ where the tumor is located. Different metastatic sites 
in the same patient may have different platinum concentrations. Hepatic metastases have 
the highest platinum concentrations, but these are similar to the platinum concentrations 
in normal liver. Maximum red blood cell concentrations of platinum are reached within 
90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner 
with a terminal half-life of 36 to 47 days. 
Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions 
varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered 
platinum is excreted in the urine in 24 hours. Over five days following administration of 
40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of 
35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary 
recoveries of platinum of about 14% to 30% of the dose are found following five daily 
administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered 
platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in 
the urine in 24 hours is excreted within the first few hours. Platinum-containing species 
excreted in the urine are the same as those found following the incubation of cisplatin 
with urine from healthy subjects, except that the proportions are different. 
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of 
the dose excreted within one hour after administration of 50 mg/m2. The mean renal 
clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following 
administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively. 
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular 
filtration rate indicating that cisplatin or other platinum-containing molecules are actively 
secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable 
and is dependent on dose, urine flow rate, and individual variability in the extent of active 
secretion and possible tubular reabsorption. 
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There is a potential for accumulation of ultrafilterable platinum plasma concentrations 
whenever cisplatin is administered on a daily basis but not when dosed on an intermittent 
basis.
No significant relationships exist between the renal clearance of either free platinum or 
cisplatin and creatinine clearance. 
Although small amounts of platinum are present in the bile and large intestine after 
administration of cisplatin, the fecal excretion of platinum appears to be insignificant. 
INDICATIONS AND USAGE 
PLATINOL (cisplatin for injection, USP) is indicated as therapy to be employed as 
follows: 
Metastatic Testicular Tumors 
In established combination therapy with other approved chemotherapeutic agents in 
patients with metastatic testicular tumors who have already received appropriate surgical 
and/or radiotherapeutic procedures. 
Metastatic Ovarian Tumors 
In established combination therapy with other approved chemotherapeutic agents in 
patients with metastatic ovarian tumors who have already received appropriate surgical 
and/or radiotherapeutic procedures. An established combination consists of PLATINOL 
and cyclophosphamide. PLATINOL, as a single agent, is indicated as secondary therapy 
in patients with metastatic ovarian tumors refractory to standard chemotherapy who have 
not previously received PLATINOL therapy. 
Advanced Bladder Cancer 
PLATINOL is indicated as a single agent for patients with transitional cell bladder cancer 
which is no longer amenable to local treatments, such as surgery and/or radiotherapy. 
CONTRAINDICATIONS 
PLATINOL is contraindicated in patients with preexisting renal impairment. PLATINOL 
should not be employed in myelosuppressed patients, or in patients with hearing 
impairment. 
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PLATINOL is contraindicated in patients with a history of allergic reactions to 
PLATINOL or other platinum-containing compounds. 
WARNINGS
PLATINOL (cisplatin for injection, USP) produces cumulative nephrotoxicity which is 
potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen 
(BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels 
should be measured prior to initiating therapy, and prior to each subsequent course. At 
the recommended dosage, PLATINOL should not be given more frequently than once 
every 3 to 4 weeks (see ADVERSE REACTIONS). Elderly patients may be more 
susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
There are reports of severe neuropathies in patients in whom regimens are employed 
using higher doses of PLATINOL or greater dose frequencies than those recommended. 
These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove 
distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients 
may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric 
Use).
Loss of motor function has also been reported. 
Anaphylactic-like reactions to PLATINOL have been reported. These reactions have 
occurred within minutes of administration to patients with prior exposure to PLATINOL, 
and have been alleviated by administration of epinephrine, corticosteroids, and 
antihistamines. 
Since ototoxicity of PLATINOL is cumulative, audiometric testing should be performed 
prior to initiating therapy and prior to each subsequent dose of drug (see ADVERSE 
REACTIONS).
PLATINOL can cause fetal harm when administered to a pregnant woman. PLATINOL 
is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue 
culture. In mice PLATINOL is teratogenic and embryotoxic. If this drug is used during 
pregnancy or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus. Patients should be advised to avoid 
becoming pregnant. 
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The carcinogenic effect of PLATINOL was studied in BD IX rats. PLATINOL was 
administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body 
weight per week. Four hundred and fifty-five days after the first application, 33 animals 
died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma. 
The development of acute leukemia coincident with the use of PLATINOL has been 
reported. In these reports, PLATINOL was generally given in combination with other 
leukemogenic agents. 
Injection site reactions may occur during the administration of PLATINOL (see 
ADVERSE REACTIONS). Given the possibility of extravasation, it is recommended to 
closely monitor the infusion site for possible infiltration during drug administration. A 
specific treatment for extravasation reactions is unknown at this time. 
PRECAUTIONS
Peripheral blood counts should be monitored weekly. Liver function should be monitored 
periodically. Neurologic examination should also be performed regularly (see 
ADVERSE REACTIONS).
Drug Interactions 
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin 
therapy.
In a randomized trial in advanced ovarian cancer, response duration was adversely 
affected 
when 
pyridoxine 
was 
used 
in 
combination 
with 
altretamine 
(hexamethylmelamine) and PLATINOL. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
See WARNINGS.
Pregnancy 
Category D. See WARNINGS.
Nursing Mothers 
Cisplatin has been reported to be found in human milk; patients receiving PLATINOL 
should not breast-feed. 
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Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
Geriatric Use 
Insufficient data are available from clinical trials of cisplatin in the treatment of 
metastatic testicular tumors or advanced bladder cancer to determine whether elderly 
patients respond differently than younger patients. In four clinical trials of combination 
chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in 
combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 
65 years. In these trials, age was not found to be a prognostic factor for survival. 
However, in a later secondary analysis for one of these trials, elderly patients were found 
to have shorter survival compared with younger patients. In all four trials, elderly patients 
experienced more severe neutropenia than younger patients. Higher incidences of severe 
thrombocytopenia and leukopenia were also seen in elderly compared with younger 
patients, although not in all cisplatin-containing treatment arms. In the two trials where 
nonhematologic toxicity was evaluated according to age, elderly patients had a 
numerically higher incidence of peripheral neuropathy than younger patients. Other 
reported clinical experience suggests that elderly patients may be more susceptible to 
myelosuppression, infectious complications, and nephrotoxicity than younger patients.
Cisplatin is known to be substantially excreted by the kidney and is contraindicated in 
patients with preexisting renal impairment. Because elderly patients are more likely to 
have decreased renal function, care should be taken in dose selection, and renal function 
should be monitored. 
ADVERSE REACTIONS 
Nephrotoxicity 
Dose-related and cumulative renal insufficiency, including acute renal failure, is the 
major dose-limiting toxicity of PLATINOL. Renal toxicity has been noted in 28% to 36% 
of patients treated with a single dose of 50 mg/m2. It is first noted during the second week 
after a dose and is manifested by elevations in BUN and creatinine, serum uric acid 
and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and 
severe with repeated courses of the drug. Renal function must return to normal 
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before another dose of PLATINOL can be given. Elderly patients may be more 
susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
Impairment of renal function has been associated with renal tubular damage. The 
administration of PLATINOL using a 6- to 8-hour infusion with intravenous hydration, 
and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can 
occur after utilization of these procedures. 
Ototoxicity 
Ototoxicity has been observed in up to 31% of patients treated with a single dose of 
PLATINOL 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high 
frequency range (4000 to 8000 Hz). Decreased ability to hear normal conversational 
tones may occur. Deafness after the initial dose of PLATINOL has been reported. 
Ototoxic effects may be more severe in children receiving PLATINOL. Hearing loss can 
be unilateral or bilateral and tends to become more frequent and severe with repeated 
doses. Ototoxicity may be enhanced with prior or simultaneous cranial irradiation. It is 
unclear whether PLATINOL-induced ototoxicity is reversible. Ototoxic effects may be 
related to the peak plasma concentration of PLATINOL. Careful monitoring of 
audiometry should be performed prior to initiation of therapy and prior to subsequent 
doses of PLATINOL. 
Vestibular toxicity has also been reported. 
Ototoxicity may become more severe in patients being treated with other drugs with 
nephrotoxic potential. 
Hematologic
Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL. The nadirs 
in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with 
most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia 
are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g 
hemoglobin/100 mL) occurs at approximately the same frequency and with the same 
timing as leukopenia and thrombocytopenia. Fever and infection have also been reported 
in patients with neutropenia. Potential fatalities due to infection (secondary to 
myelosuppression) have been reported. Elderly patients may be more susceptible to 
myelosuppression (see PRECAUTIONS: Geriatric Use).
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In addition to anemia secondary to myelosuppression, a Coombs’ positive hemolytic 
anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course 
of treatment may be accompanied by increased hemolysis and this risk should be 
weighed by the treating physician. 
The development of acute leukemia coincident with the use of PLATINOL has been 
reported. In these reports, PLATINOL was generally given in combination with other 
leukemogenic agents. 
Gastrointestinal
Marked nausea and vomiting occur in almost all patients treated with PLATINOL, and 
may be so severe that the drug must be discontinued. Nausea and vomiting may begin 
within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, 
nausea and/or anorexia may persist for up to 1 week after treatment. 
Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) 
has occurred in patients attaining complete emetic control on the day of PLATINOL 
therapy.
Diarrhea has also been reported. 
OTHER TOXICITIES 
Vascular toxicities coincident with the use of PLATINOL in combination with other 
antineoplastic agents have been reported. The events are clinically heterogeneous and 
may 
include 
myocardial 
infarction, 
cerebrovascular 
accident, 
thrombotic 
microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various 
mechanisms have been proposed for these vascular complications. There are also reports 
of Raynaud’s phenomenon occurring in patients treated with the combination of 
bleomycin, vinblastine with or without PLATINOL. It has been suggested that 
hypomagnesemia developing coincident with the use of PLATINOL may be an added, 
although not essential, factor associated with this event. However, it is currently 
unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying 
vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any 
of these factors. 
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Serum Electrolyte Disturbances 
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia 
have been reported to occur in patients treated with PLATINOL and are probably related 
to renal tubular damage. Tetany has been reported in those patients with hypocalcemia 
and hypomagnesemia. Generally, normal serum electrolyte levels are restored by 
administering supplemental electrolytes and discontinuing PLATINOL. 
Inappropriate antidiuretic hormone syndrome has also been reported. 
Hyperuricemia 
Hyperuricemia has been reported to occur at approximately the same frequency as the 
increases in BUN and serum creatinine. 
It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid 
generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia 
effectively reduces uric acid levels. 
Neurotoxicity 
See WARNINGS.
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The 
neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic 
symptoms have been reported to occur after a single dose. Although symptoms and signs 
of PLATINOL neuropathy usually develop during treatment, symptoms of neuropathy 
may begin 3 to 8 weeks after the last dose of PLATINOL. PLATINOL therapy should be 
discontinued when the symptoms are first observed. The neuropathy, however, may 
progress further even after stopping treatment. Preliminary evidence suggests peripheral 
neuropathy may be irreversible in some patients. Elderly patients may be more 
susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).
Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have also been 
reported.
Loss 
of 
taste, 
seizures, 
leukoencephalopathy, 
and 
reversible 
posterior 
leukoencephalopathy syndrome (RPLS) have also been reported. 
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Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of 
sudden onset and short duration, have been reported and were usually associated in 
patients receiving a relatively high cumulative dose of PLATINOL and with a relatively 
advanced symptomatic stage of peripheral neuropathy. 
Ocular Toxicity 
Optic neuritis, papilledema, and cerebral blindness have been reported in patients 
receiving standard recommended doses of PLATINOL. Improvement and/or total 
recovery usually occurs after discontinuing PLATINOL. Steroids with or without 
mannitol have been used; however, efficacy has not been established. 
Blurred vision and altered color perception have been reported after the use of regimens 
with higher doses of PLATINOL or greater dose frequencies than recommended in the 
package insert. The altered color perception manifests as a loss of color discrimination, 
particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular 
retinal pigmentation of the macular area. 
Anaphylactic-Like Reactions 
Anaphylactic-like reactions have been reported in patients previously exposed to 
PLATINOL. The reactions consist of facial edema, wheezing, tachycardia, and 
hypotension within a few minutes of drug administration. Reactions may be controlled by 
intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients 
receiving PLATINOL should be observed carefully for possible anaphylactic-like 
reactions and supportive equipment and medication should be available to treat such a 
complication. 
Hepatotoxicity
Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been 
reported to be associated with PLATINOL administration at the recommended doses. 
Other Events 
Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, 
and dehydration have been reported. 
Local soft tissue toxicity has been reported following extravasation of PLATINOL. 
Severity of the local tissue toxicity appears to be related to the concentration of the 
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PLATINOL solution. Infusion of solutions with a PLATINOL concentration greater than 
0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema. 
OVERDOSAGE 
Caution should be exercised to prevent inadvertent overdosage with PLATINOL. 
Acute overdosage with this drug may result in kidney failure, liver failure, deafness, 
ocular toxicity (including detachment of the retina), significant myelosuppression, 
intractable nausea and vomiting and/or neuritis. In addition, death can occur following 
overdosage.
No proven antidotes have been established for PLATINOL overdosage. Hemodialysis, 
even when initiated four hours after the overdosage, appears to have little effect on 
removing platinum from the body because of PLATINOL’s rapid and high degree of 
protein binding. Management of overdosage should include general supportive measures 
to sustain the patient through any period of toxicity that may occur. 
DOSAGE AND ADMINISTRATION 
PLATINOL is administered by slow intravenous infusion. PLATINOL SHOULD NOT 
BE GIVEN BY RAPID INTRAVENOUS INJECTION. 
Note: Needles or intravenous sets containing aluminum parts that may come in 
contact with PLATINOL should not be used for preparation or administration. 
Aluminum reacts with PLATINOL, causing precipitate formation and a loss of 
potency.
Metastatic Testicular Tumors 
The usual PLATINOL dose for the treatment of testicular cancer in combination with 
other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle. 
Metastatic Ovarian Tumors 
The usual PLATINOL dose for the treatment of metastatic ovarian tumors in combination 
with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1). 
The dose of cyclophosphamide when used in combination with PLATINOL is 
600 mg/m2 IV once every 4 weeks (DAY 1). 
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For directions for the administration of cyclophosphamide, refer to the cyclophosphamide 
package insert. 
In combination therapy, PLATINOL and cyclophosphamide are administered 
sequentially.
As a single agent, PLATINOL should be administered at a dose of 100 mg/m2 IV per 
cycle once every 4 weeks. 
Advanced Bladder Cancer 
PLATINOL should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per 
cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation 
therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 
50 mg/m2 per cycle repeated every 4 weeks is recommended. 
All Patients 
Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a 
PLATINOL dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 
1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour 
period. If diluted solution is not to be used within 6 hours, protect solution from light. 
Adequate hydration and urinary output must be maintained during the following 24 
hours.
A repeat course of PLATINOL should not be given until the serum creatinine is below 
1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be 
given until circulating blood elements are at an acceptable level (platelets t100,000/mm3,
WBC t4000/mm3). Subsequent doses of PLATINOL should not be given until an 
audiometric analysis indicates that auditory acuity is within normal limits. 
PREPARATION OF INTRAVENOUS SOLUTIONS 
Preparation Precautions 
Caution should be exercised in handling the powder and preparing the solution of 
cisplatin. Procedures for proper handling and disposal of anticancer drugs should be 
utilized. Several guidelines on this subject have been published.1-4 To minimize the risk 
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of dermal exposure, always wear impervious gloves when handling vials and IV sets 
containing PLATINOL for injection. 
Skin reactions associated with accidental exposure to cisplatin may occur. The use of 
gloves is recommended. If PLATINOL powder or PLATINOL solution contacts the skin 
or mucosa, immediately and thoroughly wash the skin with soap and water and flush the 
mucosa with water. More information is available in the references listed below. 
Instructions for Preparation 
The 50 mg vials should be reconstituted with 50 mL of Sterile Water for Injection, USP. 
Each mL of the resulting solution will contain 1 mg of PLATINOL. 
Reconstitution as recommended results in a clear, colorless to slight yellow solution. 
The reconstituted solution should be used intravenously only and should be administered 
by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
NOTE TO PHARMACIST: Exercise caution to prevent inadvertent PLATINOL 
overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum 
and flip-off seal of vial have been imprinted with the following statement: 
CALL DR. IF DOSE>100 MG/M2/CYCLE.
STABILITY 
Unopened vials of dry powder are stable for the lot life indicated on the package when 
stored at room temperature (25q C, 77q F). 
The reconstituted solution is stable for 20 hours at room temperature (25q C, 77q F). 
Solution removed from the amber vial should be protected from light if it is not to be 
used within six hours. 
Important Note: Once reconstituted, the solution should be kept at room temperature 
(25q C, 77q F). If the reconstituted solution is refrigerated a precipitate will form. 
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HOW SUPPLIED 
PLATINOL® (cisplatin for injection, USP) 
NDC 0015-3072-20—Each amber vial contains 50 mg of cisplatin 
REFERENCES
1.
NIOSH Alert: Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control and
Prevention, National Institute for Occupational Safety and Health, DHHS
(NIOSH) Publication No. 2004-165.
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling
occupational 
exposure 
to 
hazardous 
drugs. 
OSHA, 
1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling
hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4.
Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology
Nursing Society.
Manufactured for: 
Bristol-Myers Squibb Company 
Princeton, New Jersey 08543 USA 
Made in Italy 
1192978A2
 Rev September 2010 
15
Reference ID: 3006561 
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APPENDIX E 
CYCLOPHOSPHAMIDE Prescribing Information 
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CYCLOPHOSPHAMIDE - cyclophosphamide   injection, powder, for solution 
Baxter Healthcare Corporation
DESCRIPTION
Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide monohydrate. Cyclophosphamide is a
synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the
molecular formula C7H15CI2N2O2P•H2O and a molecular weight of 279.1. The chemical name for cyclophosphamide is 2-[bis(2-
chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide is soluble in water, saline, or
ethanol and has the following structural formula:
CLINICAL PHARMACOLOGY
Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase
system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is
thought to involve cross-linking of tumor cell DNA.
Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an
elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted in
urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations
of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low
but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible
for either the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabolites of cyclophosphamide have
been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated.
INDICATIONS AND USAGE
Malignant Diseases
Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with
other antineoplastic drugs. The following malignancies are often susceptible to cyclophosphamide treatment:
1. Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular
or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma.
2. Multiple myeloma.
3. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute
myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (cyclophosphamide given during
remission is effective in prolonging its duration).
4. Mycosis fungoides (advanced disease).
5. Neuroblastoma (disseminated disease).
6. Adenocarcinoma of the ovary.
7. Retinoblastoma.
8. Carcinoma of the breast.
Nonmalignant Disease Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:
Cyclophosphamide is useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children but should
not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adrenocorticosteroid therapy or
in whom the adrenocorticosteroid therapy produces or threatens to produce intolerable side effects, cyclophosphamide may induce a
remission. Cyclophosphamide is not indicated for the nephrotic syndrome in adults or for any other renal disease.
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CONTRAINDICATIONS
Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide
is contraindicated in patients who have demonstrated a previous hypersensitivity to it. See WARNINGS and PRECAUTIONS
sections.
WARNINGS
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Second malignancies have developed in some patients treated with cyclophosphamide used alone or in association with other
antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative, or lymphoproliferative
malignancies. Second malignancies most frequently were detected in patients treated for primary myeloproliferative or
lymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically.
In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. In a single
breast cancer trial utilizing two to four times the standard dose of cyclophosphamide in conjunction with doxorubicin a small number
of cases of secondary acute myeloid leukemia occurred within two years of treatment initiation. Urinary bladder malignancies
generally have occurred in patients who previously had hemorrhagic cystitis. In patients treated with cyclophosphamide-containing
regimens for a variety of solid tumors, isolated case reports of secondary malignancies have been published. One case of carcinoma
of the renal pelvis was reported in a patient receiving long-term cyclophosphamide therapy for cerebral vasculitis. The possibility of
cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.
Cyclophosphamide can cause fetal harm when administered to a pregnant woman and such abnormalities have been reported
following cyclophosphamide therapy in pregnant women. Abnormalities were found in two infants and a six-month old fetus born
to women treated with cyclophosphamide. Ectrodactylia was found in two of the three cases. Normal infants have also been born to
women treated with cyclophosphamide during pregnancy, including the first trimester. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women
of childbearing potential should be advised to avoid becoming pregnant.
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility
appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment.
Cyclophosphamide-induced sterility may be irreversible in some patients.
Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of women
treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy.
Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have
regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late
prepubescence has been reported. Girls treated with cyclophosphamide during prepubescence subsequently have conceived.
Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normal
testosterone secretion. Sexual potency and libido are unimpaired in these patients. Boys treated with cyclophosphamide during
prepubescence develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased
gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some
patients, though the reversibility may not occur for several years after cessation of therapy. Men temporarily rendered sterile by
cyclophosphamide have subsequently fathered normal children.
Urinary System
Hemorrhagic cystitis may develop in patients treated with cyclophosphamide. Rarely, this condition can be severe and even fatal.
Fibrosis of the urinary bladder, sometimes extensive, also may develop with or without accompanying cystitis. Atypical urinary
bladder epithelial cells may appear in the urine. These adverse effects appear to depend on the dose of cyclophosphamide and the
duration of therapy. Such bladder injury is thought to be due to cyclophosphamide metabolites excreted in the urine. Forced fluid
intake helps to assure an ample output of urine, necessitates frequent voiding, and reduces the time the drug remains in the bladder.
This helps to prevent cystitis. Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may
persist. Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of severe hemorrhagic cystitis.
It is usually necessary to discontinue cyclophosphamide therapy in instances of severe hemorrhagic cystitis.
Cardiac Toxicity
Although a few instances of cardiac dysfunction have been reported following use of recommended doses of cyclophosphamide,
no causal relationship has been established. Acute cardiac toxicity has been reported with doses as low as 2.4 g/m2 to as high as 26
g/m2, usually as a portion of an intensive antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a
few instances with high doses of cyclophosphamide, severe, and sometimes fatal, congestive heart failure has occurred after the first
cyclophosphamide dose. Histopathologic examination has primarily shown hemorrhagic myocarditis. Hemopericardium has occurred
secondary to hemorrhagic myocarditis and myocardial necrosis. Pericarditis has been reported independent of any hemopericardium.
No residual cardiac abnormalities, as evidenced by electrocardiogram or echocardiogram appear to be present in patients surviving
episodes of apparent cardiac toxicity associated with high doses of cyclophosphamide.
Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity.
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Infections
Treatment with cyclophosphamide may cause significant suppression of immune responses. Serious, sometimes fatal, infections may
develop in severely immunosuppressed patients. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the
dose reduced, in patients who have or who develop viral, bacterial, fungal, protozoan, or helminthic infections.
Other
Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with
other alkylating agents has been reported.
PRECAUTIONS
General
Special attention to the possible development of toxicity should be exercised in patients being treated with cyclophosphamide if any of
the following conditions are present.
1. Leukopenia
2. Thrombocytopenia
3. Tumor cell infiltration of bone marrow
4. Previous X-ray therapy
5. Previous therapy with other cytotoxic agents
6. Impaired hepatic function
7. Impaired renal function
Laboratory Tests
During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine
the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic
cystitis.
Drug Interactions
The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high
doses of phenobarbital.
The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even though
cyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.
Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of
succinylcholine chloride.
If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
Adrenalectomy
Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement
steroids and cyclophosphamide may be necessary for the adrenalectomized patient.
Wound Healing
Cyclophosphamide may interfere with normal wound healing.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
See WARNINGS section for information on carcinogenesis, mutagenesis, and impairment of fertility.
Pregnancy
Pregnancy Category D—See WARNINGS section.
Nursing Mothers
Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for
tumorigenicity shown for cyclophosphamide in humans, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
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Pediatric Use
The safety profile of cyclophosphamide in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS
section).
Geriatric Use
Insufficient data from clinical studies of cyclophosphamide for malignant lymphoma, multiple myeloma, leukemia, mycosis
fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine
whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide was compared with
paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who
received cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published
reports of clinical trials of cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing
experience suggest that elderly patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient
response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases).
ADVERSE REACTIONS
Information on adverse reactions associated with the use of cyclophosphamide is arranged according to body system affected or type
of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the
WARNINGS section.
Reproductive System
See WARNINGS section for information on impairment of fertility.
Digestive System
Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain
and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during
therapy. These adverse drug effects generally remit when cyclophosphamide treatment is stopped.
Skin and Its Structures
Alopecia occurs commonly in patients treated with cyclophosphamide. The hair can be expected to grow back after treatment with the
drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients
receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic
epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting,
a definitive causal relationship to cyclophosphamide has not been established.
Hematopoietic System
Leukopenia occurs in patients treated with cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide.
Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and less
frequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with a
reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.
Thrombocytopenia or anemia develop occasionally in patients treated with cyclophosphamide. These hematologic effects usually can
be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after
cessation of therapy.
Urinary System
See WARNINGS section for information on cystitis and urinary bladder fibrosis.
Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with cyclophosphamide. Such lesions
usually resolve following cessation of therapy.
Infections
See WARNINGS section for information on reduced host resistance to infections.
Carcinogenesis
See WARNINGS section for information on carcinogenesis.
Respiratory System
Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in
patients receiving high doses of cyclophosphamide over a prolonged period.
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Other
Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity
with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of
cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience.
OVERDOSAGE
No specific antidote for cyclophosphamide is known. Overdosage should be managed with supportive measures, including appropriate
treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.
DOSAGE AND ADMINISTRATION
Treatment of Malignant Diseases Adults and Children
When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency
usually consists of 40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens
include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly.
Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.
Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with
evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient
decreases in the total white blood cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000 cells/
mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.
When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as
well as that of the other drugs.
Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis
system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of
cyclophosphamide metabolism, but there is no consistent evidence indicating a need for cyclophosphamide dosage modification in
patients with renal function impairment.
Treatment of Nonmalignant Diseases Biopsy Proven “Minimal Change’’ Nephrotic Syndrome in Children
An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and
azoospermia increases if the duration of cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the
probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of cyclophosphamide therapy.
See PRECAUTIONS section concerning hematologic monitoring.
Preparation and Handling of Solutions
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever
solution and container permit.
Cyclophosphamide should be prepared for parenteral use by adding 0.9% sterile sodium chloride solution if injected directly.
Cyclophosphamide should be prepared for parenteral use by infusion by adding Sterile Water for Injection, USP. Cyclophosphamide,
constituted in water, is hypotonic and should not be injected directly. Add the diluent to the vial and shake it vigorously to dissolve. If
the powder fails to dissolve immediately and completely, it is advisable to allow the vial to stand for a few minutes. Use the quantity
of diluent shown below to constitute the product:
Dosage Strength
Cyclophosphamide for Injection
Contains Cyclophosphamide Monohydrate
Quantity of Diluent
500 mg
534.5 mg
25 mL
1 g
1069.0 mg
50 mL
2 g
2138.0 mg
100 mL
Solutions of cyclophosphamide may be injected intravenously, intramuscularly, intraperitoneally, or intrapleurally if constituted by
adding 0.9% sodium chloride solution, or they may be infused intravenously in the following:
Dextrose Injection, USP (5% dextrose)
Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sodium chloride)
5% Dextrose and Ringer’s Injection
Lactated Ringer’s Injection, USP
Sodium Chloride Injection, USP (0.45% sodium chloride)
Sodium Lactate Injection, USP (1/6 molar sodium lactate)
Constituted cyclophosphamide is chemically and physically stable for 24 hours at room temperature or for six days in the refrigerator;
it does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.
The osmolarities of solutions of cyclophosphamide constituted with water and 0.9% sodium chloride solution are found in the
following table:
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Cyclophosphamide and Diluent
mOsm/L
5 mL water per 100 mg cyclophosphamide (anhydrous)
74
5 mL 0.9% sodium chloride solution per 100 mg cyclophosphamide (anhydrous)
374
Isotonic 0.9% sodium chloride solution has an osmolarity of 289 mOsm/L.
Cyclophosphamide solution in water is hypotonic.
Extemporaneous liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide in
Aromatic Elixir, N.F.& Such preparations should be stored under refrigeration in glass containers and used within 14 days.
HOW SUPPLIED
Cyclophosphamide for Injection, USP contains cyclophosphamide monohydrate and is supplied in vials for single dose use.
NDC 10019-955-01 500 mg vial, carton of 1
NDC 10019-956-01 1.0 g vial, carton of 1
NDC 10019-957-01 2.0 g vial, carton of 1
Store vials at or below 25°C (77°F) [see USP Controlled Room Temperature]. During transport or storage of cyclophosphamide
vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance can
be visually differentiated. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in
droplets in the affected vials. Do not use cyclophosphamide vials if there are signs of melting.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been
published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
REFERENCES
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA:
Oncology Nursing Society; 1999:32-41.
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the
Superintendent of Documents, US Government Printing Office, Washington, D.C. 20402.
3. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253 (11): 1590-1592.
4. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis
P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
5. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J
Australia 1983; 1:426-428.
6. Jones RB, et al: Safe Handling of chemotherapeutic agents: A Report from the Mount Sinai Medical Center. CA—A Cancer
Journal for Clinicians 1983; (Sept/Oct) 258-263.
7. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp
Pharm 1990; 47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK PRACTICE GUIDELINES). Am J Health Syst Pharm
1996; 53:1669-1685.
Manufactured by:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT-00065/4.0
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PACKAGE LABEL - PRINCIPAL DISPLAY PANEL
Container Label
NDC 10019-955-50
Cyclophosphamide
for Injection, USP
500 mg
CYTOTOXIC AGENT
FOR SINGLE DOSE USE
STERILE, NON-PYROGENIC
FOR PARENTERAL USE
Rx only
Baxter
Manufactured by Baxter Healthcare Corporation
Deerfield, IL 60015 USA
460-629-01
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, 
N DC 1001 9-955-9:l 
m 
>< 
-0 Cyclophosphamlde 
for Injection, USP 
500 mg CYTOTOXIC AGENT 
FOR SINGLE DOSE USE 
, 
STERILE. NON-PYR OOENIC 
only 
FOR PARENTERAL USE 
Baxter· 
PAanuf!ciu re,:! bv BB.Il.r le~1bca111 CofiPon li'on, 
Deerti~d. IL 6C015 USA 
4E0-629-01 
Each vial contains 500 mg cyclophoophamide. 
For· IV lrtlDsioo Use: Add 25 m L Sterile 
water for Injection, USP, rnd shake = 
\ligo ro u sly to dissolve the drug, 
= 
Fo1 Dlrec:I lnjedion Use: Add 25 ml = 
0.9% 
Sodium Chloride Injection, = .:i u 
USP, and shake vigo rously to dis- ii~ c::i 
solve the drug. 
=
gl %Q 
-
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co 
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schfdule. S~ore vial al or below 25 C =a 
ID 
(n °F) [see USP ConlroU,ed Ao:om !!!!!!!!e. ! 
TemperaliureJ. 

page 8 of 9
Carton Label
NDC 10019-955-01
Cyclophosphamide
for Injection, USP
500 mg
Rx only
MUST BE DILUTED
FOR IV INFUSION
OR DIRECT INJECTION USE
1 Single Dose Vial
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t-
66 1 
111111111 
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6w oos 
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NDC 10019-955-01 
Cyclophosphamide 
for Injection, USP 
500mg 
MUST BE DILUTED 
FOR IV INFUSION 
~only 
OR DIRECT INJECTION USE 
1 Single Dose Vial 
Ba xter 
Manufactured by 
Barter He-aHhcare Cor,oration 
Deeliield. IL 60015 UM 
67:!8 
1091 
LISA 
Each ,•ial cootains 500 mg cyclofhosphamide. 
iFa r 
11V ln1u ,ion lha: Add 25 ml Sterile l'llllor 
for lnj,ction, USP, and shake >'ig,rousty to 
dissolva the drug. 
IFor Dir-act l'njoction lloa: Md 25 ml 0.9% 
Sodium Chloride Injection, USP, and shake 
v~orously to diesoW1:11h11 drug. 
Stor•• via l at or below 25•c 177•Fj [BBo 
USP 1Con1ro lled Room T:emperature]. 
IDOSAGE: Sae accompaw1ing literature for 
direc1ions for use. Should not be pre-
,;crl bed witho ut thorough knat1ledg, of 
dose, indications and to:xicity as contained 
in accompanying literature. 
CYTOTOXIC AGENT 
IFO!I SING'LI DOSE USE 
SURIU, IION-P'IJIOGf lll.C 
IFO!I PAIIEIIJiE!RAL U6E 
460-630-01 
C 
E'.61 
ND C 10019-955-01 
Cyclophosphamide 
for Injection, USP 
500mg 
MUST BE DILUTED 
FOR IV INFUSION 
&only 
OR DIRECT INJECTION USE 
1 Single Dose Vial 
Baxter 
Manufactured by 
Bart.er He-alt~care Corporation 
Deeliield, IL 60015 USA 
lOT/EJ<P 
2636 B 507 1 
111111111 
I 
II ' ' 
I 
Cyclophosphamide 
for Injection, USP 
500 mg 
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OR DIRECT INJECTION USE 
1 Single Dose Vial 
Ii 
3 
II 
5501 

page 9 of 9
Baxter
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
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