Clinical trial NCT00515411
Conditions: Gastroesophageal Junction Adenocarcinoma Gastric Cancer
Keywords: gastroesophageal junction gastric cancer adenocarcinoma unresectable gastric cancer metastatic gastric
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2006-10-23; Completion date: 2018-10-26
Enrollment: 111 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Chemotherapy given together is a standard way to treat your cancer. One standard treatment includes a combination of docetaxel, cisplatin, and fluorouracil. However, the original combination of these three drugs can cause many side effects. This study is being done to find out if these three drugs can be given at lower doses more often, with fewer side effects and still maintain the same benefit as the standard way of giving this three drug combination. If your tumor overexpresses a protein called Her2, you are also eligible to receive trastuzumab with chemotherapy. Trastuzumab is a medicine that has been approved by the US Food and Drug Administration for the treatment of Her2 positive breast cancer. Trastuzumab is now also a standard treatment in combination with chemotherapy for the treatment of Her2 positive stomach cancer. If your tumor is Her2 positive, you would receive the modified administration schedule of docetaxel, cisplatin, and fluorouracil with trastuzumab.

Detailed description:

Arms: arm 1: Drug Dose (mg/m2) Schedule

Docetaxel 40 Day 1 IVPB (60 min) Leucovorin 400 Day 1 IVPB (30 min) Fluorouracil 400 IVP day 1 Fluorouracil 1000 mg/m2/d daily x 2 days Cisplatin 40 Day 2 OR 3 IVPB (30 min) Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments). arm 2: Docetaxel 75 Day 1 IVPB (60 min) Cisplatin 75 Day 1 IVPB (60 min) Fluorouracil 750 IVCI daily x 5 days Neulasta 6 mg subcut on d 8, 9, or 10 or Neupogen 300 or 480 mcg\* subcut x 7 d 10-17

\* 300 mcg for weight \< 60 kg, 480 mcg for weight \> 60 kg arm 3: Treatment for Her2 Positive Participants

Docetaxel 40 Day 1 IVPB (60 min) Leucovorin 400 Day 1 IVPB (30 min) Fluorouracil 400 IVP day 1 Fluorouracil 1000 mg/m2/d daily x 2 days Cisplatin 40 Day 2 OR 3 IVPB (30 min) Trastuzumab Administered on an every 2 week dosing schedule. Initial loading dose of 6 mg/kg over 90 minutes, followed by trastuzumab 4 mg/kg every 2 weeks over 30 minutes.
Interventions: intervention 1: Docetaxel, Leucovorin, Fluorouracil, Cisplatin intervention 2: Docetaxel, Cisplatin, Fluorouracil, Neulasta, or Neupogen intervention 3: Docetaxel, Leukvorin, Flurouracil, Cisplatin, Trastuzumab
Intervention descriptions: intervention 1: Drug Dose (mg/m2) Schedule Docetaxel 40 Day 1 IVPB (60 min) Leucovorin 400 Day 1 IVPB (30 min) Fluorouracil 400 IVP day 1 Fluorouracil 1000 IVCI x 48 hours Cisplatin 40 Day 2 OR 3 IVPB (30 min) intervention 2: Drug Dose (mg/m2) Schedule Docetaxel 75 Day 1 IVPB (60 min) Cisplatin 75 Day 1 IVPB (60 min) Fluorouracil 750 IVCI daily x 5 days Neulasta 6 mg subcut on d 8, 9, or 10 or Neupogen 300 or 480 mcg\* subcut x 7 d 10-17

\* 300 mcg for weight \< 60 kg, 480 mcg for weight \> 60 kg

Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 treatments). Tumor assessments will be performed following the completion of every cycle for the first 6 cycles, and then every 2 cycles thereafter. intervention 3: Treatment for Her2 Positive Participants

Docetaxel 40 Day 1 IVPB (60 min) Leucovorin 400 Day 1 IVPB (30 min) Fluorouracil 400 IVP day 1 Fluorouracil 1000 mg/m2/d daily x 2 days Cisplatin 40 Day 2 OR 3 IVPB (30 min) Trastuzumab Administered on an every 2 week dosing schedule. Initial loading dose of 6 mg/kg over 90 minutes, followed by trastuzumab 4 mg/kg every 2 weeks over 30 minutes.

Protocol documents:
Prot_SAP_000.pdf: 
 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                       IRB#: 06-103 A(17 ) 
Amended:  08/03/15 
 
A Phase II study of modified docetaxel, cisplatin, and fluorouracil (mDCF) in patients with 
unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Yelena Y. Janjigian, MD 
Office: 646.888.4186 
Fax: 646.888.4256 
Email: janjigiy@mskcc.org 
Medicine: Gastrointestinal  
 
 
Co-Principal 
Investigator(s)/Department: 
David Kelsen, MD 
Medicine: Gastrointestinal  
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                       IRB#: 06-103 A(17 )
Amended:  08/03/15 
 
A
A Phase II study of modified docetaxel, cisplatin, and fluorouracil (mDCF) in patients with 
unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL
Principal Investigator/Department: 
Yelena Y. Janjigian, MD 
Office: 646.888.4186 
Fax: 646.888.4256 
Email: janjigiy@mskcc.org 
Medicine: Gastrointestinal
 
 
Co-Principal 
Investigator(s)/Department: 
David Kelsen, MD 
Medicine: Gastrointestinal 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Investigator(s)/Department: 
Gary K. Schwartz, MD 
David Ilson, MD PhD 
Leonard Saltz, MD 
Nancy Kemeny, MD 
Diane Reidy-Lagunes, MD 
Marinela Capanu, PhD 
David D’Adamo, MD PhD 
Ki Young Chung, MD 
Neil H. Segal, MD, PHD 
Kenneth Yu, MD 
Maeve Lowery, MD 
Rona D. Yaeger, MD 
Andrew S. Epstein, MD 
Geoffrey Y. Ku, MD 
James Harding, MD 
Anna Varghese, MD 
Peter Maslak, MD 
Robert Lefkowitz, MD 
Marc Simmons, MD 
Heiko Schoder, MD 
Laura Tang, MD 
Ephraim Casper, MD 
Sree Chalasani, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Magi Khalil, MD 
Han Xiao, MD 
Avni Desai, MD 
Marisa Siebel, MD 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
 
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Epidemiology : Biostatistics 
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Leukemia  
Radiology 
Radiology 
Radiology: Nuclear Medicine 
Pathology 
Medicine: All Networks 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Mercy 
 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Consenting 
Professional(s)/Department: 
 
Yelena Y. Janjigian, MD 
David P. Kelsen, MD 
Gary K. Schwartz, MD 
David Ilson, MD PhD 
Leonard Saltz, MD 
Nancy Kemeny, MD 
Diane Reidy-Lagunes, MD 
Kenneth Yu, MD 
Maeve Lowery, MD 
Rona D. Yaeger, MD 
Andrew S. Epstein, MD 
Geoffrey Y. Ku, MDDavid 
D’Adamo, MD 
Ki Young Chung, MD 
Neil H. Segal, MD, PHD 
James Harding, MD 
Anna Varghese, MD 
Ephraim Casper, MD 
Sree Chalasani, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Magi Khalil, MD 
Han Xiao, MD 
Avni Desai, MD 
Marisa Siebel, MD 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
 
 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: All Networks 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Mercy 
 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
 
Please Note: A Consenting Professional must have completed the mandatory Human Subjects 
Education and Certification Program 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
National Coordinating 
Investigator 
Manish A. Shah, MD 
Office: 646.962.6200 
Fax: 646.962.1607 
Email: mas9313@med.cornell.edu  
 
 
 
Collaborating Institution (s): PI Name and Contact Info 
Site Role 
University of Pittsburgh 
Cancer Institute 
 
PI: Ronald G. Stoller, M.D. 
University of Pittsburgh Cancer Institute 
Hillman Cancer Center 
5115 Centre Avenue 
Pittsburgh, PA 15232 
Ph: 412-692-4724 
Fax: 412-648-6579 
Email: stollerrg@upmc.edu   
 
Data Collection 
Queens Cancer Center 
PI: Margaret Kemeny, M.D. 
Queens Cancer Center of Queens Hospital 
82-68 164th Street 
New Building – Room A531 
Jamaica, NY 11432 
Ph: 718-883-4031 
Fax: 718-883-6295 
Email: kemenym@nychhc.org 
 
 
Data Collection 
Long Island Jewish Medical 
Center 
PI: Bhoomi Mehrotra, M.D. 
Long Island Jewish Medical Center 
Division of Hematology/Oncology 
New Hyde Park, NY 11040 
Ph: 718-470-8934 
Fax: 718-470-0169 
Email: mehrotra@lij.edu 
 
Data Collection 
University Hospital  of 
Cleveland 
PI: Smitha Krishnamurthi, M.D. 
Ireland Cancer Center/University Hosp. of 
Cleveland 
Case Medical Center 
11100 Euclid Avenue 
Cleveland, OH 44106 
Ph: 216-844-5413 
Fax: 216-844- 5449 
Email: smitha.krishnamurthi@case.edu  
 
Data Collection 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Weill Medical College of 
Cornell University 
 
PI: Allyson J. Ocean, M.D. 
Assistant Professor of Medicine 
New York Presbyterian Hospital - Weill 
Medical College of 
Cornell University 
Division of Hematology/Oncology 
520 East 70th Street, Starr 365 
New York, NY 10021 
Ph: 212-746-2844 
Fax:  212-746-6645 
E-mail:  ajo9001@med.cornell.edu  
 
Data Collection 
City of Hope 
PI: Vincent Chung, M.D. FACP 
Assistant Professor 
City of Hope Comprehensive Cancer 
Center 
1500 E. Duarte Rd. 
Duarte, CA 91010 
Ph: 626-471-9200  
Fax: 626-301-8233 
E-mail: vchung@coh.org  
 
Data Collection 
Medical College of 
Wisconsin 
PI: Paul Ritch, M.D. 
Professor of Medicine 
Medical College of Wisconsin 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
Ph: 414-805-4600 
Fax: 414-805-6838 
E-mail: pritch@mcw.edu 
 
Data Collection 
Piedmont Hospital Research 
Institute (PHRI) 
 
PI: Charles Henderson, M.D. 
Piedmont Hospital Research Institute 
(PHRI) 
95 Collier Rd., Suite 2075 
Atlanta, GA 30309 
Ph: 404-350-9853 
Fax: 404-350-8407 
E-mail: chenderson@phoc.com  
 
Data Collection 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Nebraska Cancer Specialists 
 
PI: Yungpo Bernard Su, M.D.  
Nebraska Cancer Specialists 
Methodist Estabrook Cancer Center 
8303 Dodge Street, Suite 250 
Omaha, Nebraska 68114 
Ph: 402.354.8124  
Fax: 402.354.8127  
E-mail: drsu@onchemwest.com    
 
Data Collection 
Memorial Cancer Institute 
PI: Dr. Pablo Ferraro, M.D. 
Memorial Cancer Institute 
801 North Flamingo Road 
Pembroke Pines, FL 33025 
Ph: (954)430-6868 
Fax: (954)443-4747 
E-mail: pferraro@mhs.net 
 
Data Collection 
 
 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
                                         Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ........................................................................ 4 
3.0 
BACKGROUND AND RATIONALE ............................................................................... 5 
3.1 SCOPE OF DISEASE AND ROLE OF CHEMOTHERAPY ...................................................... 5 
3.2 COMBINATION CHEMOTHERAPY REGIMENS.................................................................... 5 
3.3 IS THERE A “STANDARD” CHEMOTHERAPY REGIMEN? ................................................ 7 
3.4 SUMMARY OF CHEMOTHERAPY FOR GASTRIC/GEJ ADENOCARCINOMA ............ 12 
3.5 PROPOSAL .................................................................................................................................... 13 
3.5.1 Modified DCF dose and schedule determination ...................................................................... 13 
3.5.2 Pharmacokinetic and Pharmacodynamic Considerations  (MSKCC ONLY) ....................... 17 
3.5.3  FDG-PET Response Assessment ............................................................................................... 19 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................. 22 
4.1 Design ............................................................................................................................................... 22 
4.2 
Intervention .............................................................................................................................. 23 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .................................................................... 24 
5.1  Docetaxel (TAXOTERE®) ............................................................................................................. 24 
5.2       CISPLATIN .............................................................................................................................. 27 
5.3  FLUOROURACIL ........................................................................................................................ 28 
5.4 
LEUCOVORIN ........................................................................................................................ 29 
5.5 TRASTUZUMAB ........................................................................................................................... 30 
5.6  CONCOMITANT MEDICATIONS ............................................................................................ 34 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................... 36 
6.1 
Subject Inclusion Criteria ....................................................................................................... 36 
6.2 
Subject Exclusion Criteria ...................................................................................................... 38 
7.0 
RECRUITMENT PLAN .................................................................................................. 39 
8.0 
PRETREATMENT EVALUATION................................................................................ 40 
9.0 
TREATMENT/INTERVENTION PLAN ....................................................................... 42 
9.1 CHEMOTHERAPY ADMINISTRATION .................................................................................. 42 
9.2  SUPPORTIVE CARE GUIDELINES ......................................................................................... 44 
9.3 TREATMENT PARAMETERS, DOSE DELAYS AND MODIFICATIONS ......................... 46 
9.4  CORRELATIVE STUDIES ......................................................................................................... 53 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ....................................... 56 
10.1  FOR PARTICIPATING SITES ...................................................................................... 57 
11.0 
TOXICITIES/SIDE EFFECTS ...................................................................................... 58 
11.1 CISPLATIN .................................................................................................................................. 58 
11.2 DOCETAXEL ............................................................................................................................... 59 
11.3 FLUOROURACIL ....................................................................................................................... 59 
11.4 LEUCOVORIN ............................................................................................................................. 59 
11.5 TRASTUZUMAB ......................................................................................................................... 59 
11.6 SUPPORTIVE MEDICATIONS ................................................................................................ 59 
12.1 DEFINITIONS .............................................................................................................................. 60 
12.2 EVALUATION OF TARGET LESIONS .................................................................................. 61 
12.3 EVALUATION OF NON-TARGET LESIONS ........................................................................ 61 
12.4 EVALUATION OF BEST OVERALL RESPONSE ................................................................. 62 
12.5 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE .................................... 62 
12.6 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE .................................. 63 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................... 63 
13.1 DURATION OF THERAPY / CRITERIA FOR REMOVAL FROM STUDY ..................... 63 
13.2  OFF-STUDY EVALUATION .................................................................................................... 64 
14.0 
BIOSTATISTICS ............................................................................................................. 65 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ............................................................................................................................ 67 
15.1   RESEARCH PARTICIPANT REGISTRATION ................................................................... 67 
15.3 RANDOMIZATION .................................................................................................................... 69 
16.0 
DATA  MANAGEMENT ISSUES .................................................................................. 69 
16.1 QUALITY ASSURANCE ............................................................................................................ 71 
16.2 DATA AND SAFETY MONITORING ...................................................................................... 72 
16.3 ETHICAL AND ADMINISTRATIVE ISSUES ........................................................................ 73 
16.4 INSTITUTIONAL REVIEW BOARD APPROVAL ................................................................ 73 
17.0 
PROTECTION OF HUMAN SUBJECTS ..................................................................... 75 
17.1 PRIVACY ...................................................................................................................................... 76 
17.2 SERIOUS ADVERSE EVENT (SAE) REPORTING ............................................................... 76 
17.3 SERIOUS ADVERSE EVENT REPORTING FOR OUTSIDE CENTERS........................... 79 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
18.0  INFORMED CONSENT PROCEDURES ......................................................................... 80 
18.1 FOR PARTICIPATING SITES .......................................................................................... 80 
19.0 REFERENCE(S) ................................................................................................................. 81 
20.0 APPENDICES ...................................................................................................................... 85 
 
 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA       
1.1 Objectives 
Primary:   
1) To determine the efficacy of modified docetaxel, cisplatin, and fluorouracil (mDCF) 
(ARM A) and the efficacy of parent DCF with growth factor support (ARM B) in 
patients with unresectable or metastatic gastric or gastroesophageal junction(GEJ) 
adenocarcinoma as measured by 6 month progression free survival (PFS). 
Secondary:   
2) To establish the safety of mDCF and parent DCF with growth factor support in patients 
with unresectable or metastatic gastric or GEJ adenocarcinoma. 
3) To observe other measures of efficacy of mDCF and parent DCF with growth factor 
support, including response rate, median PFS, overall and 1-year survival in patients with 
unresectable or metastatic gastric or GEJ adenocarcinoma. 
4) To explore the association of early FDG-PET imaging with treatment efficacy. 
5) To explore the differences in docetaxel pharmacology between both study arms. 
6) To bank tumor biopsy material for future planned correlative studies for association with 
chemotherapy efficacy and survival. 
7) To report the efficacy of mDCF with trastuzumab as measured by 6 month PFS amongst 
Her2 positive patients. 
8) To report the safety profile of patients receiving mDCF and trastuzumab. 
 
1.2 Eligibility 
Patients with histologically confirmed metastatic or unresectable gastric or gastroesophageal 
junction adenocarcinoma are eligible for entry into this Phase II study.  Patients may have 
received neoadjuvant and/or adjuvant chemotherapy or chemoradiotherapy.  Patients may not 
have received previous chemotherapy containing cisplatin or docetaxel.  Prior fluorouracil is 
allowed if more than 6 months have passed since the patient last received it.  Patients must 
provide written informed consent prior to study enrollment.   
Patients must be at least 18 years of age, and use birth control if male, or if female of 
childbearing age.  Patients must have a Karnofsky performance status of greater than or equal 
to 70% (ECOG < 2), and be of sound mind to sign informed consent.  Hematologic/ 
laboratory criteria for eligibility include: WBC > 3000/mm3, ANC ≥ 1500/mm3, hemoglobin 
> 9 g/dl, platelet count ≥ 100,000/mm3, serum creatinine ≤ 1.5 mg/dl.  For patients with a 
serum creatinine of 1.2-1.5, their creatinine clearance must be at least 50 ml/min. Total serum 
bilirubin ≤ 1.5, serum AST(SGOT)/ALT(SGPT) and ALK PHOS levels as per chart below: 
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤1.5x ULN 
>1.5x but ≤ 5x ULN >5x ULN 
≤ ULN 
Eligible 
Eligible 
Eligible 
Ineligible 
>1x but ≤2.5x  
Eligible 
Eligible 
Ineligible 
Ineligible 
>2.5x but ≤5x  
Eligible 
Ineligible 
Ineligible 
Ineligible 
>5x ULN 
Ineligible 
Ineligible 
Ineligible 
Ineligible 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Patients must have a PT (INR) < 1.5 and a PTT < 3 seconds above the upper limits of normal 
if they are not on anticoagulation. Women of childbearing potential must also have a 
negative pregnancy test.  Biopsy confirmation of M1 disease is encouraged, unless the risk of 
such a procedure is significant, in which case confirmation by a 2nd imaging modality is 
required. Exclusions include patients with brain or central nervous system metastases, 
patients with significant co-morbidities including cardiac diseaes, serious non-healing wound 
or ulcer, peripheral vascular disease or stroke, or significant hearing loss.  
 
December 2009 Amendment 
As of October 2009, trastuzumab plus chemotherapy is part of the NCCN standard treatment 
algorithm for the first line for advanced gastric/GEJ adenocarcinoma.  This amendment is to 
allow patients who are Her2 positive to receive trastuzumab with mDCF .  Her2 positive 
patients are defined as IHC 3+ for Her2 or FISH + (>2 HER2:CEP17).Biopsy samples (i.e 
small tissue fragments) with cohesive IHC3+ or FISH+ clones are considered  HER2 positive 
irrespective of size, i.e.<10%, as per Hofmann et al1To receive trastuzumab, patients must 
have a baseline left ventricular ejection fraction of > 50%.  Her2 positive patients who 
receive trastuzumab will be considered as a separate cohort and independent cohort. 
 
1.3 Treatment Plan 
This will be a random assignment phase II study of two different administration schedules of 
docetaxel, cisplatin, and fluorouracil in patients with unresectable or metastatic gastric or 
GEJ adenocarcinoma.  Eligible patients will be randomly assigned to receive mDCF (ARM 
A) or parent DCF with growth factor support (ARM B) as follows: 
ARM A – Modified DCF 
ARM B – Parent DCF with G-CSF 
Drug 
Dose (mg/m2) 
Schedule 
Drug 
Dose (mg/m2) 
Schedule 
Docetaxel 
40 
Day 1 IVPB (60 min) 
Docetaxel 
75 
Day 1 IVPB (60 min) 
Leucovorin 
400 
Day 1 IVPB (30 min) 
Cisplatin 
75 
Day 1 IVPB (60 min) 
Fluorouracil 
400 
IVP day 1 
Fluorouracil 
750 
IVCI daily x 5 days 
Fluorouracil 
1000 mg/m2/d 
IVCI daily x 2 days 
Neulasta 
6 mg 
subcut on d 8, 9, or 10 
Cisplatin 
40 
Day 2 OR 3 IVPB (30 
min) 
or Neupogen 
300 or 480 mcg* 
subcut x 7 d 10-17 
* 300 mcg for weight < 60 kg, 480 mcg for weight > 60 kg 
 
Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments).  
Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 
treatments).  Tumor assessments will be performed following the completion of every cycle 
for the first 6 cycles, and then every 2 cycles thereafter.   
December 2009 Amendment 
We have met the early stopping rule for Arm B, parent DCF with growth factor support.  
Arm A will continue to accrue until target accrual of 54 patients. In addition, we will treat 
Her2 positive patients with mDCF + trastuzumab.  Trastuzumab will be administered on an 
every 2 week dosing schedule, with an initial loading dose of 6 mg/kg over 90 minutes, 
followed by trastuzumab 4 mg/kg every 2 weeks over 30 mintues.   
 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
August 2010 Amendment:  
Arm A has reached target accural of 54 patients. Arm B remains closed due to toxicity. Her2 
positive patients with be enrolled onto the Trastuzumab Cohort and will receive mDCF + 
trastuzumab.  Trastuzumab will be administered on an every 2 week dosing schedule, with an 
initial loading dose of 6 mg/kg over 90 minutes, followed by trastuzumab 4 mg/kg every 2 
weeks over 30 minutes.   
 
1.4 Pharmacology and Pharmacodynamics (MSKCC patients only) 
Docetaxel is both a substrate and inhibitor of the cytochrome p450 enzyme CYP3A4, and its 
metabolism can be inhibited by CYP3A4 inhibitors such as ketoconazole, erythromycin, 
verapamil and diltiazem.  Importantly, both aprepitant and palonesetron, recently approved 
anti-emetic agents for the treatment of acute and delayed nausea, are both inhibitors of 
CYP3A4. Similarly, we hypothesize that inhibition of CYP3A4 by these anti-emetic agents 
would result in reduced docetaxel metabolism, increased drug exposure, and potentially 
increased toxicity.  
 
Pharmacokinetic blood draws will occur in patients enrolled at MSKCC only.  We will 
perform serial blood draws in approximately 20 patients (10/ arm) at the following times: 
 
1. 0.25 hours (15 min following initiation of docetaxel) 
2. 0.75 hours (45 min following initiation of docetaxel) 
3. 1 hour 
(end of docetaxel infusion) 
4. 1. 25             ( 15 min following the end of docetaxel infusion) 
5. 2 hours 
6. 4 hours 
7. 6 hours 
8. 8 hours 
9. 24 hours 
Additionally, on day 3, a CBC with differential and LFT’s (AST, ALT, Alk Phos, total 
Bilirubin) will be drawn in each of these patients.  For Arm A, these lab studies will be 
drawn prior to cisplatin administration.   
 
March 2008 Addendum: On our initial pharmacokinetic analysis, we have observed that the 
clearance of docetaxel appears to be reduced when it is administered on day 1 with cisplatin 
(Arm B), and this is associated with an increased exposure to docetaxel.  Conversely, when 
docetaxel is administered on day 1 and cisplatin is administered on day 3, docetaxel 
clearance appears to be higher and is associated with a lower AUC∞.  Recall that our 
hypothesis is that reduced clearance and higher exposure to docetaxel may be responsible for 
some of the increased toxicity observed with the parent DCF (Arm B) regimen.   Based on 
this, we will expand our pharmacokinetic evaluation and examine additional docetaxel PK 
without cisplatin in up to 6 patients randomized to parent DCF who underwent cycle 1 
docetaxel PK (when cisplatin was administered on day 1 as well).  See section 9.4.3. 
 
 


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1.5 Correlative Studies 
A. One objective is to store pre-treatment paraffin embedded tumor tissue for future tissue 
based correlative studies.  We will keep a tissue bank for these future immunohistochemistry 
based exploratory studies.   
 
HER2 testing will be performed in all patients to better characterize HER2-positive gastric 
cancer in US patients.  HER2 testing will be performed by the MSKCC diagnostic molecular 
laboratory on banked tumor specimens from the patients currently enrolled on the protocol 
and prospectively on all the patients screened for protocol participation.  FISH is performed 
using FDA-approved ERBB2 (HER2/NEU) PathVysion assay probes and procedure (Abbott-
Vysis). IHC staining is performed using FDA-approved anti-Her2/neu Ventana’s 
PATHWAY rabbit monoclonal primary antibody (clone 4B5) directed against the internal 
domain of the c-erbB-2 oncoprotein (Her2).   
 
Tissue samples for HER2 testing will be processed locally in the laboratory of investigational 
sites. The results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of HER2 
status. MSK pathology review will not be required to begin therapy on the protocol.   
Samples provided to the MSK laboratory must either be HER2 IHC slides, or  if FISH 
confirmation is necessary, a paraffin block(s) of adequate size to allow if possible for at least 
5 slides with cuts that are 5-microns thick or if a paraffin block is not available, then if 
possible at least 5 slides with cuts that are 5-microns thick will be acceptable. Archived or 
fresh tumor samples may be used. 
 
B. Another objective is to evaluate the utility of FDG-PET/CT scans to monitor response to 
treatment.  All patients will undergo a baseline staging FDG-PET/CT scan.  A second PET 
scan will be performed during week 3:  
 
ARM A: following the d 15 treatment, but before week 4 (eg during day  18, 19, or 20) 
ARM B: once on either day 18, 19, or 20 
 
We hypothesize that patients with a good PET/CT response will have RECIST evidence for 
response at their subsequent routine imaging time point and have an increased time to 
progression.  Alternatively, patients with a bad PET/CT response will progress early.  If 
successful, this would allow patients to minimize toxicity by minimizing exposure to 
ineffective therapy. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary:   
1) To determine the efficacy of modified docetaxel, cisplatin, and fluorouracil (mDCF) 
(ARM A) and the efficacy of parent DCF with growth factor support (ARM B) in 
patients with unresectable or metastatic gastric or gastroesophageal junction(GEJ) 
adenocarcinoma as measured by 6 month progression free survival. 


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Secondary:   
2) To establish the safety of mDCF and parent DCF with growth factor support in patients 
with unresectable or metastatic gastric or GEJ adenocarcinoma. 
3) To observe other measures of efficacy of mDCF and parent DCF with growth factor 
support, including response rate, median PFS, overall and 1-year survival in patients with 
unresectable or metastatic gastric or GEJ adenocarcinoma. 
4) To explore the association of early FDG-PET imaging with treatment efficacy. 
5) To explore the differences in docetaxel pharmacology between both study arms. 
6) To bank tumor biopsy material for future planned correlative studies for association with 
chemotherapy efficacy and survival. 
7) To report the efficacy of mDCF with trastuzumab as measured by 6 month PFS amongst 
Her2 positive patients. 
8) To report the safety profile of patients receiving mDCF and trastuzumab. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 SCOPE OF DISEASE AND ROLE OF CHEMOTHERAPY 
Gastric cancer is an aggressive neoplasm that is associated with an extremely poor prognosis.  
Median survival for metastatic or unresectable disease is approximately 8 to 10 months.  On a 
global basis, cancer of the stomach is the third most prevalent malignancy worldwide, with 
947,000 expected new cases in 2000, and the second leading cancer cause of death (734,000 
deaths annually). [1] 
 
Unfortunately, despite its enormous global impact, we have made little progress in the treatment 
of this disease.  Conventional chemotherapy for metastatic gastric cancer remains palliative, with 
few patients ever demonstrating long term survival.  Historically, most tumors develop rapid 
drug resistance and evidence of disease progression within a few months of initiation of therapy.  
However, palliative chemotherapy has a proven survival advantage over best supportive care for 
gastric cancer.  Four randomized trials have all shown that patients assigned to receive best 
supportive care alone, even when allowed to receive chemotherapy at a later date, did 
significantly worse than those assigned to receive immediate chemotherapy (reviewed by 
Shah[2]. 
 
3.2 COMBINATION CHEMOTHERAPY REGIMENS 
The chemotheraputic agents historically considered as active in this disease include fluorouracil, 
cisplatin, anthracyclines (doxorubicin and epirubicin), mitomycin C, and etoposide (reviewed 
previously[2, 3]).  Single agent activity ranges with response rates from 10% to 20%, though the 
data are pooled from clinical trials performed in the 1960’s and 1970’s, and may be an 
overestimation of the true single agent activity as assessed by objective radiographic 
measurements.   
 
 
 


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Several combination regimens have been developed with the aims of improving overall response 
rates and duration of response.  Table 1 summarizes the results of large random assignment 
studies involving these combination regimens.  A three arm random assignment trial comparing 
ELF (etoposide, leucovorin, fluorouracil bolus), CF (cisplatin, fluorouracil infusion), and 
FAMTX (fluorouracil bolus, adriamycin, and high dose methotrexate) was reported by 
Vanhoefer, et al in 2000[4].  Overall response rates were notably low compared to previously 
reported phase II studies, ranging from 9% to 20% in the three arms, and survival was equally 
dismal at less than 7.2 months for each of the arms.  These authors concluded that none of the 
regimens tested should be regarded as a standard treatment for metastatic or unresectable gastric 
cancer[4].  Another study compared CF, UFTM (uracil, tegafur, and mitomycin), and single 
agent 5-FU[5].  The CF regimen was associated with a modest, significant increase in 
progression free survival and response rate over 5-FU (3.9 mo and RR 34% vs. 1.9 mo and 11%, 
respectively). However, despite these improvements, overall survival was not improved with CF, 
with median and 1-year survival of 7.3 months and 29% respectively, compared with 7.1 months 
and 28% with 5-fluorouracil alone.  Notably, approximately 50% of patients who were assigned 
to fluorouracil alone received cisplatin based therapy on progression in this study (personal 
communication, Ohtsu).  These authors concluded that single agent fluorouracil should remain 
the reference standard regimen for advanced phase gastric cancer studies[5].  A similar 
conclusion was drawn by the authors of another random assignment study comparing EEP 
(etoposide, epirubicin, and cisplatin) vs. FEP (fluorouracil, epirubicin, and cisplatin). [6] 
 
Table 1.  Phase III clinical trials for gastric cancer using ‘older’ combination regimens (modified from Shah[2]). 
Reference 
Disease 
Treatment 
Regimen1 
n  
Response Rate2 
(95% CI) 
1-Year Survival 
(95% CI) 
Median 
Survival 
p value 
 
 
 
 
 
 
 
 
Tebbutt, 
2002[7] 
Esophagus + 
Gastric 
PVI 
123 
16.1% 
(9.5- 22.7%) 
22.5% 
(15.2-30%) 
6.3 mo 
NS 
PVI +  
MMC 
127 
19.1% 
(12- 26.0%) 
18.4% 
(12-25.9%) 
5.3 mo 
 
 
 
 
 
 
 
 
Ohtsu, 
2003[5] 
Gastric 
FU 
105 
11.4% 
(6– 19.1%) 
28% 
7.1 mo 
NS 
FU + 
Cisplatin 
105 
34.3% 
(25.3 - 44.2%) 
28% 
7.3 mo 
UFTM 
70 
8.6% (3 – 18 %) 
16% 
6.0 mo 
 
 
 
 
 
 
 
 
Icli, 1998[6] 
Gastric 
EEP 
64 
20.3%(12-59%) 
16 %3  
6.0 mo 
NS 
FEP 
67 
15.3%(9- 59%) 
11 %3 
5.0 mo 
 
 
 
 
 
 
 
 
Vanhoefer, 
2000[4] 
Gastric 
ELF 
132 
9% (3.5-17.5%) 
28% 
7.2 mo 
NS 
CF 
134 
20% (11 -30%) 
32% 
7.2 mo 
FAMTX 
133 
12% (6-20.5%) 
33% 
6.7 mo 
 
 
 
 
 
 
 
 
1 Treatment Regimens: PVI = continuous infusion FU (300 mg/m2/d), MMC = mitomycin, EEP = etoposide, 
epirubicin, cisplatin, FEP = fluorouracil (bolus), epirubicin, cisplatin,  CF = cisplatin, fluorouracil., UFTM = 
uracil, tegafur, mitomycin 
2 RR in evaluable patients, 3 1-year survival estimated from Kaplan-Meier curves. 
 


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3.3 IS THERE A “STANDARD” CHEMOTHERAPY REGIMEN? 
Current or modern combination chemotherapy regimens have included prolonged infusional 
schedules of fluorouracil in combination with cisplatin and epirubicin (ECF), docetaxel, cisplatin 
and a 5 day fluorouracil infusion (DCF), and irinotecan based combinations both with cisplatin 
and with fluorouracil infusions.  The data regarding these combination chemotherapy regimens 
are summarized in table 2 below.  The overall efficacy as assessed by response rate, median and 
overall survival, and 1-year survival of these combination regimens appear to be improved over 
the combination chemotherapy regimens listed in table 1.  However, as discussed below, specific 
issues surround each of these regimens that limit their general acceptability as a “standard” 
combination chemotherapy regimen for this disease. 
 
Table 2.  Recent studies for gastric cancer using modern regimens. 
Reference 
Disease 
Treatment 
Regimen1 
n  
Response Rate2 
(95% CI) 
1-Year Survival 
(95% CI) 
Median 
Survival 
p value 
ECF based Phase III studies 
Ross, 
2002[8] 
Esophagus 
+ Gastric 
ECF 
289 
42.4%  
(37– 48%) 
40.2% 
(34– 46%) 
9.4 mo 
NS 
MCF 
285 
44.1%  
(38– 50%)  
37.7% 
(27-38%) 
8.7 mo 
Webb, 
1997[9, 10] 
Esophagus + 
Gastric 
ECF 
121 
46% (37-55%) 
37% (28-45%) 
8.7 mo 
p < 
0.01 
FAMTX 
116 
21% (13-28%) 
22% (15-29%) 
6.1 mo 
DCF vs. CF phase III study 
Ajani, 
2003[11],  
Moiseyenko 
2005[12] 
Gastric + 
GEJ 
DCF 
221 
36.7% 
(30.3 – 43.4%) 
40.2% 
9.2 mo 
(8.38 – 10.58) 
p = 
0.02 
CF 
224 
25.4% 
(19.9 – 31.7%) 
31.6% 
8.6 mo 
(7.16 – 9.46) 
Irinotecan based studies(Note only the Dank is a phase III study) 
Pooled 
results [13-
15] 
Esophagus + 
Gastric 
Irinotecan/C
isplatin 
105 
48 % - 58% 
 
 
 
Pozzo et al. 
2004[16] 
Gastric + 
GEJ 
(Random 
assignment 
phase II) 
Irinotecan/C
isplatin 
56 
32.1% (20.3 – 
46%)3 
25.3% 
6.9 mo (5.55 -
8.67 mo)4 
p = 
0.002 
Irinotecan/F
U infusion/ 
FA 
59 
42.4 % (29.6 – 
55.9%)3 
44.9% 
10.7 mo 
(8.02-14.62 
mo)4 
Dank et al. 
2005[17] 
Gastric + 
GEJ 
Irinotecan/F
U infusion/ 
FA 
170 
31.8% 
 
9.0 mo (8.3 – 
10.2 mo) 
p = 
0.53 
CF 
165 
25.8% 
 
8.7 mo (7.8 – 
9.8 mo) 
1 Treatment Regimens: ECF = epirubicin, cisplatin, fluorouracil (continuous infusion), MCF = mitomycin, cisplatin, 
fluorouracil, DCF = docetaxel, cisplatin, fluorouracil, CF = cisplatin, fluorouracil. 
2 RR in evaluable patients. 3 Per protocol population, 4Full analysis population 
3.3.1 The ECF Regimen 
The ECF regimen has recently been examined in two large random assignment studies (see table 
2). First, ECF was compared with FAMTX, [10]with an update of the results recently reported 
by Waters, et al.. [9]This study randomly assigned 274 patients (137 in each group) to receive 
ECF or FAMTX.  ECF was associated with a better response rate (46% vs. 21%, p = 0.0002) and 


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an improvement in median survival (8.7 mo vs. 6.1 mo, p = 0.0005) when compared to FAMTX.  
However, this study was not generally accepted because of an apparent imbalance in the number 
of patients proceeding to surgery for locally advanced disease between the two arms.   
 
The investigators then proceeded to examine ECF versus MCF (mitomycin, cisplatin, and 
infusional fluorouracil) in what is the largest random assignment study of chemotherapy in 
metastatic or unresectable esophagogastric cancer published to date[8].  This study randomly 
assigned 574 eligible patients with esophagus (n=188), gastroesophageal junction (n=125), or 
gastric cancers (n=221) to receive either ECF (n=289) or MCF (n=285).  Response to therapy 
was equavalent (42.4% for ECF vs. 44.1% for MCF), as was survival (median survival 9.4 mo 
for ECF vs. 8.7 mo for MCF).  Although ECF appeared to have greater toxicity, global quality of 
life scores were maintained in the ECF arm, whereas they fell in the MCF arm, suggesting that 
ECF was subjectively perhaps a more tolerable regimen[8].  Notably, the fluorouracil 
administration in the MCF arm was 50% higher (300 mg/m2/day) than in the ECF arm (FU 200 
mg/m2/day) resulting in an imbalance between total fluorouracil administered between the two 
arms (net 42% higher with MCF, p < 0.00001).   Although this study confirmed the activity of 
ECF in esophagogastric tumors, it also raises the question as to the role of epirubicin in a 
cisplatin-fluorouracil combination.  The study also confirmed that the prognosis of patients with 
esophagogastric tumors not amenable to resection remains dismal (with median survival 
remaining less than 10 months).  
3.3.2 Docetaxel Based Combination Therapy 
Taxanes and taxane containing combinations have considerable activity in the treatment of 
gastric cancer.  Although both paclitaxel and docetaxel have similar single agent response rates 
in the first line setting, occasional complete responses were reported with docetaxel.  Both drugs 
have been examined with combination chemotherapy regimens with cisplatin, with associated 
improvements in response rates (ranging from 37% to 56%) and complete responses. [18, 19] 
 
Based on the single agent and early combination activity observed with docetaxel-based therapy 
in upper gastrointestinal malignancies, docetaxel was examined in combination with cisplatin 
and fluorouracil (DCF) and compared with the ‘standard’ chemotherapy regimen of CF in a large 
random assignment phase III study (see table 2). [12]The results reported at ASCO 2005 
demonstrate a significant improvement in time to progression (primary endpoint) with the 
docetaxel containing combination (5.6 vs. 3.7 months, p=0.0004) as well as an improvement in 
median and overall survival (median survival of 9.2 vs. 8.6 months, p = 0.02) with the addition 
of docetaxel to cisplatin + fluorouracil when compared with CF alone. At 6 months, 42.7% of the 
DCF-treated subjects had not progressed compared with 27.4% of the CF-treated subjects.  
 
However, both DCF and CF was associated with significant toxicity (see table 3).  Notably, in 
the DCF arm 82% of patients developed grade 3-4 neutropenia and 30% developed febrile 
neutropenia or a neutropenic infection.  This is significantly more than the control arm of 
cisplatin and fluorouracil infusion in which 57% of patients developed grade 3-4 neutropenia, 
and 13.5% of patients developed febrile neutropenia or neutropenia with infection.   


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For both arms, the majority of patients did not receive prophylactic growth factor support.  Non-
hematologic toxicity was considerable as well.   In the DCF arm, 81% of patients developed a 
non-hematologic grade 3-4 adverse event, whereas in the CF arm, there was a similar high rate of 
grade 3-4 non-hematologic toxicity of 75.4%.  Since both arms involved a 5 day infusion of 
fluorouracil, the grade 3-4 stomatitis rate was considerable (46% in DCF and 61% in CF).   
Other notable toxicity occurring in nearly half of the patients enrolled on the DCF arm include 
47% developing grade 3-4 lethargy and 45% developing grade 3-4 diarrhea.   
 
This toxicity spectrum is very similar to the toxicity we observed in an MSKCC phase II study of 
DCF (as originally prescribed) given as preoperative therapy for locally advanced gastric cancer 
(IRB 99-66, PI David Kelsen, MD).  In this study, which was closed early due to toxicity, three 
out of the first 8 patients enrolled were unable to complete 2 cycles of preoperative DCF therapy 
due to significant treatment related toxicity.  This suggests that the toxicity with the parent DCF 
regimen is significant, not only in patients with advanced, metastatic disease who may have been 
predicted to tolerate less aggressive therapy, but also in patients with locally advanced disease 
with less disease burden who generally are felt to tolerate treatment better. 
 
Table 3. Toxicity of DCF and CF [12] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall, 41.2% of patients who received DCF required a dose reduction, and 47.5% of patients 
had a treatment related adverse event that led to a delay in treatment or dose reduction.  The most 
common grade 3-4 side effects for the DCF arm included the following: lethargy, stomatitis, 
diarrhea, cancer pain, infection, nausea, vomiting, anorexia, and neuropathy.  These toxicities 
were not considerably different than that experienced with cisplatin and fluorouracil infusion 
(CF).  However, hematologic toxicity was considerable and significantly more with DCF than 
with CF.  Specifically, 82.3% of  patients who received DCF developed grade 3-4 neutropenia 
and 30% of patients developed febrile neutropenia or neutropenic infection.  Notably, a portion 
Adverse Event 
Grade 3-4 
Grade 3-4 
 
DCF 
CF 
Hematologic Toxicity 
 
 
Neutropenia 
82.3 
56.8 
Febrile neutropenia or neutropenic 
infection 
30 
13.5 
Non-Hematologic  Toxicity 
 
 
Neurosensory 
17 
7 
Infection 
36 
23 
Anorexia 
29 
26 
Nausea 
35 
42 
Vomiting 
33 
42 
Lethargy 
47 
40 
Diarrhea 
45 
18 
Stomatitis 
46 
61 
At least one grade 3-4 Adverse Event 
81.4 
75.4 
Deaths during treatment or within 30d of Tx 
10.4 
8.5 


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of patients (n = 41 or only 18.6% of the total study population) received prophylactic G-CSF.  In 
this group, 63.4 % of patients developed grade 3-4 neutropenia and 12.2% of patients developed 
febrile neutropenia or neutropenic infection.    
 
At this time, the question remains whether the toxicity attributable to the addition of docetaxel to 
CF will outweigh the modest observed improvement in survival.  However, it is clear that 
docetaxel is an active chemotherapy agent in the treatment of this disease and that it’s addition to 
cisplatin and fluorouracil may confer a clinically important survival advantage.   Based on these 
data, the FDA has recently approved the use of docetaxel with cisplatin and fluorouracil in the 
first line treatment setting for gastric and GEJ adenocarcinoma. 
 
To capitalize on the potential survival advantage with docetaxel, efforts to reduce toxicity of the 
DCF regimen have been and are being pursued.  These include substituting carboplatin for 
cisplatin, reducing FU to low-dose continuous infusion[20-22], or limiting the infusion of FU to 
24 hours[23, 24] or 72 hours[25].  Unfortunately, these modifications are not clearly superior to 
the ‘parent’ DCF regimen. For example, the regimen developed by SAKK involves fluorouracil 
administered as a low dose continuous infusion at 300 mg/m2/day for 2 out of 3 weeks is furthest 
along in development.  Although investigators observed approximate equivalent efficacy, they 
also noted approximate equivalent toxicity to the parent DCF regimen[22].  Specifically, they 
reported a 76% incidence of grade 3-4 neutropenia, 39% rate of febrile neutropenia, and a 44% 
rate of dose reductions/cycle.   
 
Another study evaluated an alternative schedule of FU given weekly over 24 hours with 
leucovorin (the AIO schedule). [26]  These investigators initiated a study combining this 
administration schedule of FU with cisplatin 50 mg/m2 and docetaxel 50 mg/m2 given every 
other week, and noted once again that more than 80% of patients required a dose reduction.  
They completed their phase II study with cisplatin and docetaxel at 40 mg/m2 given every other 
week, and FU 24 hour infusion administered weekly and did notice a modest improvement in 
toxicity with a slight reduction in dose adjustments (62% of patients instead of over 80%).  
Notable grade 3/4 adverse events with this schedule included 20.4% neutropenia, 6.1% febrile 
neutropenia, 22.4% diarrhea, 8.2% nausea, 10.2% vomiting, and 18.4% fatigue.  Although an 
apparent improvement over parent DCF, this schedule still was relatively toxic. 
 
On the other hand, we are not aware of studies evaluating the combination of cisplatin and 
docetaxel with the de Gramont schedule of FU administration.  This FU administration schedule 
is commonly used in colorectal cancer[27] with both irinotecan and oxaliplatin and is considered 
well tolerated and an improvement over bolus schedules and prolonged continuous infusion 
schedules of FU/LV administration.  This FU administration schedule has been examined in 
upper GI cancers with oxaliplatin[28, 29] and is felt to be quite tolerable.  Bouche et al examined 
the de Gramont administration schedule of FU with cisplatin 50 mg/m2 in gastric and GEJ 
adenocarcinoma as well, and noted a slightly lower incidence of grade 3-4 neutropenia of 60%, 
similar rates of nausea/vomiting, and notably, a 0% incidence of grade 3-4 stomatitis[30].  This 
modest improvement in toxicity over cisplatin and 5-day infusion fluorouracil is particularly 


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encouraging in light of similar (or possibly slightly improved) efficacy over what is historically 
observed with cisplatin and 5-day infusional fluorouracil.  Finally, although anecdotal, we (Dr. 
Shah and Dr. Kelsen) have personal experience with administrating cisplatin and fluorouracil 
with the de Gramont schedule of FU administration and also find the regimen quite tolerable and 
as active.   
3.3.3 Irinotecan based combination therapy 
Recently, irinotecan based combinations have been evaluated in random assignment phase II and 
III clinical trials[16, 17, 30] (see table 2).  The largest study is a random assignment phase III 
study involving 337 patients comparing irinotecan + fluorouracil (IF) versus cisplatin + 
fluorouracil (CF). [17] In this study, fluorouracil was administered weekly over 22 hours with 
leucovorin in the IF arm, and fluorouracil was administered as a continuous infusion over 5 days 
as is commonplace in the CF arm.  There was no improvement in survival with IF (hazard ratio 
1.08; 95%CI: 0.86-1.35), however this arm did appear to have a reduction in grade 3-4 toxicity.  
A second study performed by Bouche et al is a random assignment phase II study of irinotecan 
with fluorouracil and cisplatin with fluorouracil, using the De Gramont schedule of fluorouracil 
administration in both arms[30].  This study demonstrated similar results of approximate equal 
efficacy[30] with potentially less toxicity with irinotecan than with cisplatin. 
 
3.3.4 Rationale for addition of trastuzumab to mDCF in HER2-postive gastric/GEJ 
adenocarcinoma patients. 
Trastuzumab is a humanized monoclonal antibody (IgG1 isotype) directed against the 
extracellular region of HER2 that has been developed as a therapeutic modality for treating 
HER2-positive breast cancer.   Trastuzumab is approved by the U.S. Food and Drug 
Administration (FDA) for the adjuvant treatment of patients with HER2-overexpressing, node-
positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, 
and paclitaxel. Trastuzumab is also indicated as a single agent and in combination with paclitaxel 
for the treatment of patients with HER2-positive metastatic breast cancer. In these patients, the 
combination of trastuzumab plus paclitaxel results in improved response rate, time to disease 
progression, and overall survival compared with single-agent paclitaxel. 
 
With the results of the recent phase III ToGA study, the benefit of trastuzumab in combination 
with cisplatin and fluoropyrimidine (CF) chemotherapy in HER2-positive metastatic gastric/GEJ 
adenocarcinoma has been established.2 In this study, HER2-positive patients (FISH+ and/or IHC 
3+) were randomly assigned to receive CF alone or with trastuzumab. Patients assigned to 
receive trastuzumab + CF had a significant improvement in overall survival (13.8 mo vs 11.1 
mo, HR 0.74 [0.6-0.91], p = 0.0046).  Trastuzumab is the first biological strategy to show a 
survival benefit in advanced GC.  Based on these results, trastuzumab is now in the NCCN 
compendium for treatment of patients with HER2-positive advance gastric cancer in combination 
with systemic chemotherapy.   
 
This amendment is written to ensure that Her2 positive gastric cancer patients are able to receive 
trastuzumab with chemotherapy in the first line setting in gastric cancer.  Notably, the ToGA 
study involved an acceptable standard two drug chemotherapy regimen to which the addition of 


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trastuzumab was randomly assigned.  The rationale to incorporate trastuzumab in this study is to 
report the efficacy of a three drug gastric cancer regimen with trastuzumab amongst a cohort of 
Her2 positive patients.   
 
3.3.5 HER2 testing in gastric/GEJ adenocarcinoma patients 
Accurate HER2 testing is crucial for the successful application of trastuzumab in the clinical 
setting.  In ToGA, HER2 positivity was defined using IHC published by Hofmann et al 
specifically for  gastric cancer.1  In a validation study of HER2 scoring in 168 gastric cancer 
resection specimens, Hofmann et al noted  in gastric cancer a higher rate of tumor heterogeneity 
and incomplete basolateral membranous compared to breast cancer tumors.  Hofmann et al 
investigated the application in gastric cancer of the testing methodologies commonly used to 
detect HER2  in breast cancer specimens and proposed a refined HER2 IHC scoring system 
suitable to score gastric cancer samples accurately and reproducibly. Most notably, according to 
the Hofmann criteria, biopsy samples with cohesive IHC3+ or FISH+ clones are considered  
HER2 positive irrespective of size, i.e.<10%. (In Breast Cancer for example, IHC3+ requires a 
minimum of 30% IHC membranous staining.) 
 
To determine if the breast ASCO/CAP guidelines for HER2 assessment can be used to accurately 
determine HER2 status in gastric cancer, we studied HER2 status of tumor specimens from 133 
advanced gastric cancer patients undergoing treatment at MSKCC.  HER2 IHC and FISH was 
performed for all specimens using ASCO/CAP guidelines and the Hofmann et al criteria. We 
found that HER2 in gastric cancer can be accurately evaluated using the breast cancer 
ASCO/CAP guidelines, with the exception that in small biopsy specimens with any cohesive 
HER2  IHC3+ or FISH+ clones should be considered HER2 positive.  For the purposes of this 
protocol, patients that are IHC 1+ or 2+ will undergo FISH testing to confirm HER2 positivity.  
Patients with IHC 3+ or FISH+ (>2 HER2:CEP17) will be eligible to receive treatment with 
trastuzumab on study.   
 
3.4 SUMMARY OF CHEMOTHERAPY FOR GASTRIC/GEJ ADENOCARCINOMA 
A careful review of the data described above reveals that there is no consensus standard 
chemotherapy regimen for the first line treatment of unresectable or metastatic gastric/GEJ 
adenocarcinoma at this time.  Although chemotherapy is better than best supportive care, we 
have observed little to no improvement in overall survival beyond 8-10 months in randomized 
controlled clinical trials examining several different combination treatments.  Cisplatin and 
fluorouracil based therapy is most commonly used as the reference arm in these random 
assignment phase III studies, and as a component of the investigational arm in several of these 
random assignment phase III studies.   
 
The addition of docetaxel to cisplatin and fluorouracil is superior to cisplatin and fluorouracil 
alone.  Based on this, docetaxel has received FDA and European Union approval in combination 
with fluorouracil and cisplatin for the first line treatment of gastric and GEJ adenocarcinoma.  
However, the toxicity of this three drug regimen, although not significantly worse than cisplatin 


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and fluororaucil infusion alone, is still significant, and is the primary limitation of its widespread 
acceptance.   
December 2009 Amendment 
With the recent compendium listing of trastuzumab as part of the first line treatment of gastric 
cancer, trastuzumab is now indicated in the first line setting with combination chemotherapy for 
the treatment of advanced gastric/GEJ adenocarcinoma.  Patients who are Her2 positive should 
receive standard combination chemotherapy with trastuzumab.  Patients who receive 
trastuzumab will be considered as a separate and independent cohort from the primary analysis. 
3.5 PROPOSAL 
With recent FDA and European Union approval, a combination of docetaxel, cisplatin and 
fluorouracil is now an acceptable standard regimen for the first line treatment of gastric and 
gastroesophageal junction adenocarcinomas.  However, the toxicity of the parent DCF regimen 
as originally prescribed has prevented its widespread acceptance and usage.   
 
We therefore propose to evaluate two modifications of the parent DCF regimen in a random 
assignment phase II clinical trial.  In ARM A, we propose a modified DCF schedule with the 
following specific modifications to parent DCF: (1) a de Gramont schedule for FU 
administration, (2) reduced bi-monthly doses of cisplatin and docetaxel, and (3) the 
administration of docetaxel and cisplatin on consecutive days instead of immediately following 
one another.  See section 3.5.1 for detailed discussion for the rationale of the mDCF schedule. 
 
In ARM B, we will examine parent DCF with prophylactic growth factor support.  Recall that in 
the TAX325 study, patients who received prophylactic G-CSF had a significantly reduced 
incidence of grade 3-4 neutropenia and incidence of febrile neutropenia or neutropenia with 
infection.   
 
With this study, we will establish the efficacy and tolerability of modified DCF and of parent 
DCF with growth factor support.  If mDCF appears to maintain the efficacy of the parent DCF 
regimen with less toxicity, we will have established a new treatment regimen for this disease to 
which targeted agents can be examined. 
 
December 2009 Amendment 
Due to toxicity, Arm B is now closed to further accrual.  Arm A will continue to enroll until 
target accrual.  In addition, patients who are Her2 positive will receive trastuzumab with mDCF, 
in a separate, independent cohort. 
 
August 2010 Amendment  
We have reached target accrual in Arm A. Her2 positive patients will receive trastuzumab with 
mDCF, in a separate, independent cohort. 
 
3.5.1 Modified DCF dose and schedule determination 
The specific modifications to parent DCF that we have proposed include (1) a de Gramont 
schedule for FU administration, (2) reduced bi-monthly doses of cisplatin and docetaxel, and (3) 


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the administration of docetaxel and cisplatin on consecutive days instead of immediately 
following one another.   
We believe that a modified FU administration schedule (bolus + 48 hour infusion of FU) will 
confer less toxicity than longer infusion schedules of FU currently in use (eg. 5 day infusion used 
in parent DCF) with similar efficacy.  Several lines of evidence from gastric cancer studies 
support altering the FU schedule to a bolus + 48 hour infusion and to administering 
chemotherapy bi-monthly at reduced doses.  The most convincing is from Bouche et al. that 
describes a three arm random assignment phase II study with each arm receiving LV5FU2[30].  
LV5FU2 is the same FU administration schedule as we have proposed in this study (bolus + 48 
hr infusion).  In the Bouche  study, Arm A was LF5FU2 alone, arm B was cisplatin 50 mg/m2 
with LV5FU2, and arm C was irinotecan + LV5FU2.  The response rate and survival of LV5FU2 
(arm A) is consistent with that reported for single agent FU[5].  In addition, the response rate and 
survival of arm B (Cisplatin + LV5FU2) is consistent with that reported for cisplatin and FU x 5 
day infusion schedules[5, 11, 17].  Notably, the efficacy is maintained while keeping the relative 
dose intensity for cisplatin identical to the historical standard of cisplatin and fluorouracil 5-day 
infusion. Specifically when cisplatin is administered with the 5-day infusion of FU, it is given at 
100 mg/m2 every 4-weeks which yields a dose intensity of 25 mg/m2/week.  When cisplatin is 
administered with LV5FU2, it is administered at 50 mg/m2 every other week, which yields an 
equivalent dose intensity of 25mg/m2/week.   
 
The table below describes the efficacy of cisplatin and infusional FU (control arms) as observed 
in 3 recent large phase III studies and of cisplatin + LV5FU2 as described in the Bouche et al 
study. 
Reference 
Treatment 
Regimen 
n 
Response Rate2 
(95% CI) 
1-Year Survival 
(95% CI) 
Median 
Survival 
Ajani, 
2003[11],  
Moiseyenko 
2005[12] 
Cisplatin + 
Infusional FU 
224 
25.4% 
(19.9 – 31.7%) 
31.6% 
8.6 mo 
(7.16 – 9.46) 
Ohtsu, 
2003[5] 
Cisplatin + 
Infusional FU 
105 
34.3% 
(25.3 - 44.2%) 
28% 
7.3 mo 
Dank 
2005[17] 
Cisplatin + 
Infusional FU 
165 
25.8% 
 
8.7 mo  
(7.8 – 9.8 mo) 
 
 
 
 
 
 
Bouche, 2004 
[30] 
Cisplatin + 
LV5FU2 
44 
27% 
(14% - 40%) 
43% 
9.5 mo 
(6.9 – 12.2 mo) 
The FU administration schedule (bolus + 48 hour, or LV5FU2) with bi-monthly cisplatin 
administration confers approximate equal efficacy with regard to response rate, 1-year 
survival, and median survival when compared to the traditional cisplatin + infusional FU x 5 
day schedule. 
 
 
 
 
 
 


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With regard to the question of equal or reduced toxicity, the table below summarizes the relevant 
toxicity comparison:  
 
Toxicity (Grade 3-4) 
Cisplatin + LV5FU2 
(Bouche et al) (n=44) 
Cisplatin + 5-day FU Infusion 
(Moiseyenko et al) (n=224) 
Neutropenia 
61% 
57% 
Febrile neutropenia  
18% 
14% 
Nausea/vomiting 
23% 
42% 
Diarrhea 
2% 
18% 
Mucositis 
0% 
61% 
 
As shown, the toxicity of the bolus + 48 hour FU infusion and reduced bi-monthly 
administration of cisplatin schedule is significantly less toxic with regard to diarrhea, mucositis, 
nausea and vomiting.  Neutropenia is approximately equivalent.  Thus, because of approximate 
equal efficacy with considerably less toxicity, the proposed administration schedule is a 
significant improvement over the traditional cisplatin + 5-day FU infusion schedule.  Finally, we 
also have experience with docetaxel and cisplatin administered with this fluorouracil 
administration schedule in several patients with upper GI malignancies and have found the 
regimen be both quite tolerable and active (Shah and Kelsen, personal communication).  Based 
on these data above, we feel that administering fluorouracil as per the De Gramont schedule 
(bolus + 48 hour infusion) provides approximate equivalent efficacy to 5 day FU administration 
schedules.  When coupled with less frequent dosing of cisplatin, the combination is associated 
with less toxicity. 
 
With regard to the best dose of cisplatin and docetaxel when both drugs are administered 
together with fluorouracil, two gastric cancer studies provide additional support (Lorenzen 
described here and Oh described below).  A phase II study by Lorenzen and collegues was 
reported at the 2006 GI Cancer symposium (San Francisco, CA) in which docetaxel and cisplatin 
(50 mg/m2 each) were administered every other week in combination with a 24 hour infusion of 
FU (2,000 mg/m2 over 24 hours) which was administered weekly[26].  The investigators felt that 
the combination at those doses of cisplatin and docetaxel was still too toxic and amended their 
study to administer docetaxel and cisplatin at a reduced dose of 40 mg/m2 every other week.  
With these lower doses (eg. the doses that we have proposed), the investigators reported 
approximately equal efficacy to parent DCF with slightly improved toxicity including grade 3-4 
neutropenia 20% and nausea/vomiting 20%, thus supporting our proposal. 
 
Finally, by separating the docetaxel and cisplatin, we believe we will have even less toxicity due, 
in part, to improving docetaxel clearance when compared to the combined administration.   The 
rationale for this is that docetaxel is both a substrate and inhibitor of the cytochrome p450 
enzyme CYP3A4, and the standard antiemetics used when giving cisplatin (eg. aprepitant and 
palonesetronn) also are CYP3A4 inhibitors. Thus, by administering cisplatin on a different day 
from docetaxel, the clearance of docetaxel should improve, thus reducing toxicity.  This will be 
examined in the parallel random assignment study in which one arm will be mDCF and the other 


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arm will be parent DCF in which the docetaxel and cisplatin are administered on the same day 
immediately following one another. 
A recent phase II report of a Korean study of docetaxel + cisplatin + fluorouracil provides 
support for this hypothesis[31].  Specifically, in this phase II study, docetaxel was administered 
on day 1 (70 mg/m2), cisplatin was administered on days 2 and 3 (40 mg/m2 each day), and 
fluorouracil was administered over 10 hours on days 1, 2 and 3.  The regimen was repeated every 
3 weeks and again demonstrated approximate equal efficacy to parent DCF.  However most 
interestingly, the incidence of grade 3 or 4 toxicity including nausea, vomiting, diarrhea, 
leucopenia or neutropenia, and mucositis was each less than 10%, which is a remarkable 
improvement over the parent DCF regimen in which these toxicities were 40% or higher and 
80% for grade 3-4 neutropenia.  The investigators were unable to explain this reduced toxicity 
and hypothesized that it may be related to the Korean population of the study.  Alternatively, a 
potential PK interaction between cisplatin anti-emetics and docetaxel may explain this improved 
toxicity.   
 
The table below describes the relative dose intensity of the parent DCF (as scheduled and as 
actually delivered) and modified DCF: 
Modified DCF q other week 
ARM B – Parent DCF q 3 weeks 
Drug 
Dose 
(mg/m2) 
 
Dose Intensity  
(mg/m2 per wk) 
Drug 
Scheduled 
Dose 
(mg/m2) 
Dose 
Intensity 
(mg/m2/wk) 
Delivered Dose 
Intensity 
(mg/m2/wk) 
Docetaxel 
40 
20 
Docetaxel 
75 
25 
22 
Cisplatin 
40 
20 
Cisplatin 
75 
25 
22 
Leucovorin 
400 
X 
 
 
 
 
Fluorouracil 
400 
X 
Fluorouracil 
750 
X 
X 
Fluorouracil 
1000 
X 
 
 
 
 
 
As shown, the proposed dose of docetaxel and cisplatin in the modified DCF regimen represent 
80% of the scheduled dose of the parent DCF regimen.  However, the proposed dose is in fact 
90% of the delivered dose of the parent regimen.   
 
Thus, based on the data shown above, there is sufficient evidence from a number of sources to 
consider modified DCF as a reasonably safe and effective DCF regimen.   
(1) The bolus and 48 hour infusion schedule of FU is equivalent to the 5-day infusion 
schedule of FU but is associated with less toxicity. 
 
(2) Administering reduced bi-monthly doses of docetaxel and cisplatin with FU confers 
less toxicity also while maintaining efficacy.  This toxicity profile may be further 
improved by administering docetaxel and cisplatin on different days due to a possible 
pharmacokinetic interaction between docetaxel and the delayed emesis regimen used 
for cisplatin. 
(3) The dose intensity of cisplatin and docetaxel in the proposed mDCF regimen is 
insignificantly different from what was delivered in the parent DCF regimen. 
 


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3.5.2 Pharmacokinetic and Pharmacodynamic Considerations  (MSKCC ONLY) 
Two initial phase I studies examined the combination of docetaxel and cisplatin[32, 33].  Pronk 
and colleagues evaluated two schedules of administration: Schedule A administered cisplatin as a 
3 hour infusion 3 hours folloing 1-hour docetaxel infusion (D1hour  3hr break  C3hour), and 
Schedule B administered cisplatin over 3 hours one day prior to docetaxel (C3hour day 1   D1hour 
day 2).  These investigators noted that there was a trend toward greater hematologic toxicity with 
schedule B where cisplatin is given prior to docetaxel. This is consistent with the previous data 
regarding the sequence of administration of cisplatin and paclitaxel[34], and may be related to 
higher DNA-adduct formation and intracellular accumulation of cisplatin in human leukocytes if 
given prior to the taxane[35].  Pronk noted no significant differences in the pharmacokinetic 
parameters of cisplatin and docetaxel with the two schedules examined in their study[32].  
However, the authors did point out the 21 hour time interval between cisplatin and docetaxel in 
schedule B, and noted that when cisplatin precedes paclitaxel by 6 hours, paclitaxel clearance 
reduced by 25% [34].  The 2nd phase I study by Millward et al. administered cisplatin over 1 hour 
immediately following docetaxel 1 hour infusion[33].  They also noted no pharmacokinetic 
interactions.  In addition, they also evaluated the Pronk schedule A sequence of D1hour  3hr 
break  C3hour and it appeared that in a small number of patients, there was increased toxicity 
when administering cisplatin 3 hours following docetaxel instead of immediately following 
docetaxel.  Since these studies were published in 1997, the convention for virtually all 
subsequent evaluations involving the combination of docetaxel and cisplatin administered the 
drugs as described by Millward et al with docetaxel given over 1 hour and then followed 
immediately with cisplatin administered over 1 hour.   
 
Docetaxel is both a substrate and inhibitor of the cytochrome p450 enzyme CYP3A4, and its 
metabolism can be inhibited by CYP3A4 inhibitors such as ketoconazole, erythromycin, 
verapamil and diltiazem[36].  Importantly, both aprepitant and palonesetron, recently approved 
anti-emetic agents for the treatment of acute and delayed nausea, are both inhibitors of 
CYP3A4[37, 38]. Indeed, this inhibition results in reduced clearance of the concomitantly 
administered steroid, dexamethasone, resulting in the recommened reduced dose of 
dexamethasone when administered with aprepitant and palonesetron[39].  Similarly, inhibition of 
CYP3A4 by these anti-emetic agents could result in reduced docetaxel metabolism, increased 
drug exposure, and potentially increased toxicity.  However, a recent evaluation demonstrated no 
significant role of aprepitant on the pharmacokinetics of docetaxel[40].  However, this study did 
not examine docetaxel metabolites.  In one study, detection of the M4 docetaxel metabolite may 
indicate reduced docetaxel clearance and possibly increased myelosuppression[41]. 
 
In our experience, we have obsereved that the co-administration of docetaxel and cisplatin on the 
same day in combination with fluorouracil infusion is associated with signficant nausea, 
vomiting, and delayed emesis – in particular, significantly more so than when either cisplatin or 
docetaxel is administered alone with the same fluorouracil schedule.  Aprepitant and 
palonesetron may be used to prevent acute and delayed emesis from cisplatin.  However, it may 
inadvertently result in reduced docetaxel clearance and increased docetaxel related toxicity, or if 
not the parent compound, possibly reduced clearance of a metabolite.  We note that the anti-
emetic drugs, aprepitant and palonesetron, are administered primarily for cisplatin associated 


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nausea and vomiting.  Based on these findings, we have moved cisplatin to be administered 1-2 
days following docetaxel in several patients treated with mDCF already.  Interestingly, we have 
anecdotally (in approximately 10 patients) noted a considerable improvement in their tolerance 
to the mDCF, thus supporting this hypothesis and warranting its further evaluation.    
 
To examine this further and more formally, we propose to evaluate the pharmacokinetics of 
docetaxel and its metabolites in approximately 10 patients in each arm.  Recall that docetaxel and 
cisplatin in Arm B are both given on day 1, along with initiation of the 5 day fluorouracil 
infusion.  We believe there will be a significant difference in docetaxel clearance in the two arms 
that may explain, in part, the signficant toxicity of the parent DCF regimen.   
 
Pharmacokinetic blood draws will occur in patients enrolled at MSKCC only.  We will perform 
serial blood draws in approximately 20 patients (10/ arm) at the following times: 
 
1. 0.25 hours (15 min following initiation of docetaxel) 
2. 0.75 hours (45 min following initiation of docetaxel) 
3. 1 hour 
(end of docetaxel infusion) 
4. 1. 25             ( 15 min following the end of docetaxel infusion) 
5. 2 hours 
6. 4 hours 
7. 6 hours 
8. 8 hours 
9. 24 hours 
 
Additionally, on day 3, a CBC with differential and LFT’s (AST, ALT, Alk Phos, total Bilirubin) 
will be drawn in each these patients.  For Arm A, these lab studies will be drawn prior to 
cisplatin administration.   
 
March 2008 Addendum: On our initial pharmacokinetic analysis, we have observed that the 
clearance of docetaxel appears to be reduced when it is administered on day 1 with cisplatin 
(Arm B), and this is associated with an increased exposure to docetaxel.  Conversely, when 
docetaxel is administered on day 1 and cisplatin is administered on day 3, docetaxel clearance 
appears to be higher and is associated with a lower AUC∞.  Recall that our hypothesis is that 
reduced clearance and higher exposure to docetaxel may be responsible for some of the increased 
toxicity observed with the parent DCF (Arm B) regimen.   Based on this, we will expand our 
pharmacokinetic evaluation and examine additional docetaxel PK without cisplatin in up to 6 
patients randomized to parent DCF who underwent cycle 1 docetaxel PK (when cisplatin was 
administered on day 1 as well).  See section 9.4.3. 
 
 
 
 
 
 


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3.5.3  FDG-PET Response Assessment 
We are interested in the utility of 
functional imaging to predict and 
monitor treatment response in gastric 
cancer.  To begin to examine this 
question, we initiated an NCI sponsored 
phase II clinical trial of preoperative 
chemotherapy with irinotecan and 
cisplatin for locally advanced gastric 
cancer (NCI 5917).  We planned to use 
functional imaging with FDG-PET/CT 
scans early in the treatment plan to predict treatment efficacy.  Patients with high-risk 
gastric cancer (preoperative stage T2N+, T3-T4, 
Nany, M0) were eligible.  The study schema is 
provided in the figure below.  Enrolled patients 
received preoperative chemotherapy with 
cisplatin 30 mg/m2 and irinotecan 65 mg/m2 
during weeks 1, 2, 4, 5, 7, 8, 10, and 11, prior to 
surgical resection. FDG-PET/CT scans were 
performed prior to initiation of therapy, during 
week 3 and week 6 (day 15 and 35, respectively), 
and following completion of pre-operative 
therapy, prior to surgery. Thus far, 42 patients 
have enrolled on this phase II study with the 
following patient characteristics: median age 62 (range 25-83), male 29, KPS 90% (70%-
90%).   
We first demonstrate that pathologic treatment response is a surrogate for 
treatment efficacy.  Pathologic assessment of treatment response is assessed 
histologically, by visual assessment, based on the identification of residual cancer cells 
and on the extent of fibrosis[42].  In this system, a tumor regression grade (TRG) is 
established, and quantitated into five grades, ranging from TRG 1 (complete regression) 
to TRG 5 (complete absence of regressive changes).  Response assessment is based on 
areas of tumor treatment effect that are characterized by the replacement of neoplastic 
tissue with fibrous tissue and scattered inflammatory cells.  We have converted this 
grading system to a percent treatment response score from 0 to 100%, such that a TRG1 
score has a 100% treatment response score, and a TRG5 has a treatment response of less 
than 10%.  We evaluated the histopathologic response to treatment with disease free 
recurrence.  32 patients are evaluable thus far.  Our median follow up period for these 
patients is 14 months and thus far, 13 patients (out of 32) have recurred.  Based on this 
preliminary analysis, there is a significant correlation between pathologic response to 
therapy and disease free recurrence (see figure to the right).  These data suggest that a 
10% increase in pathologic response corresponds to a 49% risk reduction of recurrence (p 
= 0.013).   


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Next, we demonstrate the correlation between change in functional imaging and 
pathologic response.  The two graphs below demonstrate the correlation between FDG-
PET/CT response and pathologic response.  It is important to point out that the FDG 
response assessment occurs at day 15 and at day 35, where one could potentially switch 
the chemotherapy regimen to alternative treatments in the hopes of improving response to 
therapy.  Notably, the pathologic response assessment described above occurs at the time 
of surgical resection, approximately at day 127.  At that time point, it is too late to switch 
therapy from ineffective therapy (eg. that associated with a minimal pathologic response 
to treatment) to a potentially more effective therapy. This is highlighted below by the 
pathologic response axis (y-axis on both graphs).  Specifically, all of the patients who 
have recurred (red plus symbols) had a pathologic response of 20% or less. Knowing that 
one is destined for a poor pathologic response a priori would warrant a change in therapy 
with the hopes of improving this response.  We have already demonstrated preliminary 
evidence that a poor pathologic response increases the probability of early recurrence, 
and certainly death from disease.  With this in mind, the figures below demonstrate that 
with a high FDG response (eg. above 40% by day 15, or above 50% by day 35), the 
chance of achieving a high pathologic response to preoperative chemotherapy is quite 
high, whereas a lower FDG response is associated with a lesser degree of pathologic 
response and a higher chance of disease recurrence.  
 
 
Correspondence between decrease in FDG SUV from baseline to on-treatment scan and 
pathologic response.  In the graphs above, the open circles are patients who have not had 
a recurrence and the plus symbols represent patients who have had a recurrence.   
These data support the fact that an early 
FDG-PET scan can predict response to 
chemotherapy that is identified histopathologically 
in the surgical resection specimen almost 3 months 
later.  We then evaluated the association of FDG-
PET response to recurrence and again found a 
strong and significant association (see figure to the 
left).  This figure demonstrates the high correlation 
with FDG response (at day 35 in this case) and risk 


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of recurrence.  A 50% or greater reduction in FDG-SUV by day 35 of the chemotherapy 
treatment plan is associated with an extremely low chance of disease recurrence, whereas 
a less than 50% reduction in FDG-SUV is associated with a significantly higher 
probability of disease recurrence (p = 0.045).  Altogether, these data suggest that an early 
FDG-PET/CT scan, when compared with a baseline scan, may be predictive of response 
to preoperative chemotherapy as assessed by histopathologic response assessment and by 
disease free recurrence. 
 
3.5.4 Discontinuation of chemotherapy after 6 months. 
 
The study will allow for discontinuation of docetaxel, cisplatin, and/or 
fluorouracil at the discretion of the treating physician after having completed 6 months of 
chemotherapy.  The rationale for this comes from a growing body of evidence that 
suggests that patients with solid tumor malignancies need not received cytotoxic 
chemotherapy until disease progression. For example, in metastatic NSCLC, it is well 
accepted that 4 to 6 cycles of platinum based chemotherapy is a superior strategy as 
compared to maintenance chemotherapy(Pfister, JCO 2003).  In metastatic colorectal 
cancer, the OPTIMOX1 study shows that intermittent dosing of oxaliplatin is less toxic 
and associated with an equivalent progression free survival and overall 
survival(Tournigand, JCO 2006).  Similarly, in prostate cancer, patients who receive 
intermittent androgen ablation also demonstrate no evidence of decreased survival or 
time to progression, and did have a benefit of reduced toxicity(Calais Da Silva, ASCO 
2006).  Our primary endpoint is a landmark analysis of progression at 6 months.  
Allowing patients to discontinue cytotoxic therapy after 6 months does not interfere with 
our primary endpoint, and may reduce cumulative toxicity (particularly from docetaxel 
and cisplatin) without adversely treatment efficacy.   
 
3.5.5 Assessment of Quality of Life 
 
The study will include an assessment of quality of life on both arms of the study 
at baseline, and periodically during the course of treatment.  We will use the EORTC 
QLQ-C30 instrument to examine quality of life.  This is a validated instrument that has 
been used in many large studies, including in gastric and gastroesophageal randomized 
studies(Aaronson, JNCI 1993; Glimelius, Ann Onc 1997; Ross, JCO 2002).  We will 
administer the questionnaire at baseline, 6 weeks, 3 months, and 6, 9, and 12 months.   
 
3.5.6 Volumetric CT Analysis of Response to Therapy (MSKCC only) 
 
At MSKCC only and in collaboration with Larry Schwartz, MD, we will also 
initiate an exploratory volumetric CT analysis of Response to therapy.  This study will 
make use of already acquired image data from this clinical trial. No additional human 
material or CT scans will be needed.  The standard CT scan data (acquired either during 
PET/CT scanning or CT scanning) will be electronically transferred, via the hospital 
network, from the hospital PACS to the research PACS server, where patient 
identification information are de-identified.  Volumetric CT will be used in an 
exploratory way to assess tumor response during therapy to compare with RECIST.  The 
volumetric analysis, however, will not affect patient care and will not be communicated 


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to the patient or clinical investigator.  To study effects of a wider range of slice thickness 
on the performance of the segmentation algorithms and reproducibility of tumor 
measurements, thinner section CT images will be reconstructed with CT raw data 
acquired for the radiographic assessment in the trial.  The volumetric CT technique used 
in this study may be able to detect asymmetric or small change in tumor size at the level 
that may not be possible with the conventional uni-dimensional RECIST criteria.   
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
          4.1 Design 
This will be a random assignment phase II study of two different administration schedules of 
docetaxel, cisplatin, and fluorouracil in patients with unresectable or metastatic gastric or GEJ 
adenocarcinoma.  Patients may have received neoadjuvant and/or adjuvant chemotherapy or 
chemoradiotherapy.  Patients may not have received previous chemotherapy containing cisplatin 
or docetaxel.  Prior fluorouracil is allowed if more than 6 months have passed since the patient 
last received it.  Patients must provide written informed consent prior to study enrollment.   
At baseline, patients will require a full medical history and physical examination, 
including assessments of body weight, height, calculated body surface area, and vital 
signs (blood pressure, heart rate, respiratory rate, and temperature).  Laboratory 
assessment will include CBC with differential, PT, PTT, comprehensive biochemical 
screening profile (which includes electrolytes, BUN, creatinine, AST, ALT, total 
bilirubin, total protein, albumin, alkaline phosphatase, and glucose), Ca, Mg, Phosphorus, 
LDH, and urinalysis. For females of childbearing potential, a serum pregnancy test is also 
required.  Additional evaluation will include baseline ECG and a signed informed 
consent.  CT scan of chest, abdomen, and pelvis will be performed in all patients and 
documentation of tumor measurement, in centimeters will be done. A baseline PET/CT 
scan will be performed as well for staging. In cases where there are multiple metastases, a 
representative sample of large masses, up to a total of five, will be chosen as the index 
lesions to be followed for a response, as per RECIST criteria.  Measurable disease is not a 
requirement for study entry.  Biopsy confirmation of M1 disease is encouraged, unless 
the risk of such a procedure is significant, in which case confirmation by a 2nd imaging 
modality is required (eg. PET/CT scan may be sufficient if tumor and metastases are both 
FDG avid). 
December 2009 Amendment 
As of October 2009, trastuzumab plus chemotherapy is part of the NCCN standard 
treatment algorithm for the first line for advanced gastric/GEJ adenocarcinoma.  This 
amendment is to allow patients who are Her2 positive to receive trastuzumab with 
mDCF.  Her2 positive patients are defined as FISH + and/or IHC 3+ for Her2 . Biopsy 
samples with cohesive IHC3+ or FISH+ clones are considered  HER2 positive 
irrespective of size, i.e.<10%.  FISH+ defined as >2 HER2:CEP17.  To receive 
trastuzumab, patients must have a baseline left ventricular ejection fraction of > 50%. 


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4.2 
Intervention 
Eligible patients will be randomly assigned to receive mDCF (ARM A) or parent DCF 
with growth factor support (ARM B) as follows: 
ARM A – Modified DCF 
ARM B – Parent DCF with G-CSF 
Drug 
Dose (mg/m2) 
Schedule 
Drug 
Dose (mg/m2) 
Schedule 
Docetaxel 
40 
Day 1 IVPB (60 min) 
Docetaxel 
75 
Day 1 IVPB (60 min) 
Leucovorin 
400 
Day 1 IVPB (30 min) 
Cisplatin 
75 
Day 1 IVPB (60 min) 
Fluorouracil 
400 
IVP day 1 
Fluorouracil 
750 
IVCI daily x 5 days 
Fluorouracil 
1000 mg/m2/d 
IVCI daily x 2 days 
Neulasta 
6 mg 
subcut on d 8, 9, or 10 
Cisplatin 
40 
Day 2 or 3 IVPB (30 min) or Neupogen 
300 or 480 mcg* 
subcut x 7 d 10-17 
* 300 mcg for weight < 60 kg, 480 mcg for weight > 60 kg. 
Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments).  
Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 
treatments).   
 
December 2009 Amendment 
We have met the early stopping rule for Arm B, parent DCF with growth factor support.  Arm A 
will continue to accrue until target accrual of 54 patients. In addition, we will treat Her2 positive 
patients with mDCF + trastuzumab.  Trastuzumab will be administered on an every 2 week 
dosing schedule, with an initial loading dose of 6 mg/kg over 90 minutes, followed by 
trastuzumab 4 mg/kg every 2 weeks over 30 mintues.   
 
A given treatment may be moved +/- 14 days for specific administrative reasons, in particular 
clinic closure for holidays.  Tumor assessments will be performed following the completion of 
every cycle for the first 6 cycles, and then every 2 cycles thereafter.  Therapy will be 
administered in an outpatient setting, under the supervision of a physician and/or chemotherapy 
nurse, as is standard for chemotherapy administration at the treating institution.  
Clinical evaluation: All assessments may be performed within one day of the planned treatment.   
ARM A – Modified DCF 
Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of cycle one (e.g. on day 1, day 15, and day 29 of cycle 1).  In cycle 2 and all 
subsequent cycles, a physician evaluation (e.g. physical examination and toxicity assessment) 
will be performed prior to treatment on day 1 and day 29 treatments.  Additional nurse or 
physician visits will be at the discretion of the treating physician.  It is encouraged that an 
oncology nurse toxicity evaluation be performed prior to each treatment, especially if the patient 
is not assessed by a physician.  
Patients treated with mDCF plus trastuzumab therapy should be monitored for signs and 
symptoms of CHF (i.e., dyspnea, tachycardia, new unexplained cough, neck vein distention, 
cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and 
rapid unexplained weight gain).   
ARM B – Parent DCF with G-CSF 


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Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of every cycle. 
Laboratory evaluation:  
ARM A – Modified DCF 
On or within 1 day of the beginning of each cycle, a CBC with differential and platelet count, 
serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, alkaline 
phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, LDH, and 
tumor markers will be performed.  A CBC with differential and platelet count is required prior to 
each subsequent treatment (eg. day 15 and day 29).  A BUN and Creatinine is required before the 
day 15 treatment (treatment #2), and a serum chemistry (electrolytes, BUN, Creatinine, glucose) 
is required before each day 29 treatment (#3). LFTs are required before each treatment (#1, #2 
and #3) of cycle 1, and before treatment #1 and #3 for each subsequent cycle.  Any patient with 
excessive LFTs abnormalities (see section 9.3) will require repeat LFTs prior to the next 
docetaxel administration. 
 
ARM B – Parent DCF with G-CSF 
On or within 1 day of the beginning of each treatment, a CBC with differential and platelet 
count, serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, 
alkaline phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, 
LDH, and tumor markers are required.   
 
Radiology evaluation: For both treatment arms, radiographic studies upon which tumor 
measurements were made will be repeated every cycle (six week intervals for most patients) for 
6 cycles, and then after every two cycles of therapy (e.g. after cycles 1, 2, 3, 4, 5, 6, 8, 10, 12 
etc.), to rule out progression of disease and to determine response for measurable disease.  
Patients will remain on study until disease progression, patient withdrawal, unacceptable toxicity 
despite dose attenuation, or if the treating physician deems it is in the best interest of the patient 
following discussion with the principal investigator.  Tolerability of this regimen will be 
determined from blood test results and toxicity assessment. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1  Docetaxel (TAXOTERE®) 
For complete details, please see the package insert for further information. 
5.1.1  Description 
Docetaxel is an antineoplastic agent belonging to the taxoid family.  It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of 
yew plants.  Docetaxel is a white to almost-white powder with an empirical formula of 


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C43H53N014-3H20, and a molecular weight of 861.9.  It is highly lipophilic and practically 
insoluble in water.   
5.1.2  Preparation and Administration  
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, 
caution should be exercised when handling and preparing DOCETAXEL solutions. The 
use of gloves is recommended. Please refer to Handling and Disposal section. 
If Docetaxel Injection Concentrate, initial diluted solution, or final dilution for infusion 
should come into contact with the skin, immediately and thoroughly wash with soap and 
water. If Docetaxel Injection Concentrate, initial diluted solution, or final dilution for 
infusion should come into contact with mucosa, immediately and thoroughly wash with 
water. 
Contact of the Docetaxel concentrate with plasticized PVC equipment or devices used to 
prepare solutions for infusion is not recommended. In order to minimize patient exposure 
to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC 
infusion bags or sets, the final Docetaxel dilution for infusion should be stored in bottles 
(glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered 
through polyethylene-lined administration sets. 
Docetaxel Injection Concentrate requires two dilutions prior to administration. Please 
follow the preparation instructions provided below. Note: Both the Docetaxel Injection 
Concentrate and the diluent vials contain an overfill to compensate for liquid loss during 
preparation.  This overfill ensures that after dilution with the entire contents of the 
accompanying diluent, there is an initial diluted solution containing 10 mg/mL docetaxel. 
The table below provides the fill range of the diluent, the approximate extractable volume 
of diluent when the entire contents of the diluent vial are withdrawn, and the 
concentration of the initial diluted solution for DOCETAXEL 20 mg and DOCETAXEL 
80 mg. 
Product 
Diluent  
13% (w/w) ethanol 
 in water for injection 
Fill Range 
(mL) 
Approximate 
extractable volume of 
diluent when entire 
contents are withdrawn  
(mL) 
Concentration of 
the initial diluted 
solution 
(mg/mL docetaxel) 
 
 
 
 
Taxotere®  
20 mg/0.5 mL 
1.88 – 2.08  mL 
1.8 mL 
10 mg/mL 
Taxotere®  
80 mg/2 mL 
6.96 - 7.70 mL 
7.1 mL 
10 mg/mL 
 
A. Initial Diluted Solution 
1. Docetaxel vials should be stored between 2 and 25°C (36 and 77°F). If the vials are 
stored under refrigeration, allow the appropriate number of vials of Docetaxel Injection 
Concentrate and diluent (13% ethanol in water for injection) vials to stand at room 
temperature for approximately 5 minutes. 


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2. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 
1.8 mL for Docetaxel 20 mg and approximately 7.1 mL for Docetaxel 80 mg) into a 
syringe by partially inverting the vial, and transfer it to the appropriate vial of 
Docetaxel Injection Concentrate. If the procedure is followed as described, an initial 
diluted solution of 10mg docetaxel/mL will result. 
3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure 
full mixture of the concentrate and diluent. Do not shake. 
4. The initial diluted Docetaxel solution (10 mg docetaxel/mL) should be clear; however, 
there may be some foam on top of the solution due to the polysorbate 80. Allow the 
solution to stand for a few minutes to allow any foam to dissipate. It is not required that 
all foam dissipate prior to continuing the preparation process. 
The initial diluted solution may be used immediately or stored either in the refrigerator 
or at room temperature for a maximum of 8 hours. 
B. Final Dilution for Infusion 
1. Aseptically withdraw the required amount of initial diluted Docetaxel solution (10 mg 
docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle 
of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final 
concentration of 0.3 to 0.74 mg/mL. 
If a dose greater than 200 mg of Docetaxel is required, use a larger volume of the 
infusion vehicle so that a concentration of 0.74 mg/mL Docetaxel is not exceeded. 
2. Thoroughly mix the infusion by manual rotation. 
3. As with all parenteral products, Docetaxel should be inspected visually for particulate 
matter or discoloration prior to administration whenever the solution and container 
permit. If the Docetaxel initial diluted solution or final dilution for infusion is not clear 
or appears to have precipitation, these should be discarded. 
The final Docetaxel dilution for infusion should be administered intravenously as a 30-
minute to 60-minute infusion under ambient room temperature and lighting conditions. 
Stability: Docetaxel infusion solution, if stored between 2 and 25°C (36 and 77°F) is 
stable for 4 hours. Fully prepared Docetaxel infusion solution (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 
1 hour i.v. administration). 
How Supplied: Docetaxel Injection Concentrate is supplied in a single-dose vial as a 
sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-
pyrogenic, Diluent (13% ethanol in water for injection) vial. The following strengths are 
available: 
TAXOTERE 80 MG/2 ML 
 
(NDC 0075-8001-80) 
TAXOTERE (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 
2 mL polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in 
water for injection). Both items are in a blister pack in one carton. 


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TAXOTERE 20 MG/0.5 ML (NDC 0075-8001-20) 
TAXOTERE (docetaxel) ) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel 
in 0.5 mL polysorbate 80 and diluent for TAXOTERE 20 mg (13% (w/w) ethanol 
in water for injection). Both items are in a blister pack in one carton. 
Storage: Store between 2 and 25°C (36 and 77°F). Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs 
should be considered as per institutional guidelines.  
5.1.3  Source 
For this study, locally obtained commercial supplies of Docetaxel should be used.  
Because commercial drug will be used, accounting for Docetaxel drug supplies is not 
specifically required in this study. 
5.1.4  Safety Profile 
Principal adverse effects include neutropenia, thrombocytopenia, anemia, nausea, 
vomiting, diarrhea, ascites, mucositis, cardiac arrhythmias, hypotension, pleural effusion, 
peripheral neuropathy, rash, severe nail disorders (hypo or hyperpigmentation), 
onycholysis (loosening of the nails), alopecia, palmar-plantar dyserythroesthesia, 
hypersensitivity reaction, fatigue and fluid retention syndrome (may be irreversible). 
5.2       CISPLATIN 
For complete details, please see the package insert for further information. 
5.2.1 Description 
Cisplatin (cis-diaminedichloroplatinum, Platinol) is a heavy metal complex containing 
a central atom of platinum surrounded by two chloride atoms and two ammonia 
molecules in the cis- position. Cisplatin binds to DNA bases and produces particular 
types of cisplatin-DNA lesions or adducts. The drug is supplied in 10 and 50 mg amber 
vials. 
5.2.2 Preparation and Administration 
ARM A: Cisplatin will be given on days 1, 15, and 29 of each cycle. The drug will be 
given at a dose of 40 mg/m2 over 30 minutes on day 2 or 3 of each treatment. 
ARM B: Cisplatin will be given on days 1 and 22 of each cycle. The drug will be given at 
a dose of 75 mg/m2 over 60 minutes immediately following docetaxel administration. 
Cisplatin is available in 100mg/100 ml solution vials. The solution is then further diluted 
into saline-based solutions (preferably 100-150 ml of 0.9% NaCL for intravenous 
administration). Before drug administration the patient should be given intravenous 
hydration with at least 500 ml of 5 % dextrose in normal saline (D5W) or normal saline 
over 1-2 hours. Aluminum needles should not be used. Patients will be advised to 
maintain an oral fluid intake of at least one (1) liter per meter squared on the day of 
treatment. This regimen may be adjusted as needed, e.g., for elderly persons. 


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5.2.3 Source 
For this study, locally obtained commercial supplies of Cisplatin should be used. Because 
commercial drug will be used, accounting for Cisplatin drug supplies is not specifically 
required in this study. 
5.2.4   Safety Profile 
Cumulative nephrotoxicity associated with cisplatin is severe. Other major dose-related 
toxicities are myelosuppression, nausea and vomiting.  Ototoxicity, manifested by 
tinnitus and/or high frequency hearing loss, is significant. Anaphylactic-like reactions to 
cisplatin have been reported. Facial swelling, bronchospasm, tachycardia and 
hypotension may occur within minutes of cisplatin administration. Other side effects 
include anorexia, diarrhea, serum electrolyte disturbances (e.g., hyponatremia, 
hypomagnesemia), vascular toxicities (e.g., myocardial infarction, cerebrovascular 
accident etc.), neurotoxicity, peripheral neuropathy, autonomic neuropathy, muscle 
cramps, ocular toxicity (optic neuritis, papilledema, cerebral blindness), and 
hepatotoxicity. Other rare side effects include cardiac abnormalities, hiccoughs, elevated 
serum amylase, rash and alopecia. Local soft tissue injury has been reported following 
extravasation of cisplatin. 
 
5.3  FLUOROURACIL 
 
For complete details, please see the package insert for further information. 
5.3.1 Description 
The chemical name of fluorouracil (FU) is 5-fluoropyrimidine-2,4(1H,3H)-dione. 
Fluorouracil is also known by other names 5-Fluorouracil; Fluorouracilo; 
Fluorouracilum; 5-FU; NSC-19893; Ro-2-9757; WR-69596. Its molecular formula is 
C4H3FN2O2; it has a molecular weight of 130.1. FU is a white to almost white, 
practically odorless, crystalline powder. It is sparingly soluble in water; slightly soluble 
in alcohol; practically insoluble in chloroform and ether. A 1% solution has a pH of 4.5 to 
5.0; the USP injection has a pH of 8.6 to 9.4 and the BP injection has a pH of 8.5 to 9.1. 
Fluorouracil is commercially available, and supplied in the U.S. by ICN pharmaceuticals, 
Lyphomed, Quad Pharmaceuticals, Baxter Healthcare, Abbott Laboratories, and as 
Adrucil®hby Pharmacia & Upjohn. 
5.3.2 Preparation and Administration 
At our institution fluorouracil manufactured by Pharmacia & Upjohn (ADRUCIL®) is in 
use. It is supplied as a 50 mg/ml solution in vials of 50 ml and 100 ml. The appropriate 
volume is withdrawn into a syringe which is used for administration. No dilution is 
required. Filter ampules with aspiration needle (5µm). Compatible with D5W, 0.9% 
NaCl, D5LR. Fluorouracil will be administered as an intravenous push, usually over 1-2 
minutes followed by a 48-hour intravenous continuous infusion (further dilution is not 
required). Ensure vein patency before administration 


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Storage:  Store at room temperature and protect from light. Dark yellow color indicates 
decomposition.  Fluorouracil is stable in polypropylene syringes, and stable in PVC 
reservoirs for infusion pump usage for 12 days. Fluorouracil may adsorb to glass 
surfaces. It is stable in cellulose nitrate/acetate ester or Teflon filters. 
5.3.3 Source 
Locally obtained commercial supplies of Fluorouracil should be used. Because 
commercial drug will be used, accounting for Fluorouracil drug supplies is not 
specifically required in this study. 
5.3.4  Safety Profile 
Hematologic and gastrointestinal side effects are most frequently associated with 
fluorouracil. Hematologic toxicities of fluorouracil are leukopenia, granulocytopenia (9-
14 days), thrombocytopenia (7-14 days), and anemia. Stomatitis, gastrointestinal 
ulceration and bleeding, and diarrhea are commonly seen gastrointestinal side effects of 
fluorouracil. Nausea and vomiting, effects on the skin including rashes and 
hyperpigmentation, alopecia, ocular irritation, central neurotoxicity (notably cerebellar 
ataxia), and myocardial ischemia have been reported. A complete listing of toxicities can 
be found in the fluorouracil package insert. 
Drug Interactions 
Allopurinol may decrease efficacy of fluorouracil. Leucovorin enhances cytotoxicity of 
fluorouracil by forming a more stable tertiary complex with thymidylate synthase. 
 
5.4 LEUCOVORIN 
Please see the package insert for complete details and further information. 
5.4.1  Description 
Leucovorin calcium is commercially available, and is a stable reduced formyl derivative 
and the active form of folic acid. The following products are available: Immunex 
(formally available from Lederle): 50 mg vial, 100 mg vial, 350 mg vial. Burroughs-
Wellcome (Wellcovorin®): 100 mg vial. Chiron Therapeutics: 50 mg vial, and 100 mg 
vial. 
5.4.2 Preparation and Administration 
Leucovorin may be reconstituted with Bacteriostatic Water for Injection (BWI). 
Reconstitute 50 mg with 5 ml BWI, 100 mg vial with 10 ml BWI. Both of these will yield 
a solution of 10 mg/ml. Reconstitute 350 mg vial with 17 ml BWI to yield a solution of 
20 mg/ml. Use bacteriostatic water only with doses < 10 mg/m2.  Leucovorin will be 
administered intravenously over 30 minutes prior to fluorouracil administration. 
Storage:  Unreconstituted vials are stored at room temperature and protected from light. 
The reconstituted 10 mg/ml or 20 mg/ml solution is stable for at least 7 days at room 
temperature. 


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5.4.3 Source 
For this study, locally obtained commercial supplies of Leucovorin should be used. 
Because commercial drug will be used, accounting for leucovorin drug supplies is not 
specifically required in this study. 
5.4.4  Safety Profile 
The only adverse reaction for leucovorin is a rare report of allergic reactions to parenteral 
injections of leucovorin. This is extremely uncommon. 
5.5 TRASTUZUMAB 
     Please see the package insert for complete details and further information. 
5.5.1 Description 
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that 
selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular 
domain of the human epidermal growth factor receptor 2 protein, HER2.  The antibody is 
an IgG1 kappa that contains human framework regions with the complementarity-
determining regions of a murine antibody (4D5) that binds to HER2.  
The humanized antibody against HER2 is produced by a mammalian cell (Chinese 
Hamster Ovary) [CHO] suspension culture in a nutrient medium containing the antibiotic 
gentamicin. Gentamicin is not detectable in the final product. Trastuzumabis a sterile, 
white to pale yellow, preservative-free lyophilized powder for intravenous (IV) 
administration.  Each vial of trastuzumabcontains 400 mg of tratuzumab, 9.9 mg of 
L-histidine HCl, 6.4 mg of L-histadine, 400 mg of α,α-trehalose dihydrate, and 1.8 mg of 
polysorbate 20, USP.  Reconstitution with 20 mL of the supplied Bacteriostatic Water for 
Injection (BWFI) USP, containing 1.1% benzyl alcohol as a preservative, yields 21 mL of 
a multidose solution containing 21 mg/mL trastuzumab, at a pH of ~6. 
 
   5.5.2 Preparation, Administration, and Storage  
    
Dosage  
 
Trastuzumab will be administered on q2wk dosing schedule, with initial loading dose of  
6 mg/kg as a 90 minute infusion, followed by trastuzumab 4 mg/kg q2wk, administered 
as a 30 minute infusion if the initial loading dose was well tolerated.  Eligible HER2-
negative patients will receive mDCF alone 
 DO NOT ADMINISTER AS AN IV PUSH OR BOLUS (see ADMINISTRATION).   
Preparation 
Use appropriate aseptic technique.  Each vial of trastuzumab should be reconstituted with 
20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a multidose 
solution containing 21 mg/mL trastuzumab .  Immediately upon reconstitution with 


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BWFI, the vial of trastuzumab must be labeled in the area marked “Do not use after” with 
the future date that is 28 days from the date of reconstitution. 
If the patient has known hypersensitivity to benzyl alcohol, trastuzumab must be 
reconstituted with Sterile Water for Injection (see PRECAUTIONS).  Trastuzumab which 
has been reconstituted with SWFI must be used immediately and any unused portion 
discarded.  Use of other reconstitution diluents should be avoided. 
Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 
0.9% sodium chloride, USP.  DEXTROSE (5%) SOLUTION SHOULD NOT BE USED.  
Gently invert the bag to mix the solution.  The reconstituted preparation results in a 
colorless to pale yellow transparent solution.  Parenteral drug products should be 
inspected visually for particulates and discoloration prior to administration. 
No incompatibilities between trastuzumab and polyvinylchloride or polyethylene bags 
have been observed. 
Administration 
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  Trastuzumab administration 
should precede chemotherapy administration.  Patients should be observed for fever and 
chills or other infusion-associated symptoms (see ADVERSE REACTIONS).  If prior 
infusions are well tolerated subsequent doses of 4 mg/kg trastuzumab q2wk may be 
administered over 30 minutes. If chemotherapy is discontinued during the treatment 
phase, either because of completing a planned number of cycles of chemotherapy, or 
because of chemotherapy related toxicity,  trastuzumab should  be continued until disease 
progression or unacceptable toxicity related specifically to trastuzumab.    
Trastuzumab should not be mixed or diluted with other rugs. Trastuzumab infusions 
should not be administered or mixed with Dextrose solutions. 
Storage 
Vials of trastuzumab are stable at 2°C–8°C (36°F–46°F) prior to reconstitution.  Do not 
use beyond the expiration date stamped on the vial.  A vial of trastuzumab reconstituted 
with BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated 
at 2°C–8°C (36°F–46°F), and the solution is preserved for multiple use.  Discard any 
remaining multi-dose reconstituted solution after 28 days.  If unpreserved SWFI (not 
supplied) is used, the reconstituted trastuzumab solution should be used immediately and 
any unused portion must be discarded.  DO NOT FREEZE TRASTUZUMAB THAT 
HAS BEEN RECONSTITUTED. 
The solution of trastuzumab for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% sodium chloride for injection, USP, may be stored at 2°C–8°C 
(36°F–46°F) for up to 24 hours prior to use.  Diluted trastuzumab has been shown to be 
stable for up to 24 hours at room temperature 15°C–25°C; however, since diluted 
Trastuzumab contains no effective preservative the reconstituted and diluted solution 
should be stored refrigerated (2°C–8°C). 


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5.5.3 Source 
Genentech will provide trastuzumab free of charge to the patient. 
    
5.5.4 Safety Profile 
Cardiac Dysfunction: Signs and symptoms of cardiac dysfunction were observed in a 
number of women who received trastuzumab alone or in combination with 
chemotherapy, most often anthracycline based treatment.  Cardiac dysfunction was 
observed most frequently among patients who received trastuzumab plus AC 
chemotherapy (28%), compared with those who received AC alone (7%), trastuzumab 
plus paclitaxel (11%), paclitaxel alone (1%), or trastuzumab alone (7%).  Severe 
disability or fatal outcome due to cardiac dysfunction was observed in ~1% of all 
patients. The signs and symptoms of cardiac dysfunction usually responded to treatment.   
 
 All patients must have a baseline evaluation of cardiac function including a measurement 
of LVEF by either MUGA or ECHO prior to entry into the study.  Only patients with 
normal LVEF should be entered into this study.  All should have regular cardiac 
monitoring throughout the study. It is suggested that the first evaluation occur 4 months 
after the initiation of trastuzumab therapy.  During the course of trastuzumab therapy, 
patients should be monitored for signs and symptoms of CHF (i.e., dyspnea, tachycardia, 
new unexplained cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal 
nocturnal dyspnea, orthopnea, peripheral edema, and rapid unexplained weight gain).  
The diagnosis must be confirmed using the same method used to measure LVEF at 
baseline (either ECHO or MUGA).     
 
Management of Symptomatic Cardiac Changes.  Patients who develop signs and 
symptoms of CHF should have trastuzumab held and should receive treatment for CHF 
as prescribed by the HFSA (e.g., ACE inhibitors, angiotensin-II receptor blockers, β-
blockers, diuretics, and cardiac glycosides, as needed;  HFSA guidelines).  Consideration 
should be given to obtaining a cardiac consultation.   
 
If the symptoms of CHF resolve with treatment, and cardiac function improves, 
Trastuzumab may be continued after discussion with the patient concerning the risks and 
benefits of continued therapy.  If the patient is benefiting clinically from Trastuzumab, 
the benefit of continued treatment may outweigh the risk of cardiac dysfunction.  If 
Trastuzumab is restarted, continued surveillance with noninvasive measures of LVEF 
(MUGA or ECHO) is strongly recommended until cardiac function has normalized. 
Management of Asymptomatic Decreases in LVEF.  Trastuzumab may be continued in 
patients experiencing an asymptomatic absolute decrease in LVEF of <20 percentage 
points from baseline, when the ejection fraction remains within the imaging center’s 
range of normal limits.  Repeat measures of LVEF should be obtained using the 
methodology selected at baseline.  Close follow-up of such patients is recommended.  
Patients with an asymptomatic absolute decrease in LVEF of >20 percentage points or an 
ejection fraction below the range of normal limits, should have trastuzumab held and be 
considered for treatment of incipient CHF as prescribed by the HFSA (e.g., ACE 


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inhibitors, angiotensin-II receptor blockers, β-blockers, diuretics, and cardiac glycosides, 
as needed; see HFSA guidelines).  In light of the variability inherent in the assessment of 
ejection fraction, consideration should be given to repeating the study to confirm an 
observed decline.  Repeat measures of LVEF should be obtained using the same 
methodology selected at baseline.  If trastuzumab has been discontinued for an 
asymptomatic decline in LVEF, a repeat measure of LVEF will be obtained in 1 month to 
determine if the decline has resolved. 
 
If cardiac function improves, trastuzumab may be restarted after discussion with the 
patient concerning the risks and benefits of continued therapy.  If the patient is benefiting 
clinically from Trastuzumab, the benefit of continued treatment may outweigh the risk of 
cardiac dysfunction.  If trastuzumab is restarted, continued surveillance with noninvasive 
measures of LVEF (MUGA or ECHO), using the methodology selected at baseline, is 
strongly recommended until cardiac function has normalized. 
 
Infusion Associated Symptoms: During the first infusion with Trastuzumab, a symptom 
complex consisting of chills and/or fever is observed in approximtely 40% of patients.  
Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, 
cough, dizziness, rash, and asthenia.  These symptoms are usually mild to moderate in 
severity, and  occur infrequently with subsequent Trastuzumab infusions. These 
symptoms can be treated with an analgesic/antipyretic such as meperidine or 
paracetamol, or an antihistamine such as diphenhydramine.  
Serious Infusion-Associated Events. Serious adverse reactions to Trastuzumab infusion 
including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently.   In rare cases (4 per 
10,000), these events were associated with a clinical course culminating in a fatal 
outcome. Serious reactions have been treated with supportive therapy such as oxygen, 
beta-agonists, corticosteroids and withdrawal of Trastuzumab as indicated. 
 
Hematologic Toxicity and Neutropenic Infections: In the clinical trials, an increased 
incidence of anemia was observed in patients receiving trastuzumab plus chemotherapy 
compared with patients receiving chemotherapy alone.  The majority of these anemia 
events were mild or moderate in intensity and reversible; none resulted in discontinuation 
of trastuzumab therapy.   
 
In the clinical trials, the per-patient incidences of moderate to severe neutropenia and of 
febrile neutropenia were higher in patients receiving trastuzumab in combination with 
myelosuppressive chemotherapy as compared to those who received chemotherapy alone.  
In the post marketing setting, deaths due to sepsis in patients with severe neutropenia 
have been reported in patients receiving trastuzumab and myelosuppressive 
chemotherapy, although in controlled clinical trials (pre- and post-marketing), the 
incidence of septic deaths was not significantly increased.  The pathophysiologic basis 
for exacerbation of neutropenia has not been determined; the effect of trastuzumab on the 
pharmacokinetics of chemotherapeutic agents has not been fully evaluated.  


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Secondary acute leukemia or myelodysplastic syndrome has been reported in 4 of 
approximately 1200 patients who participated in trastuzumab clinical trials.  Patients 
treated with chemotherapeutic agents are known to be at increased risk for secondary 
leukemia.  The observed incidence of leukemia among Trastuzumab treated patients 
appears to be consistent with the expected incidence of leukemia among patients treated 
with chemotherapy for metastatic breast cancer.  Therefore, the contribution of 
Trastuzumab to the etiology of acute leukemia or myelodysplastic syndrome in these 
cases is unclear. 
 
Management of Hematologic Toxicities. Care should be taken to carefully monitor the 
patient’s hematologic status throughout the course of the trial.  Use of hematopoietic 
growth factors to ameliorate hematologic toxicity is at the discretion of the physician 
investigator and should be in accordance with the American Society of Clinical 
Oncologists (ASCO) guidelines.  
 
5.6  CONCOMITANT MEDICATIONS 
5.6.1 Anticancer or experimental therapy 
No other concurrent chemotherapy or anti-cancer therapy of any kind is permitted while 
the patient is receiving study treatment.  
5.6.2 Hematopoetic Growth Factors 
Colony-Stimulating Factor (G-CSF, GM-CSF): 
ARM A 
After cycle 1 (eg. 3 treatments of mDCF), the use of colony-stimulating factor is 
permitted at the discretion of the treating physician.  However, the administration of G-
CSF in a patient who has experienced neutropenia, or its therapeutic use in patients with 
serious neutropenic complications such as tissue infection, sepsis syndrome, fungal 
infection, fever/neutropenia, etc. is recommended.  
 
 
ARM B 
Beginning with cycle 1, pegfilgrastim (Neulasta) is given subcutaneous 6 mg on either 
day 8, 9, or 10 of every cycle.  This is the preferred hematopoietic growth factor.  
Alternatively, filgrastim (Neupogen) may be given by subcutaneous injection from day 
10 to 17.  The optimal dose is as follows:   
Body weight < 60 kg:  filgastrim 300 mcg subcut daily x 7 days  
Body weight > 60 kg:  filgrastim 480 mcg subcut daily x 7 days  
 
Epoetin alfa (Procrit or Aranesp): 
Use of epoetin alfa is permitted at the discretion of the treating physician. 
5.6.3  Antiemetics and Premedications 
 


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ARM A 
The mDCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention 
and may also decrease the incidence and severity of acute hypersensitivity reactions.   
The recommended pre-medication and delayed emesis schedule for this study is as 
follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally 
 
 
 
 
 
     evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 3: 
 
 
       pre - Cisplatin 
Dexamethasone 8 mg orally or IV 
 
 
 
 
 
 
 
Palonosetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
▪ Day 4 and 5:  
 
 
 
 
Dexamethasone 4 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
 
ARM B 
The DCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention 
and may also decrease the incidence and severity of acute hypersensitivity reactions.   
The recommended pre-medication and delayed emesis schedule for this study is as 
follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally 
 
 
 
 
       pre-Cisplatin  -     Palonesetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
 
 
 
 
 
     evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 2 and 3:  
 
 
 
 
Dexamethasone 8 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
 
Both ARMS 
For patients who have persistent nausea or vomiting with palonosetron, granisetron 2mg 
po or granisetron 1mg IV may be substituted prior to chemotherapy, and then granisetron 
2 mg po may be continued on days 2 and 3.  Metoclopramide 5-10 mg po every 4 hours 
and/or prochlorperazine 10 mg every 6 hours may be used as needed for nausea/vomiting, 


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and lorazepan may be used for anticipatory nausea/vomiting or anxiety related 
nausea/vomiting.   
For patients who have no evidence of delayed emesis, the prophylaxis may be 
discontinued as tolerated as per the treating physician. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
This is a multicenter phase II study coordinated by Memorial Sloan-Kettering Cancer Center 
(MSKCC). 
 
6.1 
Subject Inclusion Criteria 
1. Patients must have histologically or cytologically confirmed metastatic or unresectable 
gastric or gastroesophageal junction (GEJ) adenocarcinoma.  GEJ adenocarcinoma 
may be classified according to Siewert’s classification type I, II, or III[43]. 
 
2.  Histological documentation of local recurrence or metastasis is strongly encouraged, 
unless the risk of such a procedure outweighs the potential benefit of confirming the 
metastatic disease.   
• If no histologic confirmation, then the metastases or recurrence will require 
documention by a 2nd radiographic procedure (eg. PET/CT scan or MRI in 
addition to the CT scan).  If the imaging procedure does not confirm recurrent or 
metastatic disease, biopsy confirmation will be required. 
 
3. Patients must have disease that can be evaluated radiographically.  This may be 
measurable disease or non-measurable disease.  Measurable disease is defined as that 
which can be measured in at least one dimension as > 20 mm with conventional 
techniques, or >10 mm by high resolution imaging.  Disease that is identified on 
radiology studies, but does not meet the criteria for measurable disease, is considered 
non-measurable– see section 12.1.1 for further details.  
 
4. Patients may have received no prior chemotherapy for metastatic or unresectable 
disease.  Patients may have received prior adjuvant therapy (chemotherapy and/or 
chemoradiation) if more than 6 months have elapsed between the end of adjuvant 
therapy and registration.  Patients may not have received prior docetaxel or cisplatin. 
 
5. Age 18 years or older. 
 
6. Karnofsky performance status > 70% (ECOG performance status 0-1). 
 
7. Peripheral neuropathy < grade 1 
 
 
 


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8. Hematologic (minimal values) 
 
White blood cell count > 3000/mm3 
Absolute neutrophil count > 1500 cells/ mm3 
 
Hemoglobin > 9.0 g/dl 
 
Platelet count > 100,000 / mm3 
 
9. Hepatic (minimal values) 
Total bilirubin < 1.5 
AST and ALT and Alkaline phosphatase must be within the eligible range as 
described by the table below.  In determining eligibility, the more abnormal of the 
two values (AST or ALT) should be used. Patients with alkaline phosphatase 
elevation secondary to the bony metastases rather than liver dysfunction may 
proceed with treatment on protocol after discussion with the principal 
investigator.  
 
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤1.5x ULN 
>1.5x but ≤ 5x ULN >5x ULN 
≤ ULN 
Eligible 
Eligible 
Eligible 
Ineligible 
>1x but ≤2.5x  
Eligible 
Eligible 
Ineligible 
Ineligible 
>2.5x but ≤5x  
Eligible 
Ineligible 
Ineligible 
Ineligible 
>5x ULN 
Ineligible 
Ineligible 
Ineligible 
Ineligible 
 
10.  Kidney function (minimal values) 
 
serum creatinine < 1.5 mg/dl* 
* if serum creatinine is 1.2-1.5 mg/dl, the creatinine clearance (either measured or 
calculated) must be 50 ml/min or greater. 
 
 
11. The patient has a PT (INR) < 1.5 and an PTT < 3 seconds above the upper limits of 
normal if the patient is not on anticoagulation. If a patient is on full-dose 
anticoagulants, the following criteria should be met for enrollment: 
a. the patient must have an in-range INR (usually between 2 and 3) on a stable 
dose of warfarin or on stable dose of LMW heparin.   
b. the patient must not have active bleeding or pathological conditions that carry 
high risk of bleeding (e.g. tumor involving major vessels, known varices). 
 
12. Women of childbearing potential have a negative pregnancy test. 
 
13. Men and women of childbearing potential must be willing to consent to using 
effective contraception while on treatment and for at least 3 months thereafter. 
 
14. Ability to understand informed consent and signing of written informed consent 
document prior to initiation of protocol therapy. 
 


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15. Patients must have HER2-positive (FISH+ or IHC 3+) metastatic or unresectable 
gastric or gastroesophageal junction (GEJ) adenocarcinoma to be eligible for 
trastuzumab. For the purposes of this protocol, FISH+ is defined as HER2:CEP17 
ratio ≥ 2.0. Biopsy samples with cohesive IHC3+ or FISH+ clones are considered  
HER2 positive irrespective of size, i.e.<10%.  FISH+ defined as >2 HER2:CEP17. 
Note: Samples will be processed locally in the laboratory of investigational sites. The 
results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of 
HER2 status. MSK pathology review will not be required to begin therapy on the 
protocol.   Samples provided to the MSK laboratory must either be HER2 IHC slides, 
or  if FISH confirmation is necessary, a paraffin block(s) of adequate size to allow if 
possible for at least 5 slides with cuts that are 5-microns thick or if a paraffin block is 
not available, then if possible at least 5 slides with cuts that are 5-microns thick will 
be acceptable. Archived or fresh tumor samples may be used. 
 
16. Patients who are receiving trastuzumab must have a left ventricular ejection fraction 
of > 50%. 
 
6.2 
Subject Exclusion Criteria 
1. Patients who have received previous chemotherapy for the treatment of metastatic or 
unresectable gastric or GEJ adenocarcinoma are ineligible.  Patients who have 
received previous pre- or post-operative chemotherapy or chemoradiation are 
ineligible if therapy was completed less than 6 months prior to study registration.  
Patients must have recovered from adverse events from any previous therapy.   
 
2. Patients who have received previous docetaxel or cisplatin.  
 
3. Patients with a history of another neoplastic disease within the past three years, 
excluding basal cell carcinoma of the skin, cervical carcinoma in situ, or nonmetastatic 
prostate cancer. 
 
4. Patients with brain or central nervous system metastases, including leptomeningeal 
disease. 
 
5. Pregnant (positive pregnancy test) or breast feeding. 
 
6. Serious, non-healing wound, ulcer, or bone fracture. 
7. Significant cardiac disease as defined as: 
unstable angina,  New York Heart Association (NYHA) grade II or greater, 
congestive heart failure, history of myocardial infarction within 6 months 
 
8. Evidence of bleeding diathesis or coagulopathy.  
 


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9. History of a stroke or CVA within 6 months. 
 
10. Clinically significant peripheral vascular disease. 
 
11. Clinically significant hearing loss or ringing in the ears. 
 
12. Patients with a history of severe hypersenstivity reaction to Taxotere® or other drugs 
formulated with polysorbate 80. 
 
13. Inability to comply with study and/or follow-up procedures. 
 
14. Patients with any other medical condition or reason, in that investigator’s opinion, 
makes the patient unstable to participate in a clinical trial. 
 
15. For patients who are Her2 positive and will be treated on the trastuzumab + mDCF 
cohort, prior trastuzumab treatment is not allowed. 
 
16. For patients who are Her2 positive and will be treated on the trastuzumab+mDCF 
cohort, left ventricular function <50% 
 
7.0 
RECRUITMENT PLAN 
This study will be available to all patients seen at participating institutions who meet the 
eligibility criteria as outlined in section 6.0.  Memorial Hospital is a referral center for this 
disease.  In addition, the study will be placed on the MSKCC Website as well as available at 
the MSKCC satellite centers to maximize patient recruitment.  Patients will be identified from 
medical oncology clinics for treatment of their disease. 
 
 
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations.  There will be no limitation to access with regard 
to race or gender.  Patients will be required to read, agree to, and sign an IRB-approved 
informed consent form prior to registration on this trial. The registration procedure will be 
conducted as described in section 15.0. Patients will not receive payment for their 
participation on this study. The proposed study population is provided in the table below. 
 
 
Ethnic Category 
Sex/ Gender 
 
 
 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
8 
10 
 
18 
Not Hispanic or Latino 
28 
62 
 
90 
Unknown 
 
 
 
 
Ethnic Category: Total of all subjects 
36 
72 
 
108 


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Racial Category 
 
American Indian or Alaskan Native 
0 
0 
 
 
Asian 
7 
10 
 
17 
Black or African American 
4 
8 
 
12 
Native Hawaiian or other Pacific Islander 
0 
0 
 
 
White 
23 
52 
 
75 
More than one race 
0 
0 
 
0 
Unknown 
2 
2 
 
4 
Racial Category: Total of all subjects 
36 
72 
 
108 
 
Note, the results of the recent ToGA study demonstrate that for HER2 positive gastric cancer, 
patients have a survival benefit with the addition of trastuzumab to chemotherapy (see Sect 
3.3.4).  We are therefore amending the study to include a separate cohort of 35 patients who are 
Her2 positive to receive mDCF + trastuzumab (Trastuzumab cohort) 
 
Recruitment Expectations Per Site 
Memorial Sloan Kettering Cancer Center 
10 
City of Hope 
5 
University of Pittsburgh 
5 
Queens Cancer Center 
2 
Long Island Jewish Medical Center 
2 
University Hospital  of Cleveland 
2 
Weill Medical College of Cornell University 
2 
Medical College of Wisconsin 
2 
Piedmont Hospital Research Institute (PHRI) 
2 
Nebraska Cancer Specialists 
2 
Memorial Cancer Institute 
1 
Total 
35 
8.0 
PRETREATMENT EVALUATION 
To be completed within 14 days of starting therapy: 
1.  History and physical examination, including height, weight, calculated body surface area, 
vital signs, and performance status.  See Appendix A for a conversion between Karnofsky 
and ECOG performance status.  
 
2.  Serum pregnancy test for all women of childbearing potential within 14 days of starting 
therapy. If the test result is positive, the patient will not be allowed to participate in this 
study. 


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3.  PA and lateral chest radiographs. Chest radiographs may be omitted if a baseline CT scan of 
the chest is available in the same time frame. 
 
4.  Routine urinalysis. 
 
5.  CBC with differential and platelet count, serum chemistries (Na, Cl, BUN, Creatinine, K, 
Bicarb, and glucose), LFTs (AST, ALT, alkaline phosphatase, total bilirubin), calcium, 
magnesium, phosphorus, albumin, total protein, LDH, coagulation studies, and tumor 
markers as they are available. 
 
6.  EORTC QLQ-C30 questionnaire. 
 
To be completed within 30 days of starting therapy: 
7.  A 12-lead Electrocardiogram (ECG). 
 
8.  Documentation of all measurable or non-measurable disease parameters including 
radiographic imaging procedures within four weeks of study entry, and measurement of 
biochemical markers of disease (if applicable) within four weeks of study entry. The RECIST 
criteria as defined by CTEP (http://ctep.info.nih.gov/Policies) define measurable and non-
measurable disease. 
 
9.  Signed informed consent for study participation. 
 
10. Audiogram if clinically indicated. 
 
11. CT scan of the chest, abdomen and pelvis. 
 
12. Baseline PET/CT for staging.  
July 2009 Addendum: Collaborating centers that are either not able to perform the 
PET/CT at baseline (i.e., denied authorization from insurance carriers) or have opted not 
to participate in the Week 3 PET/CT may forgo performing the scan at baseline. 
 
To be completed at any time prior to starting therapy or during study: 
 
13. Placement of a MediPort, Hickman catheter or similar indwelling catheter for administration 
of continuous infusional fluorouracil chemotherapy. 
 
14. Paraffin stored tumor block or 15 unstained slides sent to MSKCC for planned future 
immunohistochemistry studies. 
 
15. A baseline assessment of left ventricular ejection fraction (usually cardiac ECHO or MUGA 
scan). 
 


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9.0 
TREATMENT/INTERVENTION PLAN 
9.1 CHEMOTHERAPY ADMINISTRATION 
Eligible patients will be randomly assigned to receive mDCF (ARM A) or parent DCF with 
growth factor support (ARM B) as follows: 
 
ARM A – Modified DCF 
ARM B – Parent DCF with G-CSF 
Drug 
Dose (mg/m2) 
Schedule 
Drug 
Dose (mg/m2) 
Schedule 
Docetaxel 
40 
Day 1 IVPB (60 min) 
Docetaxel 
75 
Day 1 IVPB (60 min) 
Leucovorin 
400 
Day 1 IVPB (30 min) 
Cisplatin 
75 
Day 1 IVPB (60 min) 
Fluorouracil 
400 
IVP day 1 
Fluorouracil 
750 
IVCI daily x 5 days 
Fluorouracil 
1000 mg/m2/d 
IVCI daily x 2 days 
Neulasta 
6 mg 
subcut on d 8, 9, or 10 
Cisplatin 
40 
Day 2 or 3 IVPB (30 min) or Neupogen 
300 or 480 mcg* 
subcut x 7 d 10-17 
* 300 mcg for weight < 60 kg, 480 mcg for weight > 60 kg. 
 
Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments).  
Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 
treatments).   
 
December 2009 Amendment 
We have met the early stopping rule for Arm B, parent DCF with growth factor support.  
Arm A will continue to accrue until target accrual of 54 patients. In addition, we will treat 
Her2 positive patients with mDCF + trastuzumab.  Trastuzumab will be administered on an 
every 2 week dosing schedule, with an initial loading dose of 6 mg/kg over 90 minutes, 
followed by trastuzumab 4 mg/kg every 2 weeks over 30 mintues.   
 
 
A given treatment may be moved +/- 14 days for specific administrative reasons, in particular 
clinic closure for holidays.  Tumor assessments will be performed following the completion of 
every cycle for the first 6 cycles, and then every 2 cycles thereafter.  Therapy will be 
administered in an outpatient setting, under the supervision of a physician and/or chemotherapy 
nurse, as is standard for chemotherapy administration at the treating institution.  
After 6 months of therapy, cisplatin, docetaxel, and/or fluorouracil may be discontinued at the 
discretion of the treating physician.  Prior to discontinuing therapy, the treating physician will 
discuss in detail with the protocol PI.  Patients without disease progression may resume 
chemotherapy at the discretion of the treating physician, or with progression if they had more 
than a 6 month treatment free interval.  
Expected adverse events are described in Section 11.0. No investigational or commercial agents 
or therapies other than those described above may be administered with the intent to treat the 
patient’s malignancy. 
Clinical evaluation: All assessments may be performed within one day of the planned treatment.   


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ARM A – Modified DCF 
Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of cycle one (e.g. on day 1, day 15, and day 29 of cycle 1).  In cycle 2 and all 
subsequent cycles, a physician evaluation (e.g. physical examination and toxicity assessment) 
will be performed prior to treatment on day 1 and day 29 treatments.  Additional nurse or 
physician visits will be at the discretion of the treating physician.  It is encouraged that an 
oncology nurse toxicity evaluation be performed prior to each treatment, especially if the patient 
is not assessed by a physician.  
Patients treated with mDCF plus trastuzumab therapy should be monitored for signs and 
symptoms of CHF (i.e., dyspnea, tachycardia, new unexplained cough, neck vein distention, 
cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and 
rapid unexplained weight gain).   
 
ARM B – Parent DCF with G-CSF 
Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of every cycle. 
Laboratory evaluation:  
ARM A – Modified DCF 
On or within 1 day of the beginning of each cycle, a CBC with differential and platelet count, 
serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, alkaline 
phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, LDH, 
tumor markers.  A CBC with differential and platelet count is required prior to each subsequent 
treatment (eg. day 15 and day 29).  A BUN and Creatinine is required before the day 15 
treatment (treatment #2), and a serum chemistry (electrolytes, BUN, Creatinine, glucose) is 
required before each day 29 treatment (#3). LFTs are required before each treatment (#1, #2 and 
#3) of cycle 1, and before treatment #1 and #3 for each subsequent cycle.  Any patient with 
excessive LFTs abnormalities (see section 9.3) will require repeat LFTs prior to the next 
docetaxel administration. 
 
ARM B – Parent DCF with G-CSF 
On or within 1 day of the beginning of each treatment, a CBC with differential and platelet 
count, serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, 
alkaline phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, 
LDH, and tumor markers are required.   
Radiology evaluation: For both treatment arms, radiographic studies upon which tumor 
measurements were made will be repeated every cycle (six week intervals for most patients) for 
6 cycles, and then after every two cycles of therapy (e.g. after cycles 1, 2, 3, 4, 5, 6, 8, 10, 12 
etc.), to rule out progression of disease and to determine response for measurable disease.  


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Patients will remain on study until disease progression, patient withdrawal, unacceptable toxicity 
despite dose attenuation, or if the treating physician deems it is in the best interest of the patient 
following discussion with the principal investigator.  Tolerability of this regimen will be 
determined from blood test results and toxicity assessment. 
Cardiac evaluation: For patients who are Her2 positive and will be treated on the 
trastuzumab+mDCF cohort left ventricular function will be assessed with echocardiograms or 
MUGA every 12 weeks while on study. 
A table of events to take place on this study is shown in section 10.0.   
9.2  SUPPORTIVE CARE GUIDELINES 
Concurrent supportive care is not restricted, including the use of narcotics for pain control and 
antiemetics and glucocorticoids for control of nausea, and antidiarrheal agents. Neither 
concurrent chemotherapy, immunotherapy, nor radiation therapy is permitted while on study. 
Hematopoetic Growth Factors 
Colony-Stimulating Factor (G-CSF, GM-CSF): 
ARM A 
Use of colony-stimulating factor is permitted at the discretion of the treating physician. 
However, the administration of G-CSF in a patient who has experienced neutropenia, or 
its therapeutic use in patients with serious neutropenic complications such as tissue 
infection, sepsis syndrome, fungal infection, fever/neutropenia, etc. is recommended.  
 
 
ARM B 
Beginning with cycle 1, pegfilgrastim (Neulasta) is given subcutaneous 6 mg on either 
day 8, 9, or 10 of every cycle.  This is the preferred hematopoietic growth factor.  
Alternatively, filgrastim (Neupogen) may be given by subcutaneous injection from day 
10 to 17.  The optimal dose is as follows:   
Body weight < 60 kg:  filgastrim 300 mcg subcut daily x 7 days  
Body weight > 60 kg:  filgrastim 480 mcg subcut daily x 7 days  
 
Epoetin alfa (Procrit or Aranesp): 
Use of epoetin alfa is permitted at the discretion of the treating physician. 
Antiemetics and Premedications 
ARM A 
The mDCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention and 
may also decrease the incidence and severity of acute hypersensitivity reactions.   
 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
The recommended pre-medication and delayed emesis schedule for this study is as follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally 
 
 
 
 
 
     evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 3: 
 
 
       pre - Cisplatin 
Dexamethasone 8 mg orally or IV 
 
 
 
 
 
 
 
Palonosetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
▪ Day 4 and 5:  
 
 
 
 
Dexamethasone 4 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
ARM B 
The DCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention and 
may also decrease the incidence and severity of acute hypersensitivity reactions.   
The recommended pre-medication and delayed emesis schedule for this study is as follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally 
 
 
 
 
       pre-Cisplatin  -     Palonesetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
 
 
 
 
 
     evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 2 and 3:  
 
 
 
 
Dexamethasone 8 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
 
Both ARMS 
For patients who have persistent nausea or vomiting with palonosetron, granisetron 2mg po or 
granisetron 1mg IV may be substituted prior to chemotherapy, and then granisetron 2 mg po may 
be continued on days 2 and 3.  Metoclopramide 5-10 mg po every 4 hours and/or 
prochlorperazine 10 mg every 6 hours may be used as needed for nausea/vomiting, and 
lorazepan may be used for anticipatory nausea/vomiting or anxiety related nausea/vomiting.   
For patients who have no evidence of delayed emesis, the prophylaxis may be discontinued as 
tolerated as per the treating physician. 
 
 


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9.3 TREATMENT PARAMETERS, DOSE DELAYS AND MODIFICATIONS 
9.3.1 Treatment Parameters 
1. Parameters for initiation of therapy (day 1) for cycle 1 are as follows: 
 White blood cell count > 3000/mm3 
 Absolute neutrophil count ≥ 1500/mm3 
 Platelet count ≥ 100,000/mm3 
 Hemoglobin > 9.0 g/dl 
 Creatinine < 1.5 mg/dl 
 Total Bilirubin < 1.5 mg/dl 
AST and ALT and Alkaline phosphatase must be within the treatment range as 
described by the table below.  In determining acceptable levels for treatment, the 
more abnormal of the two values (AST or ALT) should be used. Patients with 
alkaline phosphatase elevation secondary to the bony metastases rather than liver 
dysfunction may proceed with treatment on protocol after discussion with the 
principal investigator.  
 
2
.
 
P
a
r 
2. Parameters for all subsequent treatments: 
 Absolute Neutrophil count ≥ 1000/mm3 
 Platelet count ≥ 75,000/mm3.   
 Creatinine < 1.8 mg/dl  
o for Creatinine > 1.8 mg/dl and  
 Total bilirubin < 1.5  (should be drawn prior to treatment on week 1, week 3, and 
week 5 of cycle 1 and again prior to treatment on week 1 and week 5 of every 
subsequent cycle beginning with cycle 2 (ie. minimum of every 4 weeks). ) 
o For total bilirubin > 1.5 but < 2x ULN, docetaxel alone may be held. 
o For total bilirubin > 2x ULN, hold all three drugs (docetaxel, cisplatin, 
fluorouracil) 
 AST/ALT* and Alkaline Phosphatase as per table below (for docetaxel dosing):  
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤2x ULN 
>2x but ≤5x ULN 
>5x ULN 
≤ ULN 
Full Dose 
Full Dose 
Full Dose 
Hold 
>1x but ≤ 3x  
Full Dose 
Full Dose 
Reduce Dose 
Hold 
>3x but ≤ 5x  
Full Dose 
Reduce Dose 
Hold 
Hold 
>5x ULN 
Hold 
Hold 
Hold 
Hold 
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤2xULN 
>2x but ≤5x ULN 
>5x ULN 
≤ ULN 
Yes 
Yes 
Yes 
No 
>1x but ≤3x  
Yes 
Yes 
Yes 
No 
>3xbut ≤5x  
Yes 
Yes 
No 
No 
>5x ULN 
No 
No 
No 
No 


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IRB Protocol 
 
                           IRB#: 06-103 A(17) 
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* ARM A: LFTs should be drawn prior to treatment on week 1, week 3, and week 5 of 
cycle 1 and again prior to treatment on week 1 and week 5 of every subsequent cycle 
beginning with cycle 2 (ie. minimum of every 4 weeks).  If LFTs are drawn prior to 
treatment on week 3, the above LFT treatment parameters must still be met.  Both 
AST and ALT should be drawn. If LFTs are abnormal prior to any treatment, they 
should be drawn prior to the next docetaxel treatment. The more abnormal of the two 
values (AST or ALT) should be used in determining the dose of docetaxel.   
* ARM B: LFTs should be drawn prior to each 3-week cycle 
 
Patients with alkaline phosphatase elevation secondary to the bony metastases rather than liver 
dysfunction may proceed with treatment on protocol after discussion with the principal 
investigator. If above parameters are not met, hold until recovered, maximum 28 days, then re-
treat as per section 9.3.2 Dose Delays and Modifications.  “Recovered” is defined as meeting the 
treatment parameters for #2 above with the exception that the ANC must be at least 1500/mm3 
(ANC > 1500/mm3). 
9.3.2  Chemotherapy Dose Delays and Modifications 
Chemotherapy will be held for grade 3 or 4 non-hematologic toxicity (with the exception of 
grade 3 electrolyte abnormalities) or for not meeting treatment parameters as described above on 
the day of treatment.  If the toxicity has resolved and the patient meets treatment parameters but 
experienced interval toxicity, then for the purposes of determining dose reductions, the grade of 
toxicity should be that seen despite maximal medical management (i.e. intensive loperamide or 
tincture of opium for diarrhea).  If multiple toxicities are seen the dose administered for a 
particular drug should be based on the most severe toxicity noted.  In general, when multiple 
toxicities are experienced that can result in the dose reduction of multiple drugs, reducing 
multiple drugs at one time is the preferred approach.   Treatment may resume when the toxicity 
has resolved to < grade 2, except as indicated below. 
 
Generally, when therapy is held for chemotherapy related toxicity, all three drugs (cisplatin, 
docetaxel, and fluorouracil) will be held.  For hepatotoxicity, docetaxel alone should be held (ie. 
Total bilirubin > ULN but < 2x ULN, and AST/ALT and Alkphos as per table above) and 
cisplatin and fluorouracil may continue without treatment delay.  For an elevated creatinine or 
for ototoxicity (see below criteria), cisplatin alone may be held and the patient may continue with 
docetaxel and fluorouracil without treatment delay.  If all three drugs are held for more than 4 
weeks for toxicity, patients will be taken off study, unless there is a clinical benefit. If there is a 
clinical benefit, patients may be retreated at a lower dose after resolution of toxicity to ≤ NCI-
CTCAE v3.0 grade 2, except as indicated below.  Cisplatin, docetaxel, and fluorouracil may each 
be dose attenuated, either in combination, or individually.   
 
 
 
 
 
 


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                           IRB#: 06-103 A(17) 
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ARM A: CHEMOTHERAPY DOSE ATTENUATION TABLE 
 
Dose level 0 (mg/m2) 
Dose level -1 (mg/m2) 
Dose level -2 (mg/m2) 
Docetaxel 
40 
30 
20 
Cisplatin 
40 
30 
20 
Fluorouracil (IVP)/ 
Leucovorin 
400/ 400 
300/ 300 
200/ 200 
Fluorouracil IVCI / day 
1000 
800 
600 
 
ARM B: CHEMOTHERAPY DOSE ATTENUATION TABLE 
 
Dose level 0 (mg/m2) 
Dose level -1 (mg/m2) 
Dose level -2 (mg/m2) 
Docetaxel 
75 
60 
50 
Cisplatin 
75 
60 
50 
Fluorouracil IVCI / day 
750 
600 
500 
 
Dose attenuations will be based on toxicity as described below: 
Neutropenia 
 Docetaxel dose attenuation by one dose level may occur for any treatment delay due to 
neutropenia (i.e. ANC < 1000 /cc on a treatment day following Cycle 1 Week 1).   
 For ARM A,, Neulasta or Neupogen (GCSF) should be given for subsequent treatments 
following any treatment delay due to neutropenia if a dose reduction is not required and 
not pursued.  The recommended treatment is Neulasta 6 mg subcutaneously on day 3, day 
4, or day 5 of the treatment cycle or neupogen (GCSF) for 3 to 5 days from day 9 to day 
13. 
 Grade 3 and Grade 4 neutropenia with recovery prior to next planned cycle do not require 
a dose attenuation in docetaxel with the following exceptions:  
 Grade 4, afebrile neutropenia ≥ 7 days 
 Grade 3 or 4 neutropenia associated with fever (one reading of oral temperature > 38.5° 
C, or three readings of oral temperature > 38.0° C in a 24-hour period)   
 Cisplatin and fluorouracil may be dose attenuated by one dose level at the treating 
physicians’ discretion in addition to docetaxel dose attenuation, particularly with 
persistent delays due to neutropenia. 
 
Thrombocytopenia 
 For treatment delay due to thrombocytopenia (i.e. platelet count < 75,000/cc), reduce 
docetaxel by one dose level. 
 For any platelet count of < 50,000/cc, reduce docetaxel by one dose level. 
 
Nausea/Vomiting 
 Grade 1 nausea/vomiting does not require a dose reduction or treatment delay. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 Grade 2 nausea/vomiting – hold treatment for 1 week.  Reduce cisplatin by 1 dose level 
for persistent grade 2 nausea/ vomiting (eg. lasting for more than 5 days). 
 For Grade 3 or 4 nausea/ vomiting, reduce cisplatin dose by one dose level.  Docetaxel 
and fluorouracil may also be dose attenuated by one dose level at the treating physicians 
discretion. 
 
Anorexia 
 Grade 1 or 2 anorexia does not require a dose reduction 
 For grade 3 or 4 anorexia, reduce cisplatin and docetaxel by one dose level. 
 
Stomatitis 
 
If stomatitis is present on day 1 of any cycle, treatment should be held until the stomatitis 
has resolved.   
 
For ARM A: 
o If stomatitis is ≤ grade 1 prior to treatment #2 or #3 of any cycle, treat at current 
dose. 
o For interval grade 2 stomatitis prior to treatment #2 or #3, reduce fluorouracil 
infusion by one dose level without treatment delay.  For a subsequent grade 2 
stomatitis event, reduce docetaxel by one dose level. 
 For ARM B: 
o For interval grade 2 stomatitis that completely resolves prior to the next cycle, 
reduce fluorouracil infusion by one dose level without treatment delay. For a 
subsequent grade 2 stomatitis event, reduce docetaxel by one dose level. 
 If Grade 3 or 4 stomatitis occurs at any time, hold chemotherapy until resolution to < 
grade 1, and then retreat with docetaxel and fluorouracil each reduced by one dose level. 
 
Neurotoxicity 
 
If neuropathy ≥ grade 2 is present on day 1 of any cycle, treatment should be held until 
neuropathy improves to ≤  grade 1.  
 
For ARM A (treatment #2 and 3 of each cycle): 
o If neuropathy is ≤ grade 1 on treatment #2 or #3 of any cycle, treat at current dose 
of all chemotherapy drugs. 
o If neuropathy is grade 2 on treatment #2 or #3, reduce docetaxel by one dose level 
and treat without delay. 
 
For ARM B (treatment #2 of each cycle): 
o If neuropathy is < grade 1 on treatment #2, treat at current dose of all 
chemotherapy drugs. 
o If neuropathy is grade 2 on treatment #2, reduce docetaxel by one dose level and 
treat without delay. 
 
For Grade 3 or 4 neuropathy, treatment should be held until neuropathy returns to grade < 
1. Reduce cisplatin and docetaxel each by one dose level. 
 
Kidney 
 Serum creatinine must be < 1.5 mg/dl to initiate therapy 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 For each subsequent treatment, the serum creatinine must be < 1.8 mg/dl to continue 
treatment at the current dose level. 
 If serum creatinine is > 1.8 but < 2 mg/dl, administer cisplatin at a single reduced dose 
level. A treatment delay is not required. Subsequent treatments may occur without further 
cisplatin dose attenuation if the serum creatinine remains stable at > 1.8 but < 2 mg/dl. 
 If serum creatinine is > 2.0 mg/dl, cisplatin will be held. Docetaxel and fluorouracil may 
be administered without treatment delay at the treating physicians discretion. 
 Up to a 6-week treatment delay in cisplatin will be allowed. If the serum creatinine has 
not returned to less than 2.0 mg/dl within 6 weeks, then cisplatin will be discontinued. 
 Patients should be euvolemic for the determination of serum creatinine.  
 If the value of the serum creatinine is >1.8 mg/dl the value may be confirmed by a 
second serum creatinine after hydration. Treatment may resume within the next day. 
 Creatinine clearance will not be used for dose adjustments. 
 
Diarrhea 
 Grade 1 diarrhea dose not require treatment delay or dose reduction. 
 For grade 2 diarrhea, hold treatment by 1 week. 
 For grade 3 or 4 diarrhea, reduce fluorouracil by 1 dose level.  Cisplatin may be dose 
reduced as well, at the treating physicians discretion. 
 
 
Ototoxicity 
 For grade 1 or 2 ototoxicity, no dose reduction in cisplatin is required. 
 For grade 3 or 4 ototoxicity, hold cisplatin until it resolves to < grade 1, and then resume 
therapy with cisplatin dose reduced by one dose level. 
 
Trastuzumab related cardiac dysfunction: 
 
Symptomatic CHF 
 
 Hold trastuzumab, refer to cardiology for treatment  (e.g., ACE inhibitors, angiotensin-II 
receptor blockers, β-blockers, diuretics, and cardiac glycosides).  
 If the symptoms of CHF resolve with treatment, and cardiac function improves, 
trastuzumab may be continued after discussion with the patient concerning the risks and 
benefits of continued therapy. If the patient is benefiting clinically from trastuzumab, the 
benefit of continued treatment may outweigh the risk of cardiac dysfunction.   
 If trastuzumab is restarted, cardiac function should be monitored with echocardiogram 
every cycle 
 
Asymptomatic drop in LVEF 
 Trastuzumab may be continued in patients experiencing an asymptomatic absolute 
decrease in LVEF of <20 percentage points from baseline, when the ejection fraction 
remains ≥ 50%.  Such patients should be monitored with echocardiograms every cycle.   


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 Patients with an asymptomatic absolute decrease in LVEF of ≥20 percentage points or 
ejection fraction < 50%, should have trastuzumab held.   Consider cardiology referral for 
treatment of incipient CHF.   
 If trastuzumab is discontinued for an asymptomatic decline in LVEF, a repeat 
echocardiogram will be obtained in 1 month to determine if the decline has resolved. 
 If cardiac function improves, trastuzumab may be restarted after discussion with the 
patient concerning the risks and benefits of continued therapy.  If the patient is benefiting 
clinically from trastuzumab , the benefit of continued treatment may outweigh the risk of 
cardiac dysfunction.   
 
Hypersensitivity Reactions 
 Trastuzumab treatment should be discontinued for Grade 4 hypersensitivity reactions.  
There are no dose reductions for hypersensitivity reactions. 
 Docetaxel treatment should be discontinued for Grade 4 hypersensitivity reactions.  There 
are no dose reductions for hypersensitivity reactions. 
 
MANAGEMENT OF ACUTE HYPERSENSITIVITY 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized 
cutaneous reactions such as mild 
pruritus, flushing, rash 
· 
consider decreasing the rate of infusion until recovery from 
symptoms, stay at bedside and monitor patient 
· 
then, complete Taxotere infusion at the initial planned rate 
Moderate symptoms: any 
symptom that is not listed above 
(mild symptoms) or below 
(severe symptoms) such as 
generalized pruritus, flushing, 
rash, dyspnea, hypotension with 
systolic  
BP > 80 mm Hg  
 
· 
interrupt Taxotere infusion 
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until resolution of 
symptoms  
· 
resume Taxotere infusion after recovery of symptoms; 
depending on the physician’s assessment of the patient, 
Taxotere infusion should be resumed at a slower rate, then 
increased incrementally to the initial planned rate, (eg. 
infuse at a 4-hour rate for 3 minutes, then at a 2-h rate for 
3 minutes, then at a 1-h rate for 3 minutes, then finally, 
resume at the initial planned rate. 
· 
depending on the intensity of the reaction observed, 
additional oral or IV premedication with an antihistamine 
should also be given for the next cycle of treatment, and the 
rate of infusion should be decreased initially and then 
increased back to initial planned rate, (eg. infuse at a 4-hour 
rate for 3 minutes, then at a 2-h rate for 3 minutes, then at a 
1-h rate for 3 minutes, and finally, administer at the initial 
planned rate.) 
Severe symptoms: any reaction 
such as bronchospasm, 
generalized urticaria, systolic BP 
≤ 80mm Hg, angioedema 
· 
immediately discontinue Taxotere infusion  
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as needed; 
monitor patient until resolution of symptoms 
· 
the same treatment guidelines outlined under moderate 
symptoms (i.e. the third and fourth bullets) should be 
followed. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Anaphylaxis (NCI CTCAE v. 3.0 
grade 4 reaction) 
· 
NO FURTHER STUDY DRUG THERAPY 
 
Fluid Retention 
 There are no dose reductions for fluid retention. 
 Patients developing new onset edema or ascites, progression of existing edema or ascites, 
or another sign of fluid retention (eg. 2 pound weight gain) are to be treated with oral 
diuretics.  Regimens found to be effective in the management of fluid retention due to 
docetaxel are listed below: 
o 
Triamterene/hydrochlorothiazide one capsule po qd up to tid. 
o 
Furosemide 40 mg po daily if edema progresses despite 
Triamterene/hydrochlorothiazide therapy.  Potassium supplementation should be 
given as needed. 
o 
If after a two-week trial, furosemide 40 mg po qd is ineffective, the patient may 
be treated with furosemide 20 mg po daily plus metolazone 2.5 mg po daily with 
potassium supplementation as needed. 
 Further diuretic therapy should be customized depending upon the clinical situation.  The 
clinical tolerance of the patient, the overall tumor response and the medical judgment of 
the investigator will determine if it is in the patient’s best interest to continue or 
discontinue treatment.  
 
Hyperlacrimation 
 The following guidelines may be taken for patients experiencing clinically significant 
hyperlacrimation: 
 Dose reduction in fluorouracil treatment. 
 Withhold docetaxel treatment until resolution. 
 Frequent instillation of artificial tears. 
 Steroid ophthalmic solution starting the day before docetaxel administration in patients 
without a history of herpetic eye disease. 
 Ophthalmologist consult. 
 
If a dose attenuation is required in any chemotherapy drug that is already at dose level -2, the 
other chemotherapy drugs may be reduced by one dose level instead.  For cumulative toxicity, 
cisplatin, fluorouracil, leucovorin or docetaxel may be discontinued following discussion with 
the protocol principal investigator.  If more than one grade 3 or 4 event occurred, then the 
chemotherapy to be dose attenuation should be that of the most severe toxicity. 
 
For patients experiencing intolerable toxicity based on the treating physician’s clinical 
assessment, individual chemotherapy doses may be attenuation following consultation with the 
Principal Investigator.  
 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
9.4  CORRELATIVE STUDIES 
9.4.1 To bank tumor biopsy material for future planned correlative studies for association with 
chemotherapy efficacy and survival. 
 
We plan to store pre-therapy paraffin embedded tumor tissue for future tissue based correlative 
studies.  We will plan to examine this tissue bank by immunohistochemistry if markers for 
disease sensitivity or resistance to docetaxel based therapy is identified in ongoing trials.  Any 
IHC studies performed will be selected for based on clinical significance, feasibility, and 
reproducibility, in conjunction with a reference pathologist (eg. Laura Tang, MD PhD).  We will 
not require new tissue procurement for research purposes.  Prior to tissue use, we will submit a 
proposal for approval by the MSKCC Human Tissue Utilization Committee.  
 
HER2 testing will be performed in all patients to better characterize HER2-positive gastric 
cancer in US patients.  HER2 testing will be performed by the MSKCC diagnostic molecular 
laboratory on banked tumor specimens from the patients currently enrolled on the protocol and 
prospectively on all the patients screened for protocol participation.  FISH is performed using 
FDA-approved ERBB2 (HER2/NEU) PathVysion assay probes and procedure (Abbott-Vysis). 
IHC staining is performed using FDA-approved anti-Her2/neu Ventana’s PATHWAY rabbit 
monoclonal primary antibody (clone 4B5) directed against the internal domain of the c-erbB-2 
oncoprotein (Her2).  Biopsy samples with cohesive IHC3+ or FISH+ clones are considered  
HER2 positive irrespective of size, i.e.<10%.  FISH+ defined as >2 HER2:CEP17. 
Tissue samples for HER2 testing will be processed locally in the laboratory of investigational 
sites. The results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of HER2 status. 
MSK pathology review will not be required to begin therapy on the protocol.   Samples provided 
to the MSK laboratory must either be HER2 IHC slides, or  if FISH confirmation is necessary, a 
paraffin block(s) of adequate size to allow if possible for at least 5 slides with cuts that are 5-
microns thick or if a paraffin block is not available, then if possible at least 5 slides with cuts that 
are 5-microns thick will be acceptable. Archived or fresh tumor samples may be used. 
9.4.2 FDG-PET Response Assessment 
 
The primary aim of this correlative study is to examine the ability of an early FDG-PET/CT scan 
to predict treatment efficacy.  By identifying patients who are progressing early, patients 
exposure to cytotoxic therapy that is of no therapeutic value can be limited and the associated 
toxicity can be reduced.  As seen in patients who received preoperative chemotherapy, a 
significant drop from baseline in FDG uptake is associated with an improved pathologic 
treatment response and improved disease free survival (see Section 3.5.2).  However, the 
challenge in patients with locally advanced, but potentially curable disease is that surgery does 
cure some patients.  Thus, some patients who have a poor FDG-PET response, and an associated 
poor histopathologic tissue response, may still be cured with surgical resection of their tumor.  
However, for patients with metastatic or unresectable disease, this is not true.  Specifically, we 
hypothesize that patients with a good FDG-PET response will have RECIST evidence of 
response at their routine imaging time point and have a longer time to disease progression, when 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
compared with patients with a poor FDG-PET response.   If successful, we would be able to 
identify patients who are not benefiting from current therapy early, thereby allowing patients to 
minimize toxicity by minimizing exposure to ineffective therapy. 
 
To examine this further, we will perform a 2nd FDG-PET/CT scan on patients with FDG-avid 
primary tumors.  This 2nd scan will be performed during week 3 (following the day 15 treatment, 
but before week 4 of ARM A, and prior to the 2nd cycle of ARM B) at participating centers.  The 
PET/ CT scan is done with the patient fasting for about four to six hours, but water for hydration 
is allowed. Imaging starts about one hour after intravenous injection of a standard dose of F18-
FDG (8 to 15 mCi). Oral CT contrast is also administered for better delineation of the stomach 
and GI tract. 
 
Collaborating sites will specify at the time of study initiation if they will obtain the week 3 
PET/CT scans on all patients who have informative PET/CT scans at baseline.   
 
A low dose spiral CT is performed first, followed by acquisition of the PET images (emission 
scans only), of the neck, chest, abdomen and pelvis. The total radiation dose involved is about 1 
rem (0.5 rem from the CT and 0.5 rem from the PET).  Attenuation correction of the PET/CT 
images is then performed using the CT data. The final PET and CT image data sets are displayed 
on the fusion software for evaluation. 
 
FDG-PET/CT Data Analysis:  All images will be reviewed by a nuclear medicine physician 
independently and entered into separate data sheets.  The PET/CT images will be reviewed in all 
standard planes (3-dimensional computer display) and a maximum intensity projection. The 
images will be reviewed together with the CT and the fusion images.  Visual analysis of PET/CT 
data requires the definition of abnormal radiotracer uptake as being greater than background 
activity (on the attenuation corrected images) and outside of normal anatomic structures, which 
frequently exhibit various amount of FDG uptake (e.g., ureter, urinary bladder, bowel loops). 
Individual lesions will be graded on a scale of zero to four where 0 = definitely normal, 1 = 
probably benign, 2 = equivocal, 3 = probably malignant and 4 = definitely malignant. 
Semiquantitative analysis of tracer uptake, i.e. the standardized uptake value (SUV) will be done 
for lesions identified in the visual analysis by positioning of regions of interest (ROI) 
surrounding them. The SUV will then be calculated as below and entered into the data sheet (see 
Appendix D).  The baseline SUV value for statistical analysis will be the maximum-pixel SUV 
detected of the primary tumor.  SUVBW = decay corrected activity (mci/ml)/ injected dose (mCi)/ 
body weight (kg) 
 
9.4.3 Pharmacology and Pharmacodynamics (MSKCC patients only) 
Docetaxel is both a substrate and inhibitor of the cytochrome p450 enzyme CYP3A4, and its 
metabolism can be inhibited by CYP3A4 inhibitors such as ketoconazole, erythromycin, 
verapamil and diltiazem.  Importantly, both aprepitant and palonesetron, recently approved anti-
emetic agents for the treatment of acute and delayed nausea, are both inhibitors of CYP3A4. 
Similarly, we hypothesize that inhibition of CYP3A4 by these anti-emetic agents would result in 
reduced docetaxel metabolism, increased drug exposure, and potentially increased toxicity.  


Memorial Sloan-Kettering Cancer Center 
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Pharmacokinetic blood draws will occur in patients enrolled at MSKCC only.  We will perform 
serial blood draws in approximately 20 patients (10/ arm) at the following times: 
 
1. 0.25 hours (15 min following initiation of docetaxel) 
2. 0.75 hours (45 min following initiation of docetaxel) 
3. 1 hour 
(end of docetaxel infusion) 
4. 1.25 hours  (15 min following the completion of docetaxel) 
5. 2 hours 
6. 4 hours 
7. 6 hours 
8. 8 hours 
9. 24 hours 
 
Additionally, on day 3, a CBC with differential and LFT’s (AST, ALT, Alk Phos, total Bilirubin) 
will be drawn in each of these patients.  For Arm A, these lab studies will be drawn prior to 
cisplatin administration.   
 
Amendment March 2008:  
In our initial pharmacokinetic analysis, we noted a suggestion of a difference in docetaxel 
pharmacokinetics when co-administered with cisplatin (Arm B) or without cisplatin (Arm A). 
Pharmacokinetic data are available preliminarily on 13 patients: 8 patients who were randomized 
to parent DCF (Arm B) in which cisplatin and docetaxel are co-administered on day 1, and 5 
patients who were randomized to mDCF(Arm A) in which cisplatin is administered on day 3 and 
docetaxel is administered on day 1, and . In Arm B, when cisplatin is given concurrently with 
docetaxel, dose adjusted docetaxel PK are as follows:  
AUC∞ 74.1 ng*hr/ml/mg/m2 
CL 28.9 L/hr/m2 
Vdss 27.8 L/m2 
T1/2 18.8 hr 
 
When docetaxel is given on day 1 and cisplatin is given on day 3 (mDCF), dose adjusted 
docetaxel PK are as follows:  
AUC∞ 46.1 ng*hr/ml/mg/m2 
CL 38.1 L/hr/m2 
Vdss 17.1 L/m2 
T1/2 12.1 hr 
These results appear to demonstrate that the clearance of docetaxel is reduced when it is 
administered on day 1 with cisplatin (Arm B), and this is associated with an increased exposure 
to docetaxel.  Conversely, when docetaxel is administered on day 1 and cisplatin is administered 
on day 3, docetaxel clearance appears to be higher and is associated with a lower AUC∞.  Recall 
that our hypothesis is that reduced clearance and higher exposure to docetaxel may be 
responsible for some of the increased toxicity observed with the parent DCF (Arm B) regimen.   
 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
We would like to expand on these initial findings.  Specifically, in up to 6 patients randomized to 
the parent DCF arm (Arm B), in addition to performing docetaxel pharmacokinetics with cycle 1 
treatment (as is already specified in the protocol), we would subsequently repeat docetaxel 
pharmacokinetics for a single cycle when cisplatin is not administered on the same day as 
docetaxel.  For example, for a single subsequent cycle, we would plan to administer cisplatin on 
a later date (i.e. day 3) and repeat docetaxel pharmacokinetic sampling.  Subsequent therapies 
would be as per protocol specification.   
 
9.4.4 Volumetric CT Analysis of Response to Therapy 
 
At MSKCC only and in collaboration with Larry Schwartz, MD, we will also initiate an 
exploratory volumetric CT analysis of Response to therapy.  This study will make use of already 
acquired image data from this clinical trial. No additional human material or CT scans will be 
needed.  The standard CT scan data (acquired either during PET/CT scanning or CT scanning) 
will be electronically transferred, via the hospital network, from the hospital PACS to the 
research PACS server, where patient identification information are de-identified.  Volumetric CT 
will be used in an exploratory way to assess tumor response during therapy to compare with 
RECIST.  The volumetric analysis, however, will not affect patient care and will not be 
communicated to the patient or clinical investigator.  To study effects of a wider range of slice 
thickness on the performance of the segmentation algorithms and reproducibility of tumor 
measurements, thinner section CT images will be reconstructed with CT raw data acquired for 
the radiographic assessment in the trial.  The volumetric CT technique used in this study may be 
able to detect asymmetric or small change in tumor size at the level that may not be possible with 
the conventional uni-dimensional RECIST criteria.   
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
The table below describes the the study plan


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TABLE 4.  STUDY CALENDAR  
 
 
Cycle 1 
Cycle 2 
Cycle 
3 (a) 
Off 
Study 
(j) 
 
 
Pre-
Study 
Wk 1 
Wk 2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
 
Day Number 
 
1 
8 
15 
22 
29 
35 
42 
49 
56 
63 
70 
77 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Radiology (i) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
FDG-PET/CT (m) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Audiology Exam (k) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC QLQ-C30 (n) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Pharmacology (l) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ARM A - mDCF 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
Toxicity check 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signs, Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance Status 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
CBC w/ diff, Plts 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistry (b) 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
BUN, Creatinine (c) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
LFTs (d) 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
Total protein, LDH, Alb, 
Ca, Mg, PO4, tumor 
markers (e) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Echocardiogram/MUGAo 
X 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
ARB B -  
DCF + G-CSF 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Toxicity check 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs, Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CBC w/ diff, Plts 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Comprehensive (g) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
a Continues as per cycle 2, except the physical exam may be performed at the beginning of every cycle and as necessary 
and the toxicity check will be performed prior to the week 1 and 5 treatment of every subsequent cycle, and as needed. 
b Bicarbonate, BUN, chloride, creatinine, glucose, potassium, sodium   
d AST (SGOT), ALT (SGPT), Total Bilirubin, Alkaline Phosphatase.  Any abnormal LFTs require repeat LFTs prior to 
subsequent docetaxel therapy. Patients with alkaline phosphatase elevation secondary to the bony metastases rather than 
liver dysfunction may proceed with treatment on protocol after discussion with the principal investigator.  
 
b, c, d, e, f, g  May be performed on or within 1 day of treatment e Tumor markers as available. 
g Comprehensive = serum chemistry + LFTs + total protein, LDH, alb, Ca, Mg, PO4, and tumor markers as available. 
h For women of childbearing potential  i Includes CT of the chest, abdomen and pelvis within 30 days and a PA and lateral chest x-
ray unless a CT of the chest is available within 14 days of starting therapy. Tumor measurements are repeated after every cycle for 
the first 6 cycles and every 2 cycles thereafter.  May be performed earlier at physician discretion.  Radiologic documentation of 
progression is strongly recommended. j Patients will be monitored for overall survival following completion of study. Maybe 
performed by local physicians. k As clinically indicated, l Pharmacokinetic blood draws for MSKCC patients as per section 9.4.3.  m 
FDG-PET/CT scans are performed at baseline, and again during week 3 (following treatment #2 in ARM A, before treatment #2 in 
ARM B), participating sites only.  n EORTC QLQ-C30 is administered at baseline, 6 weeks, 3 months, 6 months, 9 months, and 12 
months.oFor patients receiving trastuzumab only, echocardiogram/MUGA will be done at baseline and every 12 weeks while on 
protocol.. 
 
 
10.1  FOR PARTICIPATING SITES  


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 
Tissue samples for HER2 testing will be processed locally in the laboratory of investigational 
sites. The results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of HER2 status. 
MSK pathology review will not be required to begin therapy on the protocol.   Samples provided 
to the MSK laboratory must either be HER2 IHC slides, or  if FISH confirmation is necessary, a 
paraffin block(s) of adequate size to allow if possible for at least 5 slides with cuts that are 5-
microns thick or if a paraffin block is not available, then if possible at least 5 slides with cuts that 
are 5-microns thick will be acceptable. Archived or fresh tumor samples may be used. 
 
Shipping of Specimen(s):  
 
All sites should ship specimens to MSKCC Principal Investigator: 
Yelena Y. Janjigian 
Memorial Sloan-Kettering Cancer Center 
300 E 66th Street BAIC 1033 
New York, NY 10065  
 
• Shipments should be batched. 
• A copy of the pathology report and patient signed informed consent should be included with 
the shipment. 
• At the time of shipment, a transmittal documenting patient ID and type 
of specimen sent should also be electronically submitted to janjigiy@mskcc.org and faxed to the 
Multicenter Core Project Coordinator (646-227-2482) 
• Shipments will not be received on Saturday or Sunday 
 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 CISPLATIN 
Cumulative nephrotoxicity associated with cisplatin is severe. Other major dose-related toxicities 
are myelosuppression, nausea and vomiting. Ototoxicity, manifested by tinnitus and/or high 
frequency hearing loss, is significant. Anaphylactic like reactions to cisplatin have been reported. 
Facial swelling, bronchospasm, tachycardia and hypotension may occur within minutes of 
cisplatin administration. Other side effects include anorexia, diarrhea, serum electrolyte 
disturbances (e.g., hyponatremia, hypomagnesemia), vascular toxicities (e.g., myocardial 
infarction, cerebrovascular accident etc.), renal insufficiency, neurotoxicity, peripheral 
neuropathy, autonomic neuropathy, muscle cramps, ocular toxicity (optic neuritis, papilledema, 
cerebral blindness), and hepatotoxicity. Other rare side effects include cardiac abnormalities, 
hiccoughs, elevated serum amylase, rash and alopecia. Local soft tissue injury has been reported 
following extravasation of cisplatin.  A complete list of toxicities can be found in the package 
insert. 
 


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                           IRB#: 06-103 A(17) 
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11.2 DOCETAXEL 
Principal adverse effects include neutropenia, thrombocytopenia, anemia, nausea, vomiting, 
diarrhea, ascites, mucositis, cardiac arrhythmias, hypotension, pleural effusion, peripheral 
neuropathy, rash, severe nail disorders (hypo or hyperpigmentation), onycholysis (loosening of 
the nails), alopecia, palmar-plantar dyserythroesthesia, hypersensitivity reaction, fatigue and 
fluid retention syndrome (may be irreversible). 
11.3 FLUOROURACIL 
Hematologic and gastrointestinal side effects are most frequently associated with fluorouracil. 
Hematologic toxicities of fluorouracil are leukopenia, granulocytopenia (9-14 days), 
thrombocytopenia (7-14 days), and anemia. Stomatitis, gastrointestinal ulceration and bleeding, 
and diarrhea are commonly seen gastrointestinal side effects of fluorouracil. Nausea and 
vomiting, effects on the skin including rashes and hyperpigmentation, alopecia, ocular irritation, 
central neurotoxicity (notably cerebellar ataxia), and myocardial ischemia have been reported. A 
complete listing of toxicities can be found in the fluorouracil package insert. 
11.4 LEUCOVORIN 
The only adverse reaction for leucovorin is a rare report of allergic reactions to parenteral 
injections of leucovorin. This is extremely uncommon. 
11.5 TRASTUZUMAB 
Principal adverse effects include cardiac dysfunction, infusion associated symptoms, potentiation 
of chemotherapy related hematologic side effects. A complete listing of toxicities can be found 
in the trastuzumab package insert. 
 
11.6 SUPPORTIVE MEDICATIONS 
G-CSF: common side effects include nausea, vomiting, bone pain, injection site irritation and 
influenza-like illness.  Rare side effects include vasculitis of the skin, and very rarely, acute 
respiratory distress syndrome and splenic rupture have been reported. 
Decadron: with chronic use, common side effects include hypertension, atrophic skin, impaired 
skin healing, hypercortisolism and primary adrenocortical insufficiency, irritation of the GI tract, 
increased risk of infection, osteoporosis, cataracts or glaucoma, and depression or euphoria. 
Hyperglycemia is common even with single use.   


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                           IRB#: 06-103 A(17) 
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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT  
For the purposes of this study, patients should be re-evaluated for response every cycle of 
chemotherapy, for the first 6 cycles of therapy. For patients remaining on therapy thereafter, 
patients are to be re-evaluated every 2 cycles of therapy. In addition to a baseline scan, 
confirmatory scans should also be obtained > 4 weeks following initial documentation of 
objective response. 
12.1 DEFINITIONS 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. Note:  Lesions are either measurable or non-
measurable using the criteria provided below. The term “evaluable” in reference to measurability 
will not be used because it does not provide additional meaning or accuracy. 
12.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as > 20 mm with conventional techniques (PET, CT, 
MRI, x-ray) or as > 10 mm with a high-resolution CT scan.  All tumor measurements must be 
recorded in millimeters or decimal fractions of centimeters.  A “high-resolution” CT scan is one 
in which images are recorded at least every 5 mm. 
12.1.2 Non-Measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 20 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural / pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable.  Stomach, GEJ, or esophageal wall 
thickening is considered non-measurable. 
12.1.3 Target lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
12.1.4 Non-target lesions 
All other lesions (or sites of disease) that are not target lesions as defined in section 12.1.3 will 
be identified as non-target lesions and should also be recorded at baseline.  Non-target lesions 
include measurable lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions.  Measurements of these lesions are required when 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
feasible, since a patient may have progressive disease on the basis of larger non-target lesions. 
The presence or absence of each non-target lesion should be noted throughout follow-up. 
12.2 EVALUATION OF TARGET LESIONS 
Complete Response (CR):  Disappearance of all target lesions. Endoscopy must be without 
evidence of tumor with negative cytologic brushings and esophageal biopsies. The patient must 
be free of all symptoms of cancer.  
Partial Response (PR):  At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions taking as reference the baseline sum LD.  Positive washing, brushing or biopsy and/or 
residual tumor may still be evident on endoscopy and/or CT scan. No lesion may increase in size 
and no new lesion may appear. 
Progression (PD):  At least a 20% increase in the sum of LD of target lesions taking as reference 
the smallest sum LD recorded since the treatment started or the appearance of one or more new 
lesions. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum LD. 
12.3 EVALUATION OF NON-TARGET LESIONS 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Non-Complete Response (non CR):  Persistence of one or more non-target lesions or/ and 
maintenance of tumor marker level above the normal limits. 
Progression (PD):  Appearance of one or more new lesions. Unequivocal progression of existing 
non-target lesions. (Although a clear progression of "non-target" lesions only is exceptional, in 
such circumstances, the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the reference radiologist (or study chair). 
Note:  
1. If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
2. Cytology and histology:  If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology if possible. These 
techniques can be used to differentiate between PR and CR in rare cases (eg. residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain). The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for 


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                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
12.4 EVALUATION OF BEST OVERALL RESPONSE 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.  
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
1.  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration". Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
2.  In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 
12.5 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
Note:  Tumor lesions in a previously irradiated area are not optimally considered measurable 
disease.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17) 
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• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
• 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to the chest, abdomen, and pelvis. Head & neck 
and extremities usually require specific protocols. 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions that are clinically not easily accessible. It is 
a possible alternative to clinical measurements of superficial palpable nodes, 
subcutaneous lesions, and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination. 
 
12.6 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation:  The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed.  In cases where confirmation of response is not feasible, it should be 
made clear when reporting the outcome of such studies that the responses are not confirmed.  To 
be assigned a status of PR or CR changes in tumor measurements must be confirmed by repeat 
studies that should be performed 4 weeks after the criteria for response are first met. In the case 
of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 8 weeks. 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented, taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
13.1 DURATION OF THERAPY / CRITERIA FOR REMOVAL FROM STUDY 
In the absence of serious toxicity or complications, all patients will receive at least one cycle of 
treatment.  In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
• 
Disease progression, defined as  
(1) Appearance of a tumor > 1 cm in size at a new site, or 
(2) Reappearance of a previously completely resolved measurable tumor  
 
 
or lesion, or 
(3) An increase in tumor measurements (total longest diameter) > 20%. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
(4) New sites of or clinical progression in non-measurable sites of disease 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), including but not limited to 
(1) grade 4 anaphylaxis 
(2) grade 4 hypertension, hemorrhage, or symptomatic grade 4 venous thromboembolism 
(3) any grade arterial thromboembolic event 
(4) grade 4 proteinuria 
(5) GI perforation or wound dehiscence (requiring medical or surgical therapy) 
• 
Patient death, 
• 
Patient decides to withdraw from the study or is lost to follow up, or 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
Patients will be discontinued from the study if they exhibit any of the following: 
• 
Dose limiting toxicity (not resolving) possibly, probably, or definitely attributable to the 
investigational agent: any Grade 3 or greater non-hematological event that does not recover 
to < grade 1. Nausea and vomiting will be dose limiting only if grade 3 despite adequate 
premedication. If a patient develops dose-limiting toxicity then the drug will be withheld 
until toxicity resolves to < grade 1, and restarted at a lower dose (Section 9.3).  
 
• 
In addition, if a patient develops an adverse experience that the Investigator feels is severe 
enough to preclude further participation, the patient will be discontinued from the study and 
receive medical treatment as determined by the Investigator.  The patient will remain under 
observation until the adverse experience is resolved.   
 
Patients will be discontinued from the study if they exhibit any of the following: 
• 
Lack of cooperation with the requirements of the study 
• 
Intercurrent illness requiring medication not allowed by the protocol 
• 
Withdrawal of consent 
The patient’s physician(s) are free to and should discontinue study treatment if this is believed to 
be in the patient’s best interest.  Furthermore, a patient is free to withdraw from study treatment 
and participation at any time for any reason.  Full documentation of the reasons and 
circumstances of all patients who withdraw must be documented in the medical record and on 
the appropriate case report forms. 
13.2  OFF-STUDY EVALUATION 
• History and physical examination, including performance status and neurological exam. 
• Laboratory: Complete blood counts and chemistry tests as required at baseline 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
• Tumor Measurements: Assessment of at least one measurable lesion (in appropriate 
patients) preferably by CT scan unless within 4 weeks of last measurements. 
• Patients will be monitored for overall survival following completion of or removal from 
the study. 
14.0 
BIOSTATISTICS 
The study will be an open-label random assignment phase II therapeutic clinical trial.  The study 
population will be patients with histologically confirmed unresectable or metastatic gastric or 
gastroesophageal adenocarcinoma.  Arm A will be modified DCF and ARM B will be ‘parent’ 
DCF with growth factor support. 
The primary endpoint for both arms is progression free survival (PFS), as measured from the 
start of the treatment to the date of either documentation of disease progression or death.  We 
will define progression of disease as per RECIST criteria.  Patients with measurable disease and 
with evaluable radiographically but non-measurable disease will be eligible for study entry.  As 
per RECIST criteria, any evidence of progression in non-measurable lesions, measurable lesions, 
or the development of new lesions, would qualify as disease progression.  The 6 month 
progression free survival for 'parent' DCF is approximately 43% (see Section 3.3.2).  Using this 
as a benchmark, we propose declaring each regimen comparable to parent DCF if the 6 months 
PFS exceeds 43%, and unworthy of further investigation if it is 26% or less. Each arm will be 
evaluated separately for this purpose. We will accrue 60 patients in each arm for a total study 
population of 120 patients.  Anticipating a 10% inevaluable rate, with 54 evaluable patients 
enrolled in each arm we will be able to differentiate between 6 month PFS of 26% and 43% with 
type I and II error rates of 10% each (exact single stage binomial design) [44].  For each arm, the 
regimen is considered promising if 19 or more patients (out of 54) are progression free at 6 
months.  We will define "evaluable" patients as patients who met eligibility requirements, have 
initiated therapy, and were not removed from the study for non-compliance or patient withdrawal 
within the first 6 months.  We anticipate enrollment to be 8 patients/ month with completion of 
accrual in approximately 15 months. 
Secondary endpoints of efficacy are response rate, median PFS, overall and 1 year survival. We 
anticipate that we will enroll approximately 40 patients with measurable disease in each arm, 
from which we can establish a response rate to within +/- 15%. This is consistent with most 
Phase II studies evaluating response.  The median PFS will be estimated using the Kaplan-Meier 
method, and 95% confidence intervals will be based on the sign test [45]. The 1 year survival 
will be estimated using the Kaplan-Meier method, and Greenwood’s formula will be used to 
calculate the standard error of the corresponding Kaplan Meier estimate and 95% confidence 
interval. Survival curves will be estimated using Kaplan-Meier methodology. 
 
A secondary objective is to demonstrate improved toxicity profile of each regimen compared to 
parent DCF.  It is reported that DCF has a grade 3-4 adverse event  rate for non-hematologic 
toxicity exceeding 80%. We hypothesize that the modified De Gramont type of FU infusion and 
more frequent dosing of cisplatin and docetaxel (eg. ARM A) will be associated with less 
toxicity.  Additionally, parent DCF administered growth factor support (eg. ARM B) will also be 
associated with less toxicity.   
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
In order to reduce patient risk, the study design includes early termination of the trial in the event 
of excessive grade 3 or 4 adverse events. We employ repeated significant testing with a constant 
significance level to monitor the grade 3/4 adverse event rate [46]. The table below provides a 
stopping boundary for this study based on an acceptable grade 3/4 adverse event rate of 50% and 
an unacceptable grade 3/4 adverse event rate of 70%.  Using this boundary, if the true adverse 
event rate is 50% then the probability of stopping early is 5%. However, if the true toxicity rate 
is 70% then the probability of stopping early increases to 87%. 
 
Stop if we observe 
12 
grade 3 or 4 adverse events in the first 
15 patients. 
 
21 
 
30  
 
30 
 
45  
 
35 
 
54  
 
Grade 3 or 4 venous thromboembolic events will not be included for the purposes of this safety 
determination.  We have previously demonstrated that the majority of these events are associated 
with minimal to no co-morbidity and are likely attributable to the disease and not the 
therapy[47]. 
 
Total accrual will be 108 evaluable patients with a 1:1 randomization.  We will stratify based on 
center, disease (measurable vs. non-measurable), and location (gastric vs. GEJ). 
 
December 2009 Amendment 
Arm B will be closed because we met the above stopping rule.  Specifically, we observed 22 
grade 3-4 adverse events in the first 30 patients enrolled on Arm B. We note that there was a 
discrepancy between the two arms with regard to the rate of grade 3-4 thromboembolism (5 in 
Arm B, and 0 in Arm A).  Because of this discrepancy, we included grade 3-4 venous 
thromboembolic events in the determination of the toxicity stopping rule.  Notably, 16 patients in 
Arm B required admission due to toxicity in the first 3 months of protocol therapy.   As a result 
of this unacceptable toxicity, the standard DCF + growth factor support arm will close.   
 
As of October 23, 2009, 26 patients are evaluable for toxicity in Arm A (mDCF). We’ve 
observed 16 grade 3-4 adverse events attributable to treatment in the first 3 months, and 8 
hospitalizations.   
 
Note, the results of the recent ToGA study demonstrate that for Her2 positive gastric cancer, 
patients have a survival benefit with the addition of trastuzumab to chemotherapy (see Sect 
3.3.4).  We are therefore amending the study to include a separate cohort of 35 patients who are 
Her2 positive to receive mDCF + trastuzumab (Trastuzumab cohort) 
.  
Total patient accrual to this protocol is fixed at 120 patients.  Arm B has closed with 31 patients 
enrolled in total.  Arm A will remain with a target accrual of 54 eligible patients.  For the 
remaining 35 patients, we will open a Trastuzumab Cohort in which Her2 positive patients with 
metastatic gastric/GEJ adenocarcinoma will receive mDCF + trastuzumab.  With 35 HER2-
positive patients, we will be able to differentiate between 6-month PFS of 43% and 64% with 
type I and II error rates of 10% each (exact single stage binomial design). The modified DCF 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
plus trastuzumab regimen will be considered promising if 19 or more Her2 positive patients (out 
of 35) are alive and progression free at 6 months.  
 
For the Trastuzumab Cohort, we will employ a similar early stopping rule for safety, as we have 
done for Arm A and Arm B. The table below provides a stopping boundary for this study based 
on an acceptable grade 3/4 adverse event rate of 50% and an unacceptable grade 3/4 adverse 
event rate of 70%.  Using this boundary, if the true adverse event rate is 50% then the probability 
of stopping early is 5%. However, if the true toxicity rate is 70% then the probability of stopping 
early increases to 87%. 
 
Stop if we observe 
12 
grade 3 or 4 adverse events in the first 
15 patients. 
 
21 
 
30  
 
For the FDG-PET/CT correlative study (section 9.4.2), the change between baseline and 2nd PET 
scan (change in SUV) will be correlated with response, time to tumor progression, and overall 
survival.  These associations will be assessed using a t-test for response (comparing the means 
between responders and non-responders), and Cox regression for overall survival and time to 
tumor progression. 
 
Another secondary objective is to explore the differences in docetaxel pharmacology between the 
two study arms.  Serial blood draws will be performed in approximately 10 patients in each arm, 
as explained in section 9.4.3.  Some patients in Arm B may have repeat docetaxel pharmacology 
tests without cisplatin administration. Standard pharmacokinetic parameters including Cmax, 
Tmax, and AUC will be estimated for each patient using non-compartmental methods, and a 
Wilcoxon rank sum test will be used to compare the distribution of levels for the two groups. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1   RESEARCH PARTICIPANT REGISTRATION 
All centers must register patients through MSKCC.  No patient can be treated unless they are 
registered through MSKCC.   
For MSKCC patients: 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations can be phoned in or faxed. The completed signature page of the written 
consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
For  Participating Centers: 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center. 
Patient registration must be initiated at Memorial Sloan Kettering Cancer Center within 48 hours 
of the patient signing the informed consent. 
To complete registration and enroll a patient from another institution, the study staff at that site 
must contact the Multicenter Core Project Coordinator  to notify him/her of patient registration. 
The study staff then needs to fax registration/eligibility documents to the Multicenter Trials Core 
at MSKCC at 646-227-2482. 
The following documents must be sent within 24 hours of informed consent form being signed 
for each enrollment:  
• 
The completed or partially completed MSKCC eligibility checklist  
• 
The signed informed consent and HIPAA Authorization form (Research    
Authorization)  
• 
Supporting source documentation for eligibility questions (laboratory results,  
pathology report, radiology reports, MD notes, physical exam sheets, medical 
history, prior treatment records, and EKG report).  
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.   If the eligibility checklist is not complete, the patient will be 
registered PENDING and the site is responsible for sending a completed form within 30 days of 
the consent.  
 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSKCC, the MSKCC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as stated 
in section 15.1.  The participant will be registered. 
 
15.2 
PROTOCOL PATIENT NUMBER 
Once eligibility has been established and the patient is registered, the patient will be assigned an 
MSKCC Clinical Research Database (CRDB) number (protocol patient number). This number is 
unique to the patient and must be written on all data and correspondence for the patient. This 
protocol patient number will be relayed back to study staff at the registering site via e-mail and 
will serve as the enrollment confirmation. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 
15.3 RANDOMIZATION 
 
After eligibility is established and immediately after consent is obtained and a patient number is 
assigned patients will be registered and randomized using the Clinical Research Database 
(CRDB).  Patients will be 1:1 randomized to the two arms.  Randomization will be accomplished 
by the method of random permuted block.  We will stratify based on center, disease (measurable 
vs. non-measurable), and location (gastric vs. GEJ). 
 
December 2009 Amendment 
Due to excessive toxicity, Arm B has been closed. Patients will no longer be randomized 
between two arms of the study.  Instead, patients will be assigned to Arm A.  If they are Her2 
positive and are eligible for trastuzumab, they will be assigned to the Trastuzumab cohort.   
 
August 2010 Amendment 
Arm B remains closed due to toxicity and target accrual has been reached for Arm A.   
Accordingly, eligibility criterion has been expanded to include Her2.  Patients eligible under 
these criteria will be assigned to the Trastuzumab cohort.   
 
16.0 
DATA  MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team.  
The data collected for this study will be entered into a secure database (Clinical Research 
Database – CRDB).  Source documentation will be available to support the computerized patient 
record.  Standardized Case Report Forms (CRFs) that meet the requirements for MSKCC data 
reporting have been generated for this study.  Adverse events, including all toxic effects of 
treatment, will be tabulated individually, and summarized by body system and to severity or 
toxicity grade.  Laboratory data will be tabulated and summarized by descriptive statistics, as 
well as on the basis of MSKCC specified normal ranges.   
16.0.1 Data Management Requirements for Participating Sites  
 
Data 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements have been 
generated for this study. Blank case report forms will be sent to the study staff at each 
participating site for use. The participating Site PI is responsible for ensuring these forms are 
completed accurately, legibly and in a timely manner.  
Please see Appendix C for the data collection schedule that each pariticipating center is expected 
to adhere to. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and evaluations 
that are subsequently recorded as data. Source documentation should be consistent with data 
entered into CRFs. Relevant source documentation to be submitted throughout the study includes 
but is not limited to:  
 
• Baseline measures to assess pre–protocol disease status (ex. CT)  
• Treatment records  
• Grade 3-5 toxicities/adverse events  
• Response designation  
 
16.0.2  Data and Source Documentation Submission for Participating Sites 
 
Participating sites should fax CRFs and source documentation to MSKCC to the contact provided 
below. Submissions should include a cover page listing all CRFs enclosed per participant.  
 
FAX: To the attention of Multicenter Trials Core at 646-227-2482 
 
16.0.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according to guidelines 
specified in Appendix A-C.  
 
SAE Reporting: 
 
Hospitalization requiring Serious Adverse Event Reporting must be reported within three 
calendar days. 
 
Please see Section 17.2.1 regarding the requirements for SAE reporting.  
 
Off-Study Requirements: 
When a patient is taken off-study all CRFs with required source documentation are required to 
be sent to MSKCC not later than 14 calendar days after the off-study date. Failure to submit 
required forms in the timelines requested will result in suspension of accrual privileges at a given  
site until data is updated, and/or withholding of contract payments if applicable. 
 
16.0.4 Data Review and Queries for Participating Site Data 
Research staff at MSKCC will review data and source documentation as it is submitted. Data will be 
monitored against source documentation and discrepancies will be sent as queries to the participating 
sites. Queries will be sent by MSKCC Research staff twice a month. 
 
Participating sites should respond to data queries within 14 days of receipt. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
16.1 QUALITY ASSURANCE 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. Random-sample data quality and protocol 
compliance audits may be conducted by the study team, at a minimum of two times per year, 
more frequently if indicated.   
16.1.1 Site Auditing 
Each site participating in the accrual of patients to this protocol will be audited by the staff of the 
MSKCC study team for protocol and regulatory compliance, data verification and source 
documentation. Audits may be accomplished in one of two ways: (1) selected patients records 
can be audited on-site at participating sites or (2) source documents for selected patients will be 
sent to MSKCC for audit. Audits will usually be determined by patient accrual numbers and rate 
of accrual, but can also be prompted by reported SAEs or request of Lead PI.  
 
Audits will be conducted at least once shortly after initiation of patient recruitment at a site, and 
if possible, at the end or closeout of the trial at a site and during the trial if the trial lasts 3 or 
more years. At a minimum, audits will be conducted once a year or more frequently, if indicated. 
The number of patients audited will be determined by available time and the complexity of the 
protocol.  
 
The audit will include a review of source documentation to evaluate compliance for:  
• 
Consent documents and procedures  
• 
Adherence to eligibility criteria  
• 
Protocol defined treatment  
• 
Required baseline, on study and follow-up protocol testing  
• 
IRB documents (submitted amendments, annual continuing review reports, SAEs)  
• 
Required specimen submission  
• 
Pharmacy review, if applicable  
• 
Case Report Form submissions to MSKCC: timing and accuracy  
 
A wrap-up session will be conducted at the outside site and preliminary findings will be 
discussed with the outside site PI and research team. The preliminary results will be sent to the 
MSKCC PI.  


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating 
institution within 30 days of the audit. The report will include a summary of findings, patient by 
patient case review, specific recommendations on any performance and/or shortcomings and 
request for corrective action, when necessary. When corrective action is required, the 
participating institution must reply within 45 days of receipt of audit report with their corrective 
action plan. 
A copy of the audit report and corrective action plan (if applicable) submitted by the outside site 
must be sent to the MSKCC IRB, CRQA and maintained in the department’s protocol regulatory 
binder.  
 
16.1.2 Response Review  
Since therapeutic efficacy is a stated primary objective, all sites patient’s responses are subject to 
review by MSKCC’s Therapeutic Response Review Committee (TRRC). Radiology, additional 
lab reports and possibly bone marrow biopsies and/or aspirates will need to be obtained from the 
outside sites for MSKCC TRRC review and confirmation of response assessment. These 
materials must be sent promptly upon request to MSKCC. 
16.1.3 Adherence to the Protocol 
The study will be conducted as described in the approved protocol, except for an emergency 
situation in which proper care for the safety of the patient requires alternative treatment.  Any 
deviation from the protocol will be reported, explained and documented in the patient's medical 
record. 
 
16.2 DATA AND SAFETY MONITORING 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.  The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The MSKCC 
Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Quality%
20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality.  There are institutional processes in place for quality assurance (eg. protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control, plus there are two 
instutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
During the protocol development and review process, each protocol will be assessed for it’s level 
of risk and degree of monitoring required.  Every type of protocol (eg. NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will bee addressed and the 
monitoring procedures will be established at the time of protocol activation. 
For Multicenter studies, standardized Case Report Forms (CRFs) have been generated from this 
study that meet the requirements of CTEP and MSKCC data reporting. A set of CRFs will be sent to 
each center (for photocopying and use) following local activation.   
16.3 ETHICAL AND ADMINISTRATIVE ISSUES 
The investigator will agree to personally conduct and supervise the proposed investigations 
according to recognized principles of good clinical practice (GCP). 
16.4 INSTITUTIONAL REVIEW BOARD APPROVAL 
This protocol and the informed consent form will be reviewed and approved by the IRB before the 
study is initiated.  The Investigator is then responsible for informing the IRB of the completion of the 
study and will provide the IRB a final study status report.  The Investigator/Study Coordinator will 
inform the IRB of all serious adverse events. 
 
 
16.5  REGULATORY DOCUMENTATION  
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MSKCC 
Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this protocol at the 
participating sites, approval for the MSKCC IRB/PB approved protocol must be obtained from the 
participating site’s IRB.   
 
The following documents must be provided to MSKCC before the participating site can be initiated 
and begin enrolling participants:  
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical license for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 
• 
Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant permission 
to proceed with enrollment.  


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 
16.5.1 Amendments 
Each change to the protocol document must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 
immediately distribute all non expedited amendments to the participating sites, for submission to 
their local IRBs. 
 
 
Participating sites must obtain approval for all non expedited amendments from their IRB within 90 
calendar days of MSKCC IRB/PB approval. If the amendment is the result of a safety issue, sites will 
not be permitted to continuing enrolling new participants until the participating site IRB approval has 
been granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines:  
• 
Participating Site IRB approval  
• 
Participating Site IRB approved informed consent form and HIPAA  authorization 
 
16.5.2  Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of study 
activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who does not 
meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in their study plan. 
If a deviation from this protocol is proposed for a potential or existing participant at MSKCC or a 
participating site, approval from the MSKCC IRB/PB is required prior to the action. Participating 
sites should contact the MSKCC PI who will in turn seek approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are identified 
after they occur, the participating site should report to MSKCC as soon as possible. The MSKCC PI 
will in turn report the violation to the MSKCC IRB/PB.  
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the participating 
site IRB for protocol deviations and violations should be submitted to MSKCC as received.  
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to local 
guidelines, and submit copies of that correspondence to MSKCC. 
 
16.5.3 Document maintenance 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to enable 
the implementation of the protocol to be fully documented and the data to be subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB approval letters 
referencing protocol version date and amendment number, IRB approved protocol, appendices, 
informed consent forms, deviations, violations, and approval of continuing reviews) is maintained in 
the regulatory binder on site and sent to MSKCC. 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper or 
electronic. 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 7 years. 
 
16.6 NONCOMPLIANCE  
 
If a participating site is noncompliant with the data and regulatory requirements set forth in section 
16.0 -16.5 accrual privileges may be suspended and/or contract payments maybe withheld (if 
applicable), until the outstanding issues have been resolved.   
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. All patients will be required to sign a statement of informed 
consent, which must conform to IRB guidelines. 
Inclusion of Women and Minorities:  Memorial Sloan-Kettering Cancer Center has filed forms HHS 
441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 680 (age 
discrimination); we also take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. Patients of all races, both male and female, will be 
accepted into the protocol. The proposed study population is as described in section 7.0. 
Exclusion of Lactating or Pregant Women:  Children have been excluded from this study. Gastric 
and GEJ adenocarcinoma is an adult cancer. Thus, the relevance of this drug to the pediatric 
population has not been established. Lactating and pregnant women are also excluded because of 
potential anti-proliferative effects of chemotherapy that may be harmful to the developing fetus or 
nursing infant. 
Benefits: It is possible that this treatment will result in shrinkage of the gastric tumor or in a 
stabilization of an otherwise progressing disease. It is not known, of course, whether these or any 
other favorable events will occur. It is not known whether this treatment will affect the overall 
survival of the patients. 
Costs: The patient will be responsible for the costs of standard medical care, including all drug 
administration fees and all hospitalizations, even for complications of treatment.  The laboratory 
correlative studies and week 3 FDG-PET/CT scans will be performed without charge to the patient. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Incentives:  No incentives will be offered to patients/subjects for participation in the study. 
 
Alternatives:  For patients with metastatic gastric cancer alternative treatments may include other 
chemotherapy regimens as well as palliative radiation therapy, and/or surgery. At present, no specific 
chemotherapy regimen represents standard treatment for the disease. Patients may be eligible for 
other investigational studies. 
  
Confidentiality:  Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. Patient’s name or any other personally identifying information will not be 
used in reports or publications resulting from this study. The Food and Drug Administration or other 
authorized agencies (eg, qualified monitors from MSKCC or collaborating institutions, the NCI, 
Sanofi-Aventis etc.), may review patients records and pathology slides, as required. 
17.1 PRIVACY 
It is the responsibility of the Research Staff to ensure that protocol subjects received the Center’s 
Notice of Privacy Practices.  If the subject has not received one, MSK personnel must provide a 
Notice of Privacy Practices and obtain acknowledgment before the subject participates in the study. 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form.  The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form.  A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board. 
 
17.2 SERIOUS ADVERSE EVENT (SAE) REPORTING 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the 
following information: 
 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of    
• 
MSKCC)  
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
• 
Detailed text that includes the following information: 
o       A explanation of how the AE was handled 
o       A description of the subject's condition 
o       Indication if the subject remains on the study 
o    If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
All adverse events, whether observed by the investigator, elicited from the patient, or volunteered by 
the patient, will be recorded The  MSKCC PI (Yelena Janjigian, MD) will report all SAE’s to the 
MSKCC IRB and to Sanofi-Aventis Pharmaceuticals and Genentech via the CRDB AE report .  
17.2.1 ADVERSE EVENT REPORTING DEFINITIONS 
Adverse Event: An adverse event is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic functions, as indicated by physical signs, symptoms, and/or laboratory 
changes occurring in any phase of the clinical trial, whether or not considered drug related. All of the 
following are to be considered adverse events:   
•  an exacerbation of a pre-existing condition. 
•  an intercurrent illness. 
•  any drug interaction. 
•  any event related to a concomitant medication. 
• 
development of an abnormal laboratory value or a significant change from baseline in a 
laboratory value within the range of normal, considered by the investigator to be clinically 
important. 
•  an unexpected significant worsening of the cancer under treatment.  Anticipated day-to-day 
fluctuations in the activity of the cancer or the anticipated progression of the cancer (other than 
death) should not be considered an adverse event. 
 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability / incapacity, or is a congenital anomaly / 
birth defect. 
 
The definition of serious adverse event (experience) also includes important medical event.  Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above.  These should also usually be 
considered serious.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
 
The definition of “related” is that there is a reasonable possibility that the drug caused the adverse 
experience. 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
Life-threatening: A life-threatening adverse event implies an immediate risk of death from the 
reaction as it occurred.  Life-threatening does not include a reaction that, had it occurred in a more 
serious form, might have caused death.  For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug-induced 
hepatitis can be fatal. 
 
 
ASSESSMENT OF SEVERITY  
This study will utilize the Cancer Therapy Evaluation Program Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0 for toxicity and Adverse Event reporting. A copy of the 
CTCAE Version 3.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). 
ASSESSMENT OF RELATIONSHIP TO STUDY MEDICATION 
The following definitions of relationship to study medication should be used in assessing the 
suspected causality of an adverse event: 
Definite:  The adverse event is clearly related to the chemotherapy or investigational agent. 
Probable: The adverse event is likely related to the chemotherapy or investigational agent. 
Possible: The adverse event may be related to the chemotherapy or investigational agent. 
Unlikely: The adverse event is doubtfully related to the chemotherapy or investigational agent. 
Unrelated: The adverse event is clearly NOT related to the chemotherapy or investigational agent. 
 
17.2.3 
REPORTING 
ADVERSE 
EVENTS 
ASSOCIATED 
WITH 
TRASTUZUMAB 
(GENENTECH)  
With the occurrence of an adverse event, the first concern will be for the safety of the subject.  
Investigators are required to report to Genentech Drug Safety any serious adverse event, whether 
expected or unexpected, and which is assessed by the investigator to be reasonably or possibly 
related to or caused by trastuzumab.  All events meeting these criteria will be reported for the time 
period beginning with any amount of exposure to trastuzumab through the protocol-defined follow-
up period.  Serious criteria, definitions, and guidance for reporting follow. 
 
Reporting Serious Adverse Events Associated With Trastuzumab  
All SAEs that are serious and reasonably or probably related to the use of Trastuzumab (this applies 
to both expected and unexpected events) should faxed to: 
Genentech Drug Safety Contact Line 
Tele: 1-888-835-2555 
Fax:  (650) 225-4682/ (650) 225-4683  
AND: 
Study Coordination Center/Principal Investigator 
Contact Information 
AND: 
IRB Contact information 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
 
17.2.4 SANOFI –AVENTIS REPORTING GUIDELINES 
All SAEs are to be reported as soon as possible to Sanofi-Aventis.   Reports by FAX should be sent 
to Aventis Pharmaceuticals Global Pharmacovigilance and Epidemiology Department (908-231-
4827), within 24 hours of receipt by investigator / sponsor.  FAX transmission should include the 
following on the provided IIT SAE REPORT, fax cover form (Appendix E): 
Reports by E-MAIL should be sent to: GPEmailbox@aventis.com , within 24 hours of receipt by 
investigator / sponsor.  E-Mail transmission should include the following:  
Investigator-Initiated (IIT #) study number:___________________  
Study Title:____________________________________________ 
Name of Principal Investigator:____________________________ 
 
17.3 SERIOUS ADVERSE EVENT REPORTING FOR OUTSIDE CENTERS 
Responsibility of Participating Sites 
 
Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail 
within 3 calendar days. 
 
Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
 
Participating sites should use the SAE Report Template (appendix E) to report SAEs to MSKCC. 
  
SAE contact information for the Coordinating Center is listed below:  
 
PI: Yelena Y. Janjigian, MD 
Tel: 646-888-4186 
Email: janjigiy@mskcc.org  
 
Multicenter Core Project Coordinator 
Fax: 646-227-2482 
 
Responsibility of MSKCC 
• The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC 
IRB/PB as specified in 17.2 [and to the funding entity as described in 17.2.3 and 17.2.4] 
• The MSKCC PI is responsible for informing all participating sites about unexpected 
SAEs within 30 days of receiving the stamped SAE from the MSKCC IRB/PB.  
• Any report pertaining to a grade 5 event will be distributed to the participating sites as 
soon as possible. 
17.4 SAFETY REPORTS  
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
• 
MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt.  
• 
MSKCC must submit safety reports to the MSKCC IRB/PB according to institutional 
guidelines. 
• 
Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines. 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information.  
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
18.1 For Participating Sites 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be given 
to the participant to be retained for their personal records. One copy will be maintained on file at 
the MSKCC. The third copy will be confidentially maintained by the participating institution. 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
A note should be placed in the medical record documenting that informed consent was obtained 
for this study, and that the participant acknowledges the risk of participation. 
 
 
19.0  REFERENCE(S) 
1. 
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10. Webb, A., D. Cunningham, J.H. Scarffe, et al., Randomized trial comparing epirubicin, 
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Chicago, IL. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
12. Moiseyenko, V.M., J.A. Ajani, S.A. Tjuladin, et al., Final results of a randomized 
controlled phase III trial (TAX 325) comparing docetaxel (T) combined with cisplatin (C) 
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15. Ilson, D., A.A. Forastier, M. Arquette, et al., A phase II trial of paclitaxel and cisplatin in 
patients with advanced carcinoma of the esophagus. Cancer J., 2000. 6(5): p. 316-23. 
16. Pozzo, C., C. Barone, J. Szanto, et al., Irinotecan in combination with 5-fluorouracil and 
folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric 
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17. Dank, M., J. Zaluski, C. Barone, et al., Randomized phase 3 trial of irinotecan (CPT-11) 
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18. Roth, A., R. Maibach, G. Martinelli, et al., Docetaxel (Taxotere)-cisplatin (TC): an 
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19. Ridwelski, K., T. Gebauer, J. Fahlke, et al., Combination chemotherapy with docetaxel 
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20. Roth, A.D., R. Maibach, N. Fazio, et al., 5-Fluorouracil as protracted continuous 
intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced 
gastric carcinoma: a phase I-II trial. Ann Oncol, 2004. 5: p. 759-764. 
21. Thuss-Patience, P., A. Kretzschmar, M. Repp, et al., Docetaxel and continuous-infusion 
fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric 
adenocarcinoma: a randomized phase II study. J Clin Onc, 2005. 23: p. 494-501. 
22. Roth, A.D., R. Maibach, S. Falk, et al., Docetaxel-cisplatin-5FU versus docetaxel-
cisplatin versus epirubicin-cisplatin-5FU as systemic treatment for advanced gastric 
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(SAKK). Proc Am Soc Clin Oncol, 2004. 22(14S): p. abs 4020. 
23. Chen, L.-T., T.-W. Liu, C.-W. Wu, et al., A phase I study of weekly docetaxel, 24-hour 
infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced 
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24. Constenla, M., R. Garcia-Arroyo, I. Lorenzo, et al., Docetaxel, 5-fluorouracil, and 
leucovorin as treatment for advanced gastric cancer: results ofa phase II study. Gastric 
Cancer, 2002. 5: p. 142-47. 
25. Park, S.R., J.H. Chun, Y.W. Kim, et al. Phase II study of low-dose 
docetaxel/fluorouracil/cisplatin in metastatic gastric cancer. in 2005 Gastrointestinal 
Cancers Symposium. 2005. Miami, FL. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
26. Lorenzen, S., J. Duyster, N. Weigert, et al. Docetaxel (T) plus Cisplatin (P) and 
leucovorin (L)/5FU (F) in first line advanced gastric cancer and adenocarcinoma of the 
gastro-esophageal junction: First results of the phase II GASTRO-TAX-1 trial. in 2006 
Gastrointestinal Cancers Symposium. 2006. San Francisco, California: American Society 
of Clinical Oncology. 
27. de Gramont, A., J.F. Bosset, C. Milan, et al., Randomized trial comparing monthly low-
dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and 
fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French 
intergroup study. J Clin Onc, 1997. 15(2): p. 808-15. 
28. Al-Batran, S.-E., A. Atmaca, S. Hegewisch-Becker, et al., Phase II trial of biweekly 
infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric 
cancer. J Clin Onc, 2004. 22(4): p. 658-63. 
29. Kim, D.Y., J.H. Kim, S.-H. Lee, et al., Phase II study of oxaliplatin, 5-fluorouracil and 
leucovorin in previously-treated patients with advanced gastric cancer. Ann Oncol, 
2003. 14: p. 383-87. 
30. Bouche, O., J.L. Raoul, F. Bonnentain, et al., Randomized multicenter phase II trial of a 
biweekly regimen of fluorouracil and leucovorin (LV5FU2), LF5FU2 plus cisplatin, or 
LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: 
a Federation Francophone de Cancerologie Digestive Group Study - FCCD 9803. J Clin 
Onc, 2004. 22(21): p. 4319-4328. 
31. Oh, D.-Y., T.-Y. Kim, J.H. Kwon, et al., Docetaxel + 5-fluorouracil + cisplatin 3-day 
combination chemotherapy as a first-line treatment in patients with unresectable gastric 
cancer. Jpn J Clin Oncol, 2005. 35(7): p. 380-85. 
32. Pronk, L.C., J.H.M. Schellens, A.S.T. Planting, et al., Phase I and pharmacologic study 
of docetaxel and cisplatin in patients with advanced solid tumors. J Clin Onc, 1997. 
15(3): p. 1071-1079. 
33. Millward, M.J., J. Zalcberg, J.F. Bishop, et al., Phase I trial of docetaxel and cisplatin in 
previously untreated patients with advanced non-small cell lung cancer. J Clin Onc, 
1997. 15(2): p. 750-58. 
34. Rowinsky, E.K., M.R. Gilbert, W.P. McGuire, et al., Sequences of taxol and cisplatin: a 
phase I and pharmacologic study. Journal of Clinical Oncology, 1991. 9(9): p. 1692-703. 
35. Ma, J., J. Verweij, A.S.T. Planting, et al., Docetaxel and paclitaxel inhibit DNA-adduct 
formation and intracellular accumulation of cisplatin in human leukocytes. Cancer 
Chemother Pharmacol, 1996. 37: p. 382-84. 
36. TM, T., [package insert]. Bridgewater, NJ; Aventis Pharmaceuticals., 2005. 
37. TM, A., [package insert]. Lugano, Switzerland: Helsinn Healthcare, 2003. 
38. Oliver, I., Aprepitant in antiemetic combinations to prevent chemotherapy-induced 
nausea and vomiting. Inter J. Clin Practice, 2004. 58(2): p. 201-6. 
39. McCrea, J.B. and e. al., Effects of neurokinin 1 receptor antagonist on the 
pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther, 
2003. 74: p. 17-24. 
40. Nygren, P., K. Hande, K.J. Petty, et al., Lack of effect of aprepitant on the 
pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol, 2005. 
55: p. 609-616. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
41. Rosing, H., V. Lustig, L.J.C. van Warmerdam, et al., Pharmacokinetics and metabolism 
of docetaxel administered as a 1-hour intravenous infusion. Cancer Chemother 
Pharmacol, 2000. 45: p. 213-18. 
42. Stein, H.J., M. Feith and J.R. Siewert, Cancer of the esophagogastric junction. Surgical 
Oncology, 2000. 9(1): p. 35-41. 
43. Mandard, A.M., F. Dalibard, J.C. Mandard, et al., Pathologic assessment of tumor 
regression after preoperative chemoradiotherapy of esophageal carcinoma: 
Clinicopathologic correlations. Cancer, 1994. 73: p. 2680-86. 
44. Chow, S.C., J. Shao and H. Wang, Sample Size Calculations in Clinical Research. 2003, 
New York: Marcell Dekker. 
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Biometrics, 1982, 38: p. 29-41. 
46. Siegmund, D., Sequential Analysis: Tests and Confidence Intervals. Springer Series in 
Statistics. 1985. 
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Incidence in Patients Receiving Irinotecan and Bevacizumab Based Therapy. J Clin Onc, 
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48.   Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S, Olak J, Stover D, 
Strawn JR, Turrisi AT, Somerfield MR. American Society of Clinical Oncology 
treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 
2004 Jan 15;22(2):330-53. Epub 2003 Dec 22. 
49.   Maindrault- Goebel F, Lledo G, Chibaudel B, Mineur L, Andre T, Bennamoun M, Mabro 
M, Artu P, Louvet C, De Gramont A. Optimox2, a large randomixed phase II study of 
maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with 
metastatic colorectal cancer (MRC). A GERCOR study. Journal of Clinical Oncology, 
2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 
2006: 3504 
50.  Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, 
Enander LK, Linne T,                 Sellstrom H, Heuman R. Randomized comparison 
between chemotherapy plus best supportive care with best supportive care in advanced 
gastric cancer. Ann Oncol 8:163–168, 1997 
51. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, 
Flechtner H, Fleishman SB, de Haes JC et al. The European Organization for Research 
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cancer—A GERCOR study. J Clin Oncol 24:394-400, 2006 
54. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing 
mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with 
epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 
20:1996-2004, 2002 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
                           IRB#: 06-103 A(17) 
Amended:  08/03/15 
 
55. Calais Da Silva FM, Bono A, Brausi M, Whelan P, Queimadelos A, Portillo J, Kirkali Z, 
Robertson C.Phase III intermittent MAB vs continuous MAB.Journal of Clinical 
Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 
Supplement), 2006: 4513 
     56.   Hofman M, Stoss O, Shi D, et al: Assessment of a Her2 scoring system for gastric cancer: 
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    57.  Van Cutsem E, Kang Y, Chung H, et al: Efficacy results from the ToGA trial: A phase III 
            study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal 
            growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J Clin Oncol 
           (Meeting Abstracts) 27:LBA4509-, 2009 
     58. Marx AH, Tharun L, Muth J, et al: Her2 amplification is highly homogenous in gastric 
           cancer. Hum Pathol 40:769-77., 2009 
 
 
20.0 
APPENDICES 
Appendix A:  KARNOFSKY / ECOG PERFORMANCE STATUS SCALES 
Appendix B:  TISSUE TRANSMITTAL SHEET 
Appendix C:  SERIOUS ADVERSE EVENT REPORT FORM FOR NON-MSKCC SITES 
    Appendix  D:  EORTC QLQ-C30 
     
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Investigator(s)/Department: 
Gary K. Schwartz, MD
David Ilson, MD PhD 
Leonard Saltz, MD 
Nancy Kemeny, MD 
Diane Reidy-Lagunes, MD 
Marinela Capanu, PhD 
David D’Adamo, MD PhD 
Ki Young Chung, MD 
Neil H. Segal, MD, PHD 
Kenneth Yu, MD 
Maeve Lowery, MD 
Rona D. Yaeger, MD 
Andrew S. Epstein, MD 
Geoffrey Y. Ku, MD 
James Harding, MD 
Anna Varghese, MD 
Peter Maslak, MD 
Robert Lefkowitz, MD 
Marc Simmons, MD 
Heiko Schoder, MD 
Laura Tang, MD 
Ephraim Casper, MD 
Sree Chalasani, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Magi Khalil, MD 
Han Xiao, MD 
Avni Desai, MD 
Marisa Siebel, MD 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
 
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Epidemiology : Biostatistics 
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Leukemia  
Radiology 
Radiology 
Radiology: Nuclear Medicine 
Pathology 
Medicine: All Networks 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Mercy 
 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Consenting 
Professional(s)/Department: 
 
Yelena Y. Janjigian, MD 
David P. Kelsen, MD 
Gary K. Schwartz, MD
David Ilson, MD PhD 
Leonard Saltz, MD 
Nancy Kemeny, MD 
Diane Reidy-Lagunes, MD 
Kenneth Yu, MD 
Maeve Lowery, MD 
Rona D. Yaeger, MD 
Andrew S. Epstein, MD 
Geoffrey Y. Ku, MDDavid 
D’Adamo, MD 
Ki Young Chung, MD 
Neil H. Segal, MD, PHD 
James Harding, MD 
Anna Varghese, MD 
Ephraim Casper, MD 
Sree Chalasani, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Magi Khalil, MD 
Han Xiao, MD 
Avni Desai, MD 
Marisa Siebel, MD 
Stefan Berger, MD 
Julie Fasano, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Philip Schulman, MD 
Steven Sugarman, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Michelle Boyar, MD 
Philip Caron, MD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
 
 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Gastrointestinal 
Medicine: Melanoma/Sarcoma 
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: Gastrointestinal  
Medicine: All Networks 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Commack 
Medicine: Mercy 
 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Mercy 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
Medicine: Phelps 
 
Please Note: A Consenting Professional must have completed the mandatory Human Subjects 
Education and Certification Program


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
National Coordinating 
Investigator 
Manish A. Shah, MD 
Office: 646.962.6200 
Fax: 646.962.1607 
Email: mas9313@med.cornell.edu  
 
 
Collaborating Institution (s): PI Name and Contact Info 
Site Role 
University of Pittsburgh 
Cancer Institute 
PI: Ronald G. Stoller, M.D.
University of Pittsburgh Cancer Institute 
Hillman Cancer Center 
5115 Centre Avenue 
Pittsburgh, PA 15232 
Ph: 412-692-4724 
Fax: 412-648-6579 
Email: stollerrg@upmc.edu   
 
Data Collection 
Queens Cancer Center 
PI: Margaret Kemeny, M.D. 
Queens Cancer Center of Queens Hospital 
82-68 164th Street 
New Building – Room A531 
Jamaica, NY 11432 
Ph: 718-883-4031 
Fax: 718-883-6295 
Email: kemenym@nychhc.org
 
 
Data Collection 
Long Island Jewish Medical 
Center 
PI: Bhoomi Mehrotra, M.D. 
Long Island Jewish Medical Center 
Division of Hematology/Oncology 
New Hyde Park, NY 11040 
Ph: 718-470-8934 
Fax: 718-470-0169 
Email: mehrotra@lij.edu 
 
Data Collection 
University Hospital  of 
Cleveland 
PI: Smitha Krishnamurthi, M.D. 
Ireland Cancer Center/University Hosp. of 
Cleveland
Case Medical Center 
11100 Euclid Avenue 
Cleveland, OH 44106 
Ph: 216-844-5413 
Fax: 216-844- 5449 
Email: smitha.krishnamurthi@case.edu  
 
Data Collection 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Weill Medical College of 
Cornell University 
 
PI: Allyson J. Ocean, M.D. 
Assistant Professor of Medicine 
New York Presbyterian Hospital - Weill 
Medical College of 
Cornell University 
Division of Hematology/Oncology 
520 East 70th Street, Starr 365 
New York, NY 10021 
Ph: 212-746-2844 
Fax:  212-746-6645 
E-mail:  ajo9001@med.cornell.edu  
 
Data Collection 
City of Hope 
PI: Vincent Chung, M.D. FACP 
Assistant Professor 
City of Hope Comprehensive Cancer 
Center 
1500 E. Duarte Rd. 
Duarte, CA 91010 
Ph: 626-471-9200  
Fax: 626-301-8233 
E-mail: vchung@coh.org  
 
Data Collection 
Medical College of 
Wisconsin 
PI: Paul Ritch, M.D. 
Professor of Medicine 
Medical College of Wisconsin 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
Ph: 414-805-4600 
Fax: 414-805-6838 
E-mail: pritch@mcw.edu 
 
Data Collection 
Piedmont Hospital Research 
Institute (PHRI) 
 
PI: Charles Henderson, M.D. 
Piedmont Hospital Research Institute 
(PHRI) 
95 Collier Rd., Suite 2075 
Atlanta, GA 30309 
Ph: 404-350-9853 
Fax: 404-350-8407 
E-mail: chenderson@phoc.com  
 
Data Collection 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Nebraska Cancer Specialists 
 
PI: Yungpo Bernard Su, M.D.  
Nebraska Cancer Specialists 
Methodist Estabrook Cancer Center 
8303 Dodge Street, Suite 250 
Omaha, Nebraska 68114 
Ph: 402.354.8124  
Fax: 402.354.8127  
E-mail: drsu@onchemwest.com    
 
Data Collection 
Memorial Cancer Institute 
PI: Dr. Pablo Ferraro, M.D.
Memorial Cancer Institute
801 North Flamingo Road 
Pembroke Pines, FL 33025 
Ph: (954)430-6868 
Fax: (954)443-4747 
E-mail: pferraro@mhs.net 
 
Data Collection 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Table of Contents 
1.0
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 1 
2.0
OBJECTIVES AND SCIENTIFIC AIMS ........................................................................ 4 
3.0
BACKGROUND AND RATIONALE ............................................................................... 5 
3.1 SCOPE OF DISEASE AND ROLE OF CHEMOTHERAPY ...................................................... 5 
3.2 COMBINATION CHEMOTHERAPY REGIMENS.................................................................... 5 
3.3 IS THERE A “STANDARD” CHEMOTHERAPY REGIMEN? ................................................ 7 
3.4 SUMMARY OF CHEMOTHERAPY FOR GASTRIC/GEJ ADENOCARCINOMA ............ 12 
3.5 PROPOSAL .................................................................................................................................... 13 
3.5.1 Modified DCF dose and schedule determination ...................................................................... 13 
3.5.2 Pharmacokinetic and Pharmacodynamic Considerations  (MSKCC ONLY) ....................... 17 
3.5.3  FDG-PET Response Assessment ............................................................................................... 19 
4.0
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................. 22 
4.1 Design ............................................................................................................................................... 22 
4.2 
Intervention .............................................................................................................................. 23 
5.0
THERAPEUTIC/DIAGNOSTIC AGENTS .................................................................... 24 
5.1  Docetaxel (TAXOTERE®) ............................................................................................................. 24 
5.2       CISPLATIN .............................................................................................................................. 27 
5.3  FLUOROURACIL ........................................................................................................................ 28 
5.4 
LEUCOVORIN ........................................................................................................................ 29 
5.5 TRASTUZUMAB ........................................................................................................................... 30 
5.6  CONCOMITANT MEDICATIONS ............................................................................................ 34 
6.0
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................... 36 
6.1 
Subject Inclusion Criteria ....................................................................................................... 36 
6.2 
Subject Exclusion Criteria ...................................................................................................... 38 
7.0
RECRUITMENT PLAN .................................................................................................. 39 
8.0
PRETREATMENT EVALUATION................................................................................ 40 
9.0
TREATMENT/INTERVENTION PLAN ....................................................................... 42 
9.1 CHEMOTHERAPY ADMINISTRATION .................................................................................. 42 
9.2  SUPPORTIVE CARE GUIDELINES ......................................................................................... 44 
9.3 TREATMENT PARAMETERS, DOSE DELAYS AND MODIFICATIONS ......................... 46 
9.4  CORRELATIVE STUDIES ......................................................................................................... 53 


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10.0
EVALUATION DURING TREATMENT/INTERVENTION ....................................... 56 
10.1 
FOR PARTICIPATING SITES ...................................................................................... 57 
11.0
TOXICITIES/SIDE EFFECTS ...................................................................................... 58 
11.1 CISPLATIN .................................................................................................................................. 58 
11.2 DOCETAXEL ............................................................................................................................... 59 
11.3 FLUOROURACIL ....................................................................................................................... 59 
11.4 LEUCOVORIN ............................................................................................................................. 59 
11.5 TRASTUZUMAB ......................................................................................................................... 59 
11.6 SUPPORTIVE MEDICATIONS ................................................................................................ 59 
12.1 DEFINITIONS .............................................................................................................................. 60 
12.2 EVALUATION OF TARGET LESIONS .................................................................................. 61 
12.3 EVALUATION OF NON-TARGET LESIONS ........................................................................ 61 
12.4 EVALUATION OF BEST OVERALL RESPONSE ................................................................. 62 
12.5 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE .................................... 62 
12.6 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE .................................. 63 
13.0
CRITERIA FOR REMOVAL FROM STUDY ............................................................... 63 
13.1 DURATION OF THERAPY / CRITERIA FOR REMOVAL FROM STUDY ..................... 63 
13.2  OFF-STUDY EVALUATION .................................................................................................... 64 
14.0
BIOSTATISTICS ............................................................................................................. 65 
15.0
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ............................................................................................................................ 67 
15.1   RESEARCH PARTICIPANT REGISTRATION ................................................................... 67 
15.3 RANDOMIZATION .................................................................................................................... 69 
16.0
DATA  MANAGEMENT ISSUES .................................................................................. 69 
16.1 QUALITY ASSURANCE ............................................................................................................ 71 
16.2 DATA AND SAFETY MONITORING ...................................................................................... 72 
16.3 ETHICAL AND ADMINISTRATIVE ISSUES ........................................................................ 73 
16.4 INSTITUTIONAL REVIEW BOARD APPROVAL ................................................................ 73 
17.0
PROTECTION OF HUMAN SUBJECTS ..................................................................... 75 
17.1 PRIVACY ...................................................................................................................................... 76 
17.2 SERIOUS ADVERSE EVENT (SAE) REPORTING ............................................................... 76 
17.3 SERIOUS ADVERSE EVENT REPORTING FOR OUTSIDE CENTERS........................... 79 


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18.0 INFORMED CONSENT PROCEDURES ......................................................................... 80 
18.1 FOR PARTICIPATING SITES .......................................................................................... 80 
19.0 REFERENCE(S) ................................................................................................................. 81 
20.0 APPENDICES ...................................................................................................................... 85 
 
 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA       
1.1 Objectives 
Primary:  
1) To determine the efficacy of modified docetaxel, cisplatin, and fluorouracil (mDCF) 
(ARM A) and the efficacy of parent DCF with growth factor support (ARM B) in 
patients with unresectable or metastatic gastric or gastroesophageal junction(GEJ) 
adenocarcinoma as measured by 6 month progression free survival (PFS). 
Secondary:  
2) To establish the safety of mDCF and parent DCF with growth factor support in patients 
with unresectable or metastatic gastric or GEJ adenocarcinoma. 
3) To observe other measures of efficacy of mDCF and parent DCF with growth factor 
support, including response rate, median PFS, overall and 1-year survival in patients with 
unresectable or metastatic gastric or GEJ adenocarcinoma. 
4) To explore the association of early FDG-PET imaging with treatment efficacy. 
5) To explore the differences in docetaxel pharmacology between both study arms. 
6) To bank tumor biopsy material for future planned correlative studies for association with 
chemotherapy efficacy and survival. 
7) To report the efficacy of mDCF with trastuzumab as measured by 6 month PFS amongst 
Her2 positive patients. 
8) To report the safety profile of patients receiving mDCF and trastuzumab. 
 
1.2 Eligibility 
Patients with histologically confirmed metastatic or unresectable gastric or gastroesophageal 
junction adenocarcinoma are eligible for entry into this Phase II study.  Patients may have 
received neoadjuvant and/or adjuvant chemotherapy or chemoradiotherapy.  Patients may not 
have received previous chemotherapy containing cisplatin or docetaxel.  Prior fluorouracil is 
allowed if more than 6 months have passed since the patient last received it.  Patients must 
provide written informed consent prior to study enrollment.   
Patients must be at least 18 years of age, and use birth control if male, or if female of 
childbearing age.  Patients must have a Karnofsky performance status of greater than or equal 
to 70% (ECOG < 2), and be of sound mind to sign informed consent.  Hematologic/ 
laboratory criteria for eligibility include: WBC > 3000/mm3, ANC ≥ 1500/mm3, hemoglobin 
> 9 g/dl, platelet count ≥ 100,000/mm3, serum creatinine ≤ 1.5 mg/dl.  For patients with a 
serum creatinine of 1.2-1.5, their creatinine clearance must be at least 50 ml/min. Total serum 
bilirubin ≤ 1.5, serum AST(SGOT)/ALT(SGPT) and ALK PHOS levels as per chart below: 
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤1.5x ULN 
>1.5x but ≤ 5x ULN >5x ULN 
≤ ULN 
Eligible 
Eligible 
Eligible
Ineligible 
>1x but ≤2.5x  
Eligible 
Eligible 
Ineligible 
Ineligible 
>2.5x but ≤5x  
Eligible 
Ineligible 
Ineligible 
Ineligible 
>5x ULN 
Ineligible 
Ineligible 
Ineligible 
Ineligible 


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Patients must have a PT (INR) < 1.5 and a PTT < 3 seconds above the upper limits of normal 
if they are not on anticoagulation. Women of childbearing potential must also have a 
negative pregnancy test.  Biopsy confirmation of M1 disease is encouraged, unless the risk of 
such a procedure is significant, in which case confirmation by a 2nd imaging modality is 
required. Exclusions include patients with brain or central nervous system metastases, 
patients with significant co-morbidities including cardiac diseaes, serious non-healing wound 
or ulcer, peripheral vascular disease or stroke, or significant hearing loss.  
December 2009 Amendment 
As of October 2009, trastuzumab plus chemotherapy is part of the NCCN standard treatment 
algorithm for the first line for advanced gastric/GEJ adenocarcinoma.  This amendment is to 
allow patients who are Her2 positive to receive trastuzumab with mDCF .  Her2 positive 
patients are defined as IHC 3+ for Her2 or FISH + (>2 HER2:CEP17).Biopsy samples (i.e 
small tissue fragments) with cohesive IHC3+ or FISH+ clones are considered  HER2 positive 
irrespective of size, i.e.<10%, as per Hofmann et al1To receive trastuzumab, patients must 
have a baseline left ventricular ejection fraction of > 50%.  Her2 positive patients who 
receive trastuzumab will be considered as a separate cohort and independent cohort. 
1.3 Treatment Plan 
This will be a random assignment phase II study of two different administration schedules of 
docetaxel, cisplatin, and fluorouracil in patients with unresectable or metastatic gastric or 
GEJ adenocarcinoma.  Eligible patients will be randomly assigned to receive mDCF (ARM 
A) or parent DCF with growth factor support (ARM B) as follows: 
ARM A – Modified DCF 
ARM B – Parent DCF with G-CSF 
Drug
Dose (mg/m2) 
Schedule 
Drug 
Dose (mg/m2) 
Schedule 
Docetaxel 
40 
Day 1 IVPB (60 min) 
Docetaxel 
75 
Day 1 IVPB (60 min) 
Leucovorin 
400 
Day 1 IVPB (30 min) 
Cisplatin 
75 
Day 1 IVPB (60 min) 
Fluorouracil 
400 
IVP day 1 
Fluorouracil 
750 
IVCI daily x 5 days 
Fluorouracil 
1000 mg/m2/d 
IVCI daily x 2 days 
Neulasta 
6 mg 
subcut on d 8, 9, or 10 
Cisplatin 
40 
Day 2 OR 3 IVPB (30 
min) 
or Neupogen 
300 or 480 mcg* 
subcut x 7 d 10-17 
* 300 mcg for weight < 60 kg, 480 mcg for weight > 60 kg 
Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments).  
Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 
treatments).  Tumor assessments will be performed following the completion of every cycle 
for the first 6 cycles, and then every 2 cycles thereafter.   
December 2009 Amendment 
We have met the early stopping rule for Arm B, parent DCF with growth factor support.  
Arm A will continue to accrue until target accrual of 54 patients. In addition, we will treat 
Her2 positive patients with mDCF + trastuzumab.  Trastuzumab will be administered on an 
every 2 week dosing schedule, with an initial loading dose of 6 mg/kg over 90 minutes, 
followed by trastuzumab 4 mg/kg every 2 weeks over 30 mintues.   
 
 


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August 2010 Amendment:  
Arm A has reached target accural of 54 patients. Arm B remains closed due to toxicity. Her2 
positive patients with be enrolled onto the Trastuzumab Cohort and will receive mDCF + 
trastuzumab.  Trastuzumab will be administered on an every 2 week dosing schedule, with an 
initial loading dose of 6 mg/kg over 90 minutes, followed by trastuzumab 4 mg/kg every 2 
weeks over 30 minutes.   
1.4 Pharmacology and Pharmacodynamics (MSKCC patients only) 
Docetaxel is both a substrate and inhibitor of the cytochrome p450 enzyme CYP3A4, and its 
metabolism can be inhibited by CYP3A4 inhibitors such as ketoconazole, erythromycin, 
verapamil and diltiazem.  Importantly, both aprepitant and palonesetron, recently approved 
anti-emetic agents for the treatment of acute and delayed nausea, are both inhibitors of 
CYP3A4. Similarly, we hypothesize that inhibition of CYP3A4 by these anti-emetic agents 
would result in reduced docetaxel metabolism, increased drug exposure, and potentially 
increased toxicity.  
 
Pharmacokinetic blood draws will occur in patients enrolled at MSKCC only.  We will 
perform serial blood draws in approximately 20 patients (10/ arm) at the following times: 
 
1. 0.25 hours (15 min following initiation of docetaxel) 
2. 0.75 hours (45 min following initiation of docetaxel) 
3. 1 hour 
(end of docetaxel infusion) 
4. 1. 25             ( 15 min following the end of docetaxel infusion) 
5. 2 hours 
6. 4 hours 
7. 6 hours 
8. 8 hours 
9. 24 hours 
Additionally, on day 3, a CBC with differential and LFT’s (AST, ALT, Alk Phos, total 
Bilirubin) will be drawn in each of these patients.  For Arm A, these lab studies will be 
drawn prior to cisplatin administration.   
 
March 2008 Addendum: On our initial pharmacokinetic analysis, we have observed that the 
clearance of docetaxel appears to be reduced when it is administered on day 1 with cisplatin 
(Arm B), and this is associated with an increased exposure to docetaxel.  Conversely, when 
docetaxel is administered on day 1 and cisplatin is administered on day 3, docetaxel 
clearance appears to be higher and is associated with a lower AUC∞.  Recall that our 
hypothesis is that reduced clearance and higher exposure to docetaxel may be responsible for 
some of the increased toxicity observed with the parent DCF (Arm B) regimen.   Based on 
this, we will expand our pharmacokinetic evaluation and examine additional docetaxel PK 
without cisplatin in up to 6 patients randomized to parent DCF who underwent cycle 1 
docetaxel PK (when cisplatin was administered on day 1 as well).  See section 9.4.3. 


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1.5 Correlative Studies 
A. One objective is to store pre-treatment paraffin embedded tumor tissue for future tissue 
based correlative studies.  We will keep a tissue bank for these future immunohistochemistry 
based exploratory studies.   
HER2 testing will be performed in all patients to better characterize HER2-positive gastric 
cancer in US patients.  HER2 testing will be performed by the MSKCC diagnostic molecular 
laboratory on banked tumor specimens from the patients currently enrolled on the protocol 
and prospectively on all the patients screened for protocol participation.  FISH is performed 
using FDA-approved ERBB2 (HER2/NEU) PathVysion assay probes and procedure (Abbott-
Vysis). IHC staining is performed using FDA-approved anti-Her2/neu Ventana’s 
PATHWAY rabbit monoclonal primary antibody (clone 4B5) directed against the internal 
domain of the c-erbB-2 oncoprotein (Her2).   
Tissue samples for HER2 testing will be processed locally in the laboratory of investigational 
sites. The results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of HER2 
status. MSK pathology review will not be required to begin therapy on the protocol.   
Samples provided to the MSK laboratory must either be HER2 IHC slides, or  if FISH 
confirmation is necessary, a paraffin block(s) of adequate size to allow if possible for at least 
5 slides with cuts that are 5-microns thick or if a paraffin block is not available, then if 
possible at least 5 slides with cuts that are 5-microns thick will be acceptable. Archived or 
fresh tumor samples may be used. 
B. Another objective is to evaluate the utility of FDG-PET/CT scans to monitor response to 
treatment.  All patients will undergo a baseline staging FDG-PET/CT scan.  A second PET 
scan will be performed during week 3:  
 
ARM A: following the d 15 treatment, but before week 4 (eg during day  18, 19, or 20) 
ARM B: once on either day 18, 19, or 20 
 
We hypothesize that patients with a good PET/CT response will have RECIST evidence for 
response at their subsequent routine imaging time point and have an increased time to 
progression.  Alternatively, patients with a bad PET/CT response will progress early.  If 
successful, this would allow patients to minimize toxicity by minimizing exposure to 
ineffective therapy. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary:   
1) To determine the efficacy of modified docetaxel, cisplatin, and fluorouracil (mDCF) 
(ARM A) and the efficacy of parent DCF with growth factor support (ARM B) in 
patients with unresectable or metastatic gastric or gastroesophageal junction(GEJ) 
adenocarcinoma as measured by 6 month progression free survival. 


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Secondary:  
2) To establish the safety of mDCF and parent DCF with growth factor support in patients 
with unresectable or metastatic gastric or GEJ adenocarcinoma. 
3) To observe other measures of efficacy of mDCF and parent DCF with growth factor 
support, including response rate, median PFS, overall and 1-year survival in patients with 
unresectable or metastatic gastric or GEJ adenocarcinoma. 
4) To explore the association of early FDG-PET imaging with treatment efficacy. 
5) To explore the differences in docetaxel pharmacology between both study arms. 
6) To bank tumor biopsy material for future planned correlative studies for association with 
chemotherapy efficacy and survival. 
7) To report the efficacy of mDCF with trastuzumab as measured by 6 month PFS amongst 
Her2 positive patients. 
8) To report the safety profile of patients receiving mDCF and trastuzumab. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 SCOPE OF DISEASE AND ROLE OF CHEMOTHERAPY 
Gastric cancer is an aggressive neoplasm that is associated with an extremely poor prognosis.  
Median survival for metastatic or unresectable disease is approximately 8 to 10 months.  On a 
global basis, cancer of the stomach is the third most prevalent malignancy worldwide, with 
947,000 expected new cases in 2000, and the second leading cancer cause of death (734,000 
deaths annually). [1] 
 
Unfortunately, despite its enormous global impact, we have made little progress in the treatment 
of this disease.  Conventional chemotherapy for metastatic gastric cancer remains palliative, with 
few patients ever demonstrating long term survival.  Historically, most tumors develop rapid 
drug resistance and evidence of disease progression within a few months of initiation of therapy.  
However, palliative chemotherapy has a proven survival advantage over best supportive care for 
gastric cancer.  Four randomized trials have all shown that patients assigned to receive best 
supportive care alone, even when allowed to receive chemotherapy at a later date, did 
significantly worse than those assigned to receive immediate chemotherapy (reviewed by 
Shah[2]. 
3.2 COMBINATION CHEMOTHERAPY REGIMENS 
The chemotheraputic agents historically considered as active in this disease include fluorouracil, 
cisplatin, anthracyclines (doxorubicin and epirubicin), mitomycin C, and etoposide (reviewed 
previously[2, 3]).  Single agent activity ranges with response rates from 10% to 20%, though the 
data are pooled from clinical trials performed in the 1960’s and 1970’s, and may be an 
overestimation of the true single agent activity as assessed by objective radiographic 
measurements.   
 
 
 


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Several combination regimens have been developed with the aims of improving overall response 
rates and duration of response.  Table 1 summarizes the results of large random assignment 
studies involving these combination regimens.  A three arm random assignment trial comparing 
ELF (etoposide, leucovorin, fluorouracil bolus), CF (cisplatin, fluorouracil infusion), and 
FAMTX (fluorouracil bolus, adriamycin, and high dose methotrexate) was reported by 
Vanhoefer, et al in 2000[4].  Overall response rates were notably low compared to previously 
reported phase II studies, ranging from 9% to 20% in the three arms, and survival was equally 
dismal at less than 7.2 months for each of the arms.  These authors concluded that none of the 
regimens tested should be regarded as a standard treatment for metastatic or unresectable gastric 
cancer[4].  Another study compared CF, UFTM (uracil, tegafur, and mitomycin), and single 
agent 5-FU[5].  The CF regimen was associated with a modest, significant increase in 
progression free survival and response rate over 5-FU (3.9 mo and RR 34% vs. 1.9 mo and 11%, 
respectively). However, despite these improvements, overall survival was not improved with CF, 
with median and 1-year survival of 7.3 months and 29% respectively, compared with 7.1 months 
and 28% with 5-fluorouracil alone.  Notably, approximately 50% of patients who were assigned 
to fluorouracil alone received cisplatin based therapy on progression in this study (personal 
communication, Ohtsu).  These authors concluded that single agent fluorouracil should remain 
the reference standard regimen for advanced phase gastric cancer studies[5].  A similar 
conclusion was drawn by the authors of another random assignment study comparing EEP 
(etoposide, epirubicin, and cisplatin) vs. FEP (fluorouracil, epirubicin, and cisplatin). [6] 
 
Table 1.  Phase III clinical trials for gastric cancer using ‘older’ combination regimens (modified from Shah[2]). 
Reference 
Disease 
Treatment 
Regimen1 
n  
Response Rate2 
(95% CI) 
1-Year Survival 
(95% CI) 
Median 
Survival 
p value 
 
 
 
Tebbutt, 
2002[7] 
Esophagus + 
Gastric 
PVI 
123
16.1% 
(9.5- 22.7%) 
22.5% 
(15.2-30%) 
6.3 mo 
NS 
PVI +  
MMC 
127
19.1% 
(12- 26.0%) 
18.4% 
(12-25.9%) 
5.3 mo 
 
 
 
Ohtsu, 
2003[5] 
Gastric 
FU 
105
11.4% 
(6– 19.1%)
28% 
7.1 mo 
NS 
FU + 
Cisplatin 
105
34.3% 
(25.3 - 44.2%) 
28% 
7.3 mo 
UFTM 
70 
8.6% (3 – 18 %) 
16% 
6.0 mo 
 
 
 
Icli, 1998[6] 
Gastric 
EEP 
64 
20.3%(12-59%) 
16 %3  
6.0 mo 
NS 
FEP 
67 
15.3%(9- 59%) 
11 %3 
5.0 mo 
 
 
 
Vanhoefer, 
2000[4] 
Gastric 
ELF 
132
9% (3.5-17.5%) 
28% 
7.2 mo 
NS 
CF 
134
20% (11 -30%) 
32% 
7.2 mo 
FAMTX 
133
12% (6-20.5%) 
33% 
6.7 mo 
 
 
 
1 Treatment Regimens: PVI = continuous infusion FU (300 mg/m2/d), MMC = mitomycin, EEP = etoposide, 
epirubicin, cisplatin, FEP = fluorouracil (bolus), epirubicin, cisplatin,  CF = cisplatin, fluorouracil., UFTM = 
uracil, tegafur, mitomycin 
2 RR in evaluable patients, 3 1-year survival estimated from Kaplan-Meier curves. 


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3.3 IS THERE A “STANDARD” CHEMOTHERAPY REGIMEN? 
Current or modern combination chemotherapy regimens have included prolonged infusional 
schedules of fluorouracil in combination with cisplatin and epirubicin (ECF), docetaxel, cisplatin 
and a 5 day fluorouracil infusion (DCF), and irinotecan based combinations both with cisplatin 
and with fluorouracil infusions.  The data regarding these combination chemotherapy regimens 
are summarized in table 2 below.  The overall efficacy as assessed by response rate, median and 
overall survival, and 1-year survival of these combination regimens appear to be improved over 
the combination chemotherapy regimens listed in table 1.  However, as discussed below, specific 
issues surround each of these regimens that limit their general acceptability as a “standard” 
combination chemotherapy regimen for this disease. 
 
Table 2.  Recent studies for gastric cancer using modern regimens. 
Reference 
Disease 
Treatment 
Regimen1 
n  
Response Rate2 
(95% CI) 
1-Year Survival 
(95% CI) 
Median 
Survival 
p value 
ECF based Phase III studies 
Ross, 
2002[8] 
Esophagus 
+ Gastric 
ECF 
289
42.4%  
(37– 48%) 
40.2% 
(34– 46%) 
9.4 mo 
NS 
MCF 
285
44.1%  
(38– 50%) 
37.7% 
(27-38%) 
8.7 mo 
Webb, 
1997[9, 10] 
Esophagus + 
Gastric 
ECF 
121
46% (37-55%) 
37% (28-45%) 
8.7 mo 
p < 
0.01 
FAMTX 
116
21% (13-28%) 
22% (15-29%) 
6.1 mo 
DCF vs. CF phase III study 
Ajani, 
2003[11],  
Moiseyenko 
2005[12] 
Gastric + 
GEJ 
DCF 
221 
36.7% 
(30.3 – 43.4%)
40.2% 
9.2 mo 
(8.38 – 10.58) 
p = 
0.02 
CF 
224
25.4% 
(19.9 – 31.7%)
31.6% 
8.6 mo 
(7.16 – 9.46)
Irinotecan based studies(Note only the Dank is a phase III study) 
Pooled 
results [13-
15] 
Esophagus + 
Gastric 
Irinotecan/C
isplatin 
105
48 % - 58% 
 
Pozzo et al. 
2004[16] 
Gastric + 
GEJ 
(Random 
assignment 
phase II) 
Irinotecan/C
isplatin 
56 
32.1% (20.3 – 
46%)3 
25.3% 
6.9 mo (5.55 -
8.67 mo)4 
p = 
0.002 
Irinotecan/F
U infusion/ 
FA 
59 
42.4 % (29.6 – 
55.9%)3 
44.9% 
10.7 mo 
(8.02-14.62 
mo)4 
Dank et al. 
2005[17] 
Gastric + 
GEJ 
Irinotecan/F
U infusion/ 
FA 
170
31.8% 
9.0 mo (8.3 – 
10.2 mo) 
p = 
0.53 
CF 
165
25.8% 
8.7 mo (7.8 – 
9.8 mo) 
1 Treatment Regimens: ECF = epirubicin, cisplatin, fluorouracil (continuous infusion), MCF = mitomycin, cisplatin, 
fluorouracil, DCF = docetaxel, cisplatin, fluorouracil, CF = cisplatin, fluorouracil. 
2 RR in evaluable patients. 3 Per protocol population, 4Full analysis population 
3.3.1 The ECF Regimen 
The ECF regimen has recently been examined in two large random assignment studies (see table 
2). First, ECF was compared with FAMTX, [10]with an update of the results recently reported 
by Waters, et al.. [9]This study randomly assigned 274 patients (137 in each group) to receive 
ECF or FAMTX.  ECF was associated with a better response rate (46% vs. 21%, p = 0.0002) and 


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an improvement in median survival (8.7 mo vs. 6.1 mo, p = 0.0005) when compared to FAMTX.  
However, this study was not generally accepted because of an apparent imbalance in the number 
of patients proceeding to surgery for locally advanced disease between the two arms.   
The investigators then proceeded to examine ECF versus MCF (mitomycin, cisplatin, and 
infusional fluorouracil) in what is the largest random assignment study of chemotherapy in 
metastatic or unresectable esophagogastric cancer published to date[8].  This study randomly 
assigned 574 eligible patients with esophagus (n=188), gastroesophageal junction (n=125), or 
gastric cancers (n=221) to receive either ECF (n=289) or MCF (n=285).  Response to therapy 
was equavalent (42.4% for ECF vs. 44.1% for MCF), as was survival (median survival 9.4 mo 
for ECF vs. 8.7 mo for MCF).  Although ECF appeared to have greater toxicity, global quality of 
life scores were maintained in the ECF arm, whereas they fell in the MCF arm, suggesting that 
ECF was subjectively perhaps a more tolerable regimen[8].  Notably, the fluorouracil 
administration in the MCF arm was 50% higher (300 mg/m2/day) than in the ECF arm (FU 200 
mg/m2/day) resulting in an imbalance between total fluorouracil administered between the two 
arms (net 42% higher with MCF, p < 0.00001).   Although this study confirmed the activity of 
ECF in esophagogastric tumors, it also raises the question as to the role of epirubicin in a 
cisplatin-fluorouracil combination.  The study also confirmed that the prognosis of patients with 
esophagogastric tumors not amenable to resection remains dismal (with median survival 
remaining less than 10 months).  
3.3.2 Docetaxel Based Combination Therapy 
Taxanes and taxane containing combinations have considerable activity in the treatment of 
gastric cancer.  Although both paclitaxel and docetaxel have similar single agent response rates 
in the first line setting, occasional complete responses were reported with docetaxel.  Both drugs 
have been examined with combination chemotherapy regimens with cisplatin, with associated 
improvements in response rates (ranging from 37% to 56%) and complete responses. [18, 19] 
 
Based on the single agent and early combination activity observed with docetaxel-based therapy 
in upper gastrointestinal malignancies, docetaxel was examined in combination with cisplatin 
and fluorouracil (DCF) and compared with the ‘standard’ chemotherapy regimen of CF in a large 
random assignment phase III study (see table 2). [12]The results reported at ASCO 2005 
demonstrate a significant improvement in time to progression (primary endpoint) with the 
docetaxel containing combination (5.6 vs. 3.7 months, p=0.0004) as well as an improvement in 
median and overall survival (median survival of 9.2 vs. 8.6 months, p = 0.02) with the addition 
of docetaxel to cisplatin + fluorouracil when compared with CF alone. At 6 months, 42.7% of the 
DCF-treated subjects had not progressed compared with 27.4% of the CF-treated subjects.  
 
However, both DCF and CF was associated with significant toxicity (see table 3).  Notably, in 
the DCF arm 82% of patients developed grade 3-4 neutropenia and 30% developed febrile 
neutropenia or a neutropenic infection.  This is significantly more than the control arm of 
cisplatin and fluorouracil infusion in which 57% of patients developed grade 3-4 neutropenia, 
and 13.5% of patients developed febrile neutropenia or neutropenia with infection.   


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Amended:  08/03/15 
 
For both arms, the majority of patients did not receive prophylactic growth factor support.  Non-
hematologic toxicity was considerable as well.   In the DCF arm, 81% of patients developed a 
non-hematologic grade 3-4 adverse event, whereas in the CF arm, there was a similar high rate of 
grade 3-4 non-hematologic toxicity of 75.4%.  Since both arms involved a 5 day infusion of 
fluorouracil, the grade 3-4 stomatitis rate was considerable (46% in DCF and 61% in CF).   
Other notable toxicity occurring in nearly half of the patients enrolled on the DCF arm include 
47% developing grade 3-4 lethargy and 45% developing grade 3-4 diarrhea.   
 
This toxicity spectrum is very similar to the toxicity we observed in an MSKCC phase II study of 
DCF (as originally prescribed) given as preoperative therapy for locally advanced gastric cancer 
(IRB 99-66, PI David Kelsen, MD).  In this study, which was closed early due to toxicity, three 
out of the first 8 patients enrolled were unable to complete 2 cycles of preoperative DCF therapy 
due to significant treatment related toxicity.  This suggests that the toxicity with the parent DCF 
regimen is significant, not only in patients with advanced, metastatic disease who may have been 
predicted to tolerate less aggressive therapy, but also in patients with locally advanced disease 
with less disease burden who generally are felt to tolerate treatment better. 
 
Table 3. Toxicity of DCF and CF [12] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall, 41.2% of patients who received DCF required a dose reduction, and 47.5% of patients 
had a treatment related adverse event that led to a delay in treatment or dose reduction.  The most 
common grade 3-4 side effects for the DCF arm included the following: lethargy, stomatitis, 
diarrhea, cancer pain, infection, nausea, vomiting, anorexia, and neuropathy.  These toxicities 
were not considerably different than that experienced with cisplatin and fluorouracil infusion 
(CF).  However, hematologic toxicity was considerable and significantly more with DCF than 
with CF.  Specifically, 82.3% of  patients who received DCF developed grade 3-4 neutropenia 
and 30% of patients developed febrile neutropenia or neutropenic infection.  Notably, a portion 
Adverse Event 
Grade 3-4 
Grade 3-4 
DCF 
CF 
Hematologic Toxicity 
 
 
Neutropenia
82.3
56.8
Febrile neutropenia or neutropenic 
infection 
30 
13.5 
Non-Hematologic  Toxicity 
 
 
Neurosensory 
17 
7 
Infection 
36 
23 
Anorexia 
29 
26 
Nausea 
35 
42 
Vomiting 
33 
42 
Lethargy
47
40
Diarrhea 
45 
18 
Stomatitis 
46 
61 
At least one grade 3-4 Adverse Event 
81.4
75.4 
Deaths during treatment or within 30d of Tx 
10.4
8.5 


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of patients (n = 41 or only 18.6% of the total study population) received prophylactic G-CSF.  In 
this group, 63.4 % of patients developed grade 3-4 neutropenia and 12.2% of patients developed 
febrile neutropenia or neutropenic infection.    
At this time, the question remains whether the toxicity attributable to the addition of docetaxel to 
CF will outweigh the modest observed improvement in survival.  However, it is clear that 
docetaxel is an active chemotherapy agent in the treatment of this disease and that it’s addition to 
cisplatin and fluorouracil may confer a clinically important survival advantage.   Based on these 
data, the FDA has recently approved the use of docetaxel with cisplatin and fluorouracil in the 
first line treatment setting for gastric and GEJ adenocarcinoma. 
 
To capitalize on the potential survival advantage with docetaxel, efforts to reduce toxicity of the 
DCF regimen have been and are being pursued.  These include substituting carboplatin for 
cisplatin, reducing FU to low-dose continuous infusion[20-22], or limiting the infusion of FU to 
24 hours[23, 24] or 72 hours[25].  Unfortunately, these modifications are not clearly superior to 
the ‘parent’ DCF regimen. For example, the regimen developed by SAKK involves fluorouracil 
administered as a low dose continuous infusion at 300 mg/m2/day for 2 out of 3 weeks is furthest 
along in development.  Although investigators observed approximate equivalent efficacy, they 
also noted approximate equivalent toxicity to the parent DCF regimen[22].  Specifically, they 
reported a 76% incidence of grade 3-4 neutropenia, 39% rate of febrile neutropenia, and a 44% 
rate of dose reductions/cycle.   
 
Another study evaluated an alternative schedule of FU given weekly over 24 hours with 
leucovorin (the AIO schedule). [26]  These investigators initiated a study combining this 
administration schedule of FU with cisplatin 50 mg/m2 and docetaxel 50 mg/m2 given every 
other week, and noted once again that more than 80% of patients required a dose reduction.  
They completed their phase II study with cisplatin and docetaxel at 40 mg/m2 given every other 
week, and FU 24 hour infusion administered weekly and did notice a modest improvement in 
toxicity with a slight reduction in dose adjustments (62% of patients instead of over 80%).  
Notable grade 3/4 adverse events with this schedule included 20.4% neutropenia, 6.1% febrile 
neutropenia, 22.4% diarrhea, 8.2% nausea, 10.2% vomiting, and 18.4% fatigue.  Although an 
apparent improvement over parent DCF, this schedule still was relatively toxic. 
 
On the other hand, we are not aware of studies evaluating the combination of cisplatin and 
docetaxel with the de Gramont schedule of FU administration.  This FU administration schedule 
is commonly used in colorectal cancer[27] with both irinotecan and oxaliplatin and is considered 
well tolerated and an improvement over bolus schedules and prolonged continuous infusion 
schedules of FU/LV administration.  This FU administration schedule has been examined in 
upper GI cancers with oxaliplatin[28, 29] and is felt to be quite tolerable.  Bouche et al examined 
the de Gramont administration schedule of FU with cisplatin 50 mg/m2 in gastric and GEJ 
adenocarcinoma as well, and noted a slightly lower incidence of grade 3-4 neutropenia of 60%, 
similar rates of nausea/vomiting, and notably, a 0% incidence of grade 3-4 stomatitis[30].  This 
modest improvement in toxicity over cisplatin and 5-day infusion fluorouracil is particularly 


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encouraging in light of similar (or possibly slightly improved) efficacy over what is historically 
observed with cisplatin and 5-day infusional fluorouracil.  Finally, although anecdotal, we (Dr. 
Shah and Dr. Kelsen) have personal experience with administrating cisplatin and fluorouracil 
with the de Gramont schedule of FU administration and also find the regimen quite tolerable and 
as active.   
3.3.3 Irinotecan based combination therapy 
Recently, irinotecan based combinations have been evaluated in random assignment phase II and 
III clinical trials[16, 17, 30] (see table 2).  The largest study is a random assignment phase III 
study involving 337 patients comparing irinotecan + fluorouracil (IF) versus cisplatin + 
fluorouracil (CF). [17] In this study, fluorouracil was administered weekly over 22 hours with 
leucovorin in the IF arm, and fluorouracil was administered as a continuous infusion over 5 days 
as is commonplace in the CF arm.  There was no improvement in survival with IF (hazard ratio 
1.08; 95%CI: 0.86-1.35), however this arm did appear to have a reduction in grade 3-4 toxicity.  
A second study performed by Bouche et al is a random assignment phase II study of irinotecan 
with fluorouracil and cisplatin with fluorouracil, using the De Gramont schedule of fluorouracil 
administration in both arms[30].  This study demonstrated similar results of approximate equal 
efficacy[30] with potentially less toxicity with irinotecan than with cisplatin. 
 
3.3.4 Rationale for addition of trastuzumab to mDCF in HER2-postive gastric/GEJ 
adenocarcinoma patients. 
Trastuzumab is a humanized monoclonal antibody (IgG1 isotype) directed against the 
extracellular region of HER2 that has been developed as a therapeutic modality for treating 
HER2-positive breast cancer.   Trastuzumab is approved by the U.S. Food and Drug 
Administration (FDA) for the adjuvant treatment of patients with HER2-overexpressing, node-
positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, 
and paclitaxel. Trastuzumab is also indicated as a single agent and in combination with paclitaxel 
for the treatment of patients with HER2-positive metastatic breast cancer. In these patients, the 
combination of trastuzumab plus paclitaxel results in improved response rate, time to disease 
progression, and overall survival compared with single-agent paclitaxel. 
 
With the results of the recent phase III ToGA study, the benefit of trastuzumab in combination 
with cisplatin and fluoropyrimidine (CF) chemotherapy in HER2-positive metastatic gastric/GEJ 
adenocarcinoma has been established.2 In this study, HER2-positive patients (FISH+ and/or IHC 
3+) were randomly assigned to receive CF alone or with trastuzumab. Patients assigned to 
receive trastuzumab + CF had a significant improvement in overall survival (13.8 mo vs 11.1 
mo, HR 0.74 [0.6-0.91], p = 0.0046).  Trastuzumab is the first biological strategy to show a 
survival benefit in advanced GC.  Based on these results, trastuzumab is now in the NCCN 
compendium for treatment of patients with HER2-positive advance gastric cancer in combination 
with systemic chemotherapy.   
This amendment is written to ensure that Her2 positive gastric cancer patients are able to receive 
trastuzumab with chemotherapy in the first line setting in gastric cancer.  Notably, the ToGA 
study involved an acceptable standard two drug chemotherapy regimen to which the addition of 


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trastuzumab was randomly assigned.  The rationale to incorporate trastuzumab in this study is to 
report the efficacy of a three drug gastric cancer regimen with trastuzumab amongst a cohort of 
Her2 positive patients.   
3.3.5 HER2 testing in gastric/GEJ adenocarcinoma patients 
Accurate HER2 testing is crucial for the successful application of trastuzumab in the clinical 
setting.  In ToGA, HER2 positivity was defined using IHC published by Hofmann et al 
specifically for  gastric cancer.1  In a validation study of HER2 scoring in 168 gastric cancer 
resection specimens, Hofmann et al noted  in gastric cancer a higher rate of tumor heterogeneity 
and incomplete basolateral membranous compared to breast cancer tumors.  Hofmann et al 
investigated the application in gastric cancer of the testing methodologies commonly used to 
detect HER2  in breast cancer specimens and proposed a refined HER2 IHC scoring system 
suitable to score gastric cancer samples accurately and reproducibly. Most notably, according to 
the Hofmann criteria, biopsy samples with cohesive IHC3+ or FISH+ clones are considered  
HER2 positive irrespective of size, i.e.<10%. (In Breast Cancer for example, IHC3+ requires a 
minimum of 30% IHC membranous staining.) 
 
To determine if the breast ASCO/CAP guidelines for HER2 assessment can be used to accurately 
determine HER2 status in gastric cancer, we studied HER2 status of tumor specimens from 133 
advanced gastric cancer patients undergoing treatment at MSKCC.  HER2 IHC and FISH was 
performed for all specimens using ASCO/CAP guidelines and the Hofmann et al criteria. We 
found that HER2 in gastric cancer can be accurately evaluated using the breast cancer 
ASCO/CAP guidelines, with the exception that in small biopsy specimens with any cohesive 
HER2  IHC3+ or FISH+ clones should be considered HER2 positive.  For the purposes of this 
protocol, patients that are IHC 1+ or 2+ will undergo FISH testing to confirm HER2 positivity.  
Patients with IHC 3+ or FISH+ (>2 HER2:CEP17) will be eligible to receive treatment with 
trastuzumab on study.   
 
3.4 SUMMARY OF CHEMOTHERAPY FOR GASTRIC/GEJ ADENOCARCINOMA 
A careful review of the data described above reveals that there is no consensus standard 
chemotherapy regimen for the first line treatment of unresectable or metastatic gastric/GEJ 
adenocarcinoma at this time.  Although chemotherapy is better than best supportive care, we 
have observed little to no improvement in overall survival beyond 8-10 months in randomized 
controlled clinical trials examining several different combination treatments.  Cisplatin and 
fluorouracil based therapy is most commonly used as the reference arm in these random 
assignment phase III studies, and as a component of the investigational arm in several of these 
random assignment phase III studies.   
 
The addition of docetaxel to cisplatin and fluorouracil is superior to cisplatin and fluorouracil 
alone.  Based on this, docetaxel has received FDA and European Union approval in combination 
with fluorouracil and cisplatin for the first line treatment of gastric and GEJ adenocarcinoma.  
However, the toxicity of this three drug regimen, although not significantly worse than cisplatin 


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and fluororaucil infusion alone, is still significant, and is the primary limitation of its widespread 
acceptance.   
December 2009 Amendment 
With the recent compendium listing of trastuzumab as part of the first line treatment of gastric 
cancer, trastuzumab is now indicated in the first line setting with combination chemotherapy for 
the treatment of advanced gastric/GEJ adenocarcinoma.  Patients who are Her2 positive should 
receive standard combination chemotherapy with trastuzumab.  Patients who receive 
trastuzumab will be considered as a separate and independent cohort from the primary analysis. 
3.5 PROPOSAL 
With recent FDA and European Union approval, a combination of docetaxel, cisplatin and 
fluorouracil is now an acceptable standard regimen for the first line treatment of gastric and 
gastroesophageal junction adenocarcinomas.  However, the toxicity of the parent DCF regimen 
as originally prescribed has prevented its widespread acceptance and usage.   
 
We therefore propose to evaluate two modifications of the parent DCF regimen in a random 
assignment phase II clinical trial.  In ARM A, we propose a modified DCF schedule with the 
following specific modifications to parent DCF: (1) a de Gramont schedule for FU 
administration, (2) reduced bi-monthly doses of cisplatin and docetaxel, and (3) the 
administration of docetaxel and cisplatin on consecutive days instead of immediately following 
one another.  See section 3.5.1 for detailed discussion for the rationale of the mDCF schedule. 
In ARM B, we will examine parent DCF with prophylactic growth factor support.  Recall that in 
the TAX325 study, patients who received prophylactic G-CSF had a significantly reduced 
incidence of grade 3-4 neutropenia and incidence of febrile neutropenia or neutropenia with 
infection.   
With this study, we will establish the efficacy and tolerability of modified DCF and of parent 
DCF with growth factor support.  If mDCF appears to maintain the efficacy of the parent DCF 
regimen with less toxicity, we will have established a new treatment regimen for this disease to 
which targeted agents can be examined. 
 
December 2009 Amendment 
Due to toxicity, Arm B is now closed to further accrual.  Arm A will continue to enroll until 
target accrual.  In addition, patients who are Her2 positive will receive trastuzumab with mDCF, 
in a separate, independent cohort. 
 
August 2010 Amendment  
We have reached target accrual in Arm A. Her2 positive patients will receive trastuzumab with 
mDCF, in a separate, independent cohort. 
 
3.5.1 Modified DCF dose and schedule determination 
The specific modifications to parent DCF that we have proposed include (1) a de Gramont 
schedule for FU administration, (2) reduced bi-monthly doses of cisplatin and docetaxel, and (3) 


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the administration of docetaxel and cisplatin on consecutive days instead of immediately 
following one another.   
We believe that a modified FU administration schedule (bolus + 48 hour infusion of FU) will 
confer less toxicity than longer infusion schedules of FU currently in use (eg. 5 day infusion used 
in parent DCF) with similar efficacy.  Several lines of evidence from gastric cancer studies 
support altering the FU schedule to a bolus + 48 hour infusion and to administering 
chemotherapy bi-monthly at reduced doses.  The most convincing is from Bouche et al. that 
describes a three arm random assignment phase II study with each arm receiving LV5FU2[30].  
LV5FU2 is the same FU administration schedule as we have proposed in this study (bolus + 48 
hr infusion).  In the Bouche  study, Arm A was LF5FU2 alone, arm B was cisplatin 50 mg/m2
with LV5FU2, and arm C was irinotecan + LV5FU2.  The response rate and survival of LV5FU2 
(arm A) is consistent with that reported for single agent FU[5].  In addition, the response rate and 
survival of arm B (Cisplatin + LV5FU2) is consistent with that reported for cisplatin and FU x 5 
day infusion schedules[5, 11, 17].  Notably, the efficacy is maintained while keeping the relative 
dose intensity for cisplatin identical to the historical standard of cisplatin and fluorouracil 5-day 
infusion. Specifically when cisplatin is administered with the 5-day infusion of FU, it is given at 
100 mg/m2 every 4-weeks which yields a dose intensity of 25 mg/m2/week.  When cisplatin is 
administered with LV5FU2, it is administered at 50 mg/m2 every other week, which yields an 
equivalent dose intensity of 25mg/m2/week.   
The table below describes the efficacy of cisplatin and infusional FU (control arms) as observed 
in 3 recent large phase III studies and of cisplatin + LV5FU2 as described in the Bouche et al 
study. 
Reference 
Treatment 
Regimen 
n 
Response Rate2 
(95% CI) 
1-Year Survival 
(95% CI) 
Median 
Survival 
Ajani, 
2003[11],  
Moiseyenko 
2005[12] 
Cisplatin + 
Infusional FU 
224 
25.4% 
(19.9 – 31.7%) 
31.6% 
8.6 mo 
(7.16 – 9.46) 
Ohtsu, 
2003[5] 
Cisplatin + 
Infusional FU 
105 
34.3% 
(25.3 - 44.2%) 
28% 
7.3 mo 
Dank 
2005[17] 
Cisplatin + 
Infusional FU 
165 
25.8% 
8.7 mo  
(7.8 – 9.8 mo) 
 
 
 
 
Bouche, 2004 
[30] 
Cisplatin + 
LV5FU2 
44 
27% 
(14% - 40%) 
43% 
9.5 mo 
(6.9 – 12.2 mo) 
The FU administration schedule (bolus + 48 hour, or LV5FU2) with bi-monthly cisplatin 
administration confers approximate equal efficacy with regard to response rate, 1-year 
survival, and median survival when compared to the traditional cisplatin + infusional FU x 5 
day schedule. 
 
 
 
 
 
 


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With regard to the question of equal or reduced toxicity, the table below summarizes the relevant 
toxicity comparison: 
Toxicity (Grade 3-4) 
Cisplatin + LV5FU2 
(Bouche et al) (n=44)
Cisplatin + 5-day FU Infusion 
(Moiseyenko et al) (n=224)
Neutropenia
61%
57%
Febrile neutropenia 
18%
14%
Nausea/vomiting
23%
42%
Diarrhea
2%
18%
Mucositis
0%
61%
As shown, the toxicity of the bolus + 48 hour FU infusion and reduced bi-monthly 
administration of cisplatin schedule is significantly less toxic with regard to diarrhea, mucositis, 
nausea and vomiting.  Neutropenia is approximately equivalent.  Thus, because of approximate 
equal efficacy with considerably less toxicity, the proposed administration schedule is a 
significant improvement over the traditional cisplatin + 5-day FU infusion schedule.  Finally, we 
also have experience with docetaxel and cisplatin administered with this fluorouracil 
administration schedule in several patients with upper GI malignancies and have found the 
regimen be both quite tolerable and active (Shah and Kelsen, personal communication).  Based 
on these data above, we feel that administering fluorouracil as per the De Gramont schedule 
(bolus + 48 hour infusion) provides approximate equivalent efficacy to 5 day FU administration 
schedules.  When coupled with less frequent dosing of cisplatin, the combination is associated 
with less toxicity. 
 
With regard to the best dose of cisplatin and docetaxel when both drugs are administered 
together with fluorouracil, two gastric cancer studies provide additional support (Lorenzen 
described here and Oh described below).  A phase II study by Lorenzen and collegues was 
reported at the 2006 GI Cancer symposium (San Francisco, CA) in which docetaxel and cisplatin 
(50 mg/m2 each) were administered every other week in combination with a 24 hour infusion of 
FU (2,000 mg/m2 over 24 hours) which was administered weekly[26].  The investigators felt that 
the combination at those doses of cisplatin and docetaxel was still too toxic and amended their 
study to administer docetaxel and cisplatin at a reduced dose of 40 mg/m2 every other week.  
With these lower doses (eg. the doses that we have proposed), the investigators reported 
approximately equal efficacy to parent DCF with slightly improved toxicity including grade 3-4 
neutropenia 20% and nausea/vomiting 20%, thus supporting our proposal. 
 
Finally, by separating the docetaxel and cisplatin, we believe we will have even less toxicity due, 
in part, to improving docetaxel clearance when compared to the combined administration.   The 
rationale for this is that docetaxel is both a substrate and inhibitor of the cytochrome p450 
enzyme CYP3A4, and the standard antiemetics used when giving cisplatin (eg. aprepitant and 
palonesetronn) also are CYP3A4 inhibitors. Thus, by administering cisplatin on a different day 
from docetaxel, the clearance of docetaxel should improve, thus reducing toxicity.  This will be 
examined in the parallel random assignment study in which one arm will be mDCF and the other 


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arm will be parent DCF in which the docetaxel and cisplatin are administered on the same day 
immediately following one another. 
A recent phase II report of a Korean study of docetaxel + cisplatin + fluorouracil provides 
support for this hypothesis[31].  Specifically, in this phase II study, docetaxel was administered 
on day 1 (70 mg/m2), cisplatin was administered on days 2 and 3 (40 mg/m2 each day), and 
fluorouracil was administered over 10 hours on days 1, 2 and 3.  The regimen was repeated every 
3 weeks and again demonstrated approximate equal efficacy to parent DCF.  However most 
interestingly, the incidence of grade 3 or 4 toxicity including nausea, vomiting, diarrhea, 
leucopenia or neutropenia, and mucositis was each less than 10%, which is a remarkable 
improvement over the parent DCF regimen in which these toxicities were 40% or higher and 
80% for grade 3-4 neutropenia.  The investigators were unable to explain this reduced toxicity 
and hypothesized that it may be related to the Korean population of the study.  Alternatively, a 
potential PK interaction between cisplatin anti-emetics and docetaxel may explain this improved 
toxicity.   
 
The table below describes the relative dose intensity of the parent DCF (as scheduled and as 
actually delivered) and modified DCF: 
Modified DCF q other week 
ARM B – Parent DCF q 3 weeks
Drug 
Dose 
(mg/m2) 
 
Dose Intensity  
(mg/m2 per wk) 
Drug 
Scheduled 
Dose 
(mg/m2) 
Dose 
Intensity 
(mg/m2/wk) 
Delivered Dose 
Intensity 
(mg/m2/wk) 
Docetaxel 
40 
20 
Docetaxel 
75 
25 
22 
Cisplatin 
40 
20 
Cisplatin 
75 
25 
22 
Leucovorin
400 
X 
 
 
 
 
Fluorouracil 
400 
X 
Fluorouracil 
750 
X 
X 
Fluorouracil 
1000 
X 
 
 
 
 
As shown, the proposed dose of docetaxel and cisplatin in the modified DCF regimen represent 
80% of the scheduled dose of the parent DCF regimen.  However, the proposed dose is in fact 
90% of the delivered dose of the parent regimen.   
Thus, based on the data shown above, there is sufficient evidence from a number of sources to 
consider modified DCF as a reasonably safe and effective DCF regimen.   
(1) The bolus and 48 hour infusion schedule of FU is equivalent to the 5-day infusion 
schedule of FU but is associated with less toxicity.
 
(2) Administering reduced bi-monthly doses of docetaxel and cisplatin with FU confers 
less toxicity also while maintaining efficacy.  This toxicity profile may be further 
improved by administering docetaxel and cisplatin on different days due to a possible 
pharmacokinetic interaction between docetaxel and the delayed emesis regimen used 
for cisplatin. 
(3) The dose intensity of cisplatin and docetaxel in the proposed mDCF regimen is 
insignificantly different from what was delivered in the parent DCF regimen. 
 


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3.5.2 Pharmacokinetic and Pharmacodynamic Considerations  (MSKCC ONLY) 
Two initial phase I studies examined the combination of docetaxel and cisplatin[32, 33].  Pronk 
and colleagues evaluated two schedules of administration: Schedule A administered cisplatin as a 
3 hour infusion 3 hours folloing 1-hour docetaxel infusion (D1hour  3hr break  C3hour), and 
Schedule B administered cisplatin over 3 hours one day prior to docetaxel (C3hour day 1   D1hour
day 2).  These investigators noted that there was a trend toward greater hematologic toxicity with 
schedule B where cisplatin is given prior to docetaxel. This is consistent with the previous data 
regarding the sequence of administration of cisplatin and paclitaxel[34], and may be related to 
higher DNA-adduct formation and intracellular accumulation of cisplatin in human leukocytes if 
given prior to the taxane[35].  Pronk noted no significant differences in the pharmacokinetic 
parameters of cisplatin and docetaxel with the two schedules examined in their study[32].  
However, the authors did point out the 21 hour time interval between cisplatin and docetaxel in 
schedule B, and noted that when cisplatin precedes paclitaxel by 6 hours, paclitaxel clearance 
reduced by 25% [34].  The 2nd phase I study by Millward et al. administered cisplatin over 1 hour 
immediately following docetaxel 1 hour infusion[33].  They also noted no pharmacokinetic 
interactions.  In addition, they also evaluated the Pronk schedule A sequence of D1hour  3hr 
break  C3hour and it appeared that in a small number of patients, there was increased toxicity 
when administering cisplatin 3 hours following docetaxel instead of immediately following 
docetaxel.  Since these studies were published in 1997, the convention for virtually all 
subsequent evaluations involving the combination of docetaxel and cisplatin administered the 
drugs as described by Millward et al with docetaxel given over 1 hour and then followed 
immediately with cisplatin administered over 1 hour.   
 
Docetaxel is both a substrate and inhibitor of the cytochrome p450 enzyme CYP3A4, and its 
metabolism can be inhibited by CYP3A4 inhibitors such as ketoconazole, erythromycin, 
verapamil and diltiazem[36].  Importantly, both aprepitant and palonesetron, recently approved 
anti-emetic agents for the treatment of acute and delayed nausea, are both inhibitors of 
CYP3A4[37, 38]. Indeed, this inhibition results in reduced clearance of the concomitantly 
administered steroid, dexamethasone, resulting in the recommened reduced dose of 
dexamethasone when administered with aprepitant and palonesetron[39].  Similarly, inhibition of 
CYP3A4 by these anti-emetic agents could result in reduced docetaxel metabolism, increased 
drug exposure, and potentially increased toxicity.  However, a recent evaluation demonstrated no 
significant role of aprepitant on the pharmacokinetics of docetaxel[40].  However, this study did 
not examine docetaxel metabolites.  In one study, detection of the M4 docetaxel metabolite may 
indicate reduced docetaxel clearance and possibly increased myelosuppression[41]. 
 
In our experience, we have obsereved that the co-administration of docetaxel and cisplatin on the 
same day in combination with fluorouracil infusion is associated with signficant nausea, 
vomiting, and delayed emesis – in particular, significantly more so than when either cisplatin or 
docetaxel is administered alone with the same fluorouracil schedule.  Aprepitant and 
palonesetron may be used to prevent acute and delayed emesis from cisplatin.  However, it may 
inadvertently result in reduced docetaxel clearance and increased docetaxel related toxicity, or if 
not the parent compound, possibly reduced clearance of a metabolite.  We note that the anti-
emetic drugs, aprepitant and palonesetron, are administered primarily for cisplatin associated 


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nausea and vomiting.  Based on these findings, we have moved cisplatin to be administered 1-2 
days following docetaxel in several patients treated with mDCF already.  Interestingly, we have 
anecdotally (in approximately 10 patients) noted a considerable improvement in their tolerance 
to the mDCF, thus supporting this hypothesis and warranting its further evaluation.    
 
To examine this further and more formally, we propose to evaluate the pharmacokinetics of 
docetaxel and its metabolites in approximately 10 patients in each arm.  Recall that docetaxel and 
cisplatin in Arm B are both given on day 1, along with initiation of the 5 day fluorouracil 
infusion.  We believe there will be a significant difference in docetaxel clearance in the two arms 
that may explain, in part, the signficant toxicity of the parent DCF regimen.   
 
Pharmacokinetic blood draws will occur in patients enrolled at MSKCC only.  We will perform 
serial blood draws in approximately 20 patients (10/ arm) at the following times: 
 
1. 0.25 hours (15 min following initiation of docetaxel) 
2. 0.75 hours (45 min following initiation of docetaxel) 
3. 1 hour 
(end of docetaxel infusion) 
4. 1. 25             ( 15 min following the end of docetaxel infusion) 
5. 2 hours 
6. 4 hours 
7. 6 hours 
8. 8 hours 
9. 24 hours 
 
Additionally, on day 3, a CBC with differential and LFT’s (AST, ALT, Alk Phos, total Bilirubin) 
will be drawn in each these patients.  For Arm A, these lab studies will be drawn prior to 
cisplatin administration.   
 
March 2008 Addendum: On our initial pharmacokinetic analysis, we have observed that the 
clearance of docetaxel appears to be reduced when it is administered on day 1 with cisplatin 
(Arm B), and this is associated with an increased exposure to docetaxel.  Conversely, when 
docetaxel is administered on day 1 and cisplatin is administered on day 3, docetaxel clearance 
appears to be higher and is associated with a lower AUC∞.  Recall that our hypothesis is that 
reduced clearance and higher exposure to docetaxel may be responsible for some of the increased 
toxicity observed with the parent DCF (Arm B) regimen.   Based on this, we will expand our 
pharmacokinetic evaluation and examine additional docetaxel PK without cisplatin in up to 6 
patients randomized to parent DCF who underwent cycle 1 docetaxel PK (when cisplatin was 
administered on day 1 as well).  See section 9.4.3. 


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3.5.3  FDG-PET Response Assessment 
We are interested in the utility of 
functional imaging to predict and 
monitor treatment response in gastric 
cancer.  To begin to examine this 
question, we initiated an NCI sponsored 
phase II clinical trial of preoperative 
chemotherapy with irinotecan and 
cisplatin for locally advanced gastric 
cancer (NCI 5917).  We planned to use 
functional imaging with FDG-PET/CT 
scans early in the treatment plan to predict treatment efficacy.  Patients with high-risk 
gastric cancer (preoperative stage T2N+, T3-T4, 
Nany, M0) were eligible.  The study schema is 
provided in the figure below.  Enrolled patients 
received preoperative chemotherapy with 
cisplatin 30 mg/m2 and irinotecan 65 mg/m2 
during weeks 1, 2, 4, 5, 7, 8, 10, and 11, prior to 
surgical resection. FDG-PET/CT scans were 
performed prior to initiation of therapy, during 
week 3 and week 6 (day 15 and 35, respectively), 
and following completion of pre-operative 
therapy, prior to surgery. Thus far, 42 patients 
have enrolled on this phase II study with the 
following patient characteristics: median age 62 (range 25-83), male 29, KPS 90% (70%-
90%).   
We first demonstrate that pathologic treatment response is a surrogate for 
treatment efficacy.  Pathologic assessment of treatment response is assessed 
histologically, by visual assessment, based on the identification of residual cancer cells 
and on the extent of fibrosis[42].  In this system, a tumor regression grade (TRG) is 
established, and quantitated into five grades, ranging from TRG 1 (complete regression) 
to TRG 5 (complete absence of regressive changes).  Response assessment is based on 
areas of tumor treatment effect that are characterized by the replacement of neoplastic 
tissue with fibrous tissue and scattered inflammatory cells.  We have converted this 
grading system to a percent treatment response score from 0 to 100%, such that a TRG1 
score has a 100% treatment response score, and a TRG5 has a treatment response of less 
than 10%.  We evaluated the histopathologic response to treatment with disease free 
recurrence.  32 patients are evaluable thus far.  Our median follow up period for these 
patients is 14 months and thus far, 13 patients (out of 32) have recurred.  Based on this 
preliminary analysis, there is a significant correlation between pathologic response to 
therapy and disease free recurrence (see figure to the right).  These data suggest that a 
10% increase in pathologic response corresponds to a 49% risk reduction of recurrence (p 
= 0.013).   


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Next, we demonstrate the correlation between change in functional imaging and 
pathologic response.  The two graphs below demonstrate the correlation between FDG-
PET/CT response and pathologic response.  It is important to point out that the FDG 
response assessment occurs at day 15 and at day 35, where one could potentially switch 
the chemotherapy regimen to alternative treatments in the hopes of improving response to 
therapy.  Notably, the pathologic response assessment described above occurs at the time 
of surgical resection, approximately at day 127.  At that time point, it is too late to switch 
therapy from ineffective therapy (eg. that associated with a minimal pathologic response 
to treatment) to a potentially more effective therapy. This is highlighted below by the 
pathologic response axis (y-axis on both graphs).  Specifically, all of the patients who 
have recurred (red plus symbols) had a pathologic response of 20% or less. Knowing that 
one is destined for a poor pathologic response a priori would warrant a change in therapy 
with the hopes of improving this response.  We have already demonstrated preliminary 
evidence that a poor pathologic response increases the probability of early recurrence, 
and certainly death from disease.  With this in mind, the figures below demonstrate that 
with a high FDG response (eg. above 40% by day 15, or above 50% by day 35), the 
chance of achieving a high pathologic response to preoperative chemotherapy is quite 
high, whereas a lower FDG response is associated with a lesser degree of pathologic 
response and a higher chance of disease recurrence.  
Correspondence between decrease in FDG SUV from baseline to on-treatment scan and 
pathologic response.  In the graphs above, the open circles are patients who have not had 
a recurrence and the plus symbols represent patients who have had a recurrence.   
These data support the fact that an early 
FDG-PET scan can predict response to 
chemotherapy that is identified histopathologically 
in the surgical resection specimen almost 3 months 
later.  We then evaluated the association of FDG-
PET response to recurrence and again found a 
strong and significant association (see figure to the 
left).  This figure demonstrates the high correlation 
with FDG response (at day 35 in this case) and risk 


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of recurrence.  A 50% or greater reduction in FDG-SUV by day 35 of the chemotherapy 
treatment plan is associated with an extremely low chance of disease recurrence, whereas 
a less than 50% reduction in FDG-SUV is associated with a significantly higher 
probability of disease recurrence (p = 0.045).  Altogether, these data suggest that an early 
FDG-PET/CT scan, when compared with a baseline scan, may be predictive of response 
to preoperative chemotherapy as assessed by histopathologic response assessment and by 
disease free recurrence. 
 
3.5.4 Discontinuation of chemotherapy after 6 months. 
 
The study will allow for discontinuation of docetaxel, cisplatin, and/or 
fluorouracil at the discretion of the treating physician after having completed 6 months of 
chemotherapy.  The rationale for this comes from a growing body of evidence that 
suggests that patients with solid tumor malignancies need not received cytotoxic 
chemotherapy until disease progression. For example, in metastatic NSCLC, it is well 
accepted that 4 to 6 cycles of platinum based chemotherapy is a superior strategy as 
compared to maintenance chemotherapy(Pfister, JCO 2003).  In metastatic colorectal 
cancer, the OPTIMOX1 study shows that intermittent dosing of oxaliplatin is less toxic 
and associated with an equivalent progression free survival and overall 
survival(Tournigand, JCO 2006).  Similarly, in prostate cancer, patients who receive 
intermittent androgen ablation also demonstrate no evidence of decreased survival or 
time to progression, and did have a benefit of reduced toxicity(Calais Da Silva, ASCO 
2006).  Our primary endpoint is a landmark analysis of progression at 6 months.  
Allowing patients to discontinue cytotoxic therapy after 6 months does not interfere with 
our primary endpoint, and may reduce cumulative toxicity (particularly from docetaxel 
and cisplatin) without adversely treatment efficacy.   
 
3.5.5 Assessment of Quality of Life 
 
The study will include an assessment of quality of life on both arms of the study 
at baseline, and periodically during the course of treatment.  We will use the EORTC 
QLQ-C30 instrument to examine quality of life.  This is a validated instrument that has 
been used in many large studies, including in gastric and gastroesophageal randomized 
studies(Aaronson, JNCI 1993; Glimelius, Ann Onc 1997; Ross, JCO 2002).  We will 
administer the questionnaire at baseline, 6 weeks, 3 months, and 6, 9, and 12 months.   
 
3.5.6 Volumetric CT Analysis of Response to Therapy (MSKCC only) 
 
At MSKCC only and in collaboration with Larry Schwartz, MD, we will also 
initiate an exploratory volumetric CT analysis of Response to therapy.  This study will 
make use of already acquired image data from this clinical trial. No additional human 
material or CT scans will be needed.  The standard CT scan data (acquired either during 
PET/CT scanning or CT scanning) will be electronically transferred, via the hospital 
network, from the hospital PACS to the research PACS server, where patient 
identification information are de-identified.  Volumetric CT will be used in an 
exploratory way to assess tumor response during therapy to compare with RECIST.  The 
volumetric analysis, however, will not affect patient care and will not be communicated 


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to the patient or clinical investigator.  To study effects of a wider range of slice thickness 
on the performance of the segmentation algorithms and reproducibility of tumor 
measurements, thinner section CT images will be reconstructed with CT raw data 
acquired for the radiographic assessment in the trial.  The volumetric CT technique used 
in this study may be able to detect asymmetric or small change in tumor size at the level 
that may not be possible with the conventional uni-dimensional RECIST criteria.   
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
          4.1 Design 
This will be a random assignment phase II study of two different administration schedules of 
docetaxel, cisplatin, and fluorouracil in patients with unresectable or metastatic gastric or GEJ 
adenocarcinoma.  Patients may have received neoadjuvant and/or adjuvant chemotherapy or 
chemoradiotherapy.  Patients may not have received previous chemotherapy containing cisplatin 
or docetaxel.  Prior fluorouracil is allowed if more than 6 months have passed since the patient 
last received it.  Patients must provide written informed consent prior to study enrollment.   
At baseline, patients will require a full medical history and physical examination, 
including assessments of body weight, height, calculated body surface area, and vital 
signs (blood pressure, heart rate, respiratory rate, and temperature).  Laboratory 
assessment will include CBC with differential, PT, PTT, comprehensive biochemical 
screening profile (which includes electrolytes, BUN, creatinine, AST, ALT, total 
bilirubin, total protein, albumin, alkaline phosphatase, and glucose), Ca, Mg, Phosphorus, 
LDH, and urinalysis. For females of childbearing potential, a serum pregnancy test is also 
required.  Additional evaluation will include baseline ECG and a signed informed 
consent.  CT scan of chest, abdomen, and pelvis will be performed in all patients and 
documentation of tumor measurement, in centimeters will be done. A baseline PET/CT 
scan will be performed as well for staging. In cases where there are multiple metastases, a 
representative sample of large masses, up to a total of five, will be chosen as the index 
lesions to be followed for a response, as per RECIST criteria.  Measurable disease is not a 
requirement for study entry.  Biopsy confirmation of M1 disease is encouraged, unless 
the risk of such a procedure is significant, in which case confirmation by a 2nd imaging 
modality is required (eg. PET/CT scan may be sufficient if tumor and metastases are both 
FDG avid). 
December 2009 Amendment 
As of October 2009, trastuzumab plus chemotherapy is part of the NCCN standard 
treatment algorithm for the first line for advanced gastric/GEJ adenocarcinoma.  This 
amendment is to allow patients who are Her2 positive to receive trastuzumab with 
mDCF.  Her2 positive patients are defined as FISH + and/or IHC 3+ for Her2 . Biopsy 
samples with cohesive IHC3+ or FISH+ clones are considered  HER2 positive 
irrespective of size, i.e.<10%.  FISH+ defined as >2 HER2:CEP17.  To receive 
trastuzumab, patients must have a baseline left ventricular ejection fraction of > 50%. 


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4.2 
Intervention 
Eligible patients will be randomly assigned to receive mDCF (ARM A) or parent DCF 
with growth factor support (ARM B) as follows: 
ARM A – Modified DCF 
ARM B – Parent DCF with G-CSF
Drug
Dose (mg/m2) 
Schedule 
Drug 
Dose (mg/m2) 
Schedule 
Docetaxel 
40 
Day 1 IVPB (60 min) 
Docetaxel 
75 
Day 1 IVPB (60 min) 
Leucovorin 
400 
Day 1 IVPB (30 min) 
Cisplatin 
75 
Day 1 IVPB (60 min) 
Fluorouracil 
400 
IVP day 1 
Fluorouracil 
750 
IVCI daily x 5 days 
Fluorouracil 
1000 mg/m2/d 
IVCI daily x 2 days 
Neulasta 
6 mg 
subcut on d 8, 9, or 10 
Cisplatin 
40 
Day 2 or 3 IVPB (30 min) or Neupogen 
300 or 480 mcg* 
subcut x 7 d 10-17 
* 300 mcg for weight < 60 kg, 480 mcg for weight > 60 kg. 
Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments).  
Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 
treatments).  
 
December 2009 Amendment 
We have met the early stopping rule for Arm B, parent DCF with growth factor support.  Arm A 
will continue to accrue until target accrual of 54 patients. In addition, we will treat Her2 positive 
patients with mDCF + trastuzumab.  Trastuzumab will be administered on an every 2 week 
dosing schedule, with an initial loading dose of 6 mg/kg over 90 minutes, followed by 
trastuzumab 4 mg/kg every 2 weeks over 30 mintues.   
A given treatment may be moved +/- 14 days for specific administrative reasons, in particular 
clinic closure for holidays.  Tumor assessments will be performed following the completion of 
every cycle for the first 6 cycles, and then every 2 cycles thereafter.  Therapy will be 
administered in an outpatient setting, under the supervision of a physician and/or chemotherapy 
nurse, as is standard for chemotherapy administration at the treating institution.  
Clinical evaluation: All assessments may be performed within one day of the planned treatment.   
ARM A – Modified DCF 
Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of cycle one (e.g. on day 1, day 15, and day 29 of cycle 1).  In cycle 2 and all 
subsequent cycles, a physician evaluation (e.g. physical examination and toxicity assessment) 
will be performed prior to treatment on day 1 and day 29 treatments.  Additional nurse or 
physician visits will be at the discretion of the treating physician.  It is encouraged that an 
oncology nurse toxicity evaluation be performed prior to each treatment, especially if the patient 
is not assessed by a physician.  
Patients treated with mDCF plus trastuzumab therapy should be monitored for signs and 
symptoms of CHF (i.e., dyspnea, tachycardia, new unexplained cough, neck vein distention, 
cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and 
rapid unexplained weight gain).   
ARM B – Parent DCF with G-CSF 


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Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of every cycle. 
Laboratory evaluation:  
ARM A – Modified DCF 
On or within 1 day of the beginning of each cycle, a CBC with differential and platelet count, 
serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, alkaline 
phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, LDH, and 
tumor markers will be performed.  A CBC with differential and platelet count is required prior to 
each subsequent treatment (eg. day 15 and day 29).  A BUN and Creatinine is required before the 
day 15 treatment (treatment #2), and a serum chemistry (electrolytes, BUN, Creatinine, glucose) 
is required before each day 29 treatment (#3). LFTs are required before each treatment (#1, #2 
and #3) of cycle 1, and before treatment #1 and #3 for each subsequent cycle.  Any patient with 
excessive LFTs abnormalities (see section 9.3) will require repeat LFTs prior to the next 
docetaxel administration. 
ARM B – Parent DCF with G-CSF 
On or within 1 day of the beginning of each treatment, a CBC with differential and platelet 
count, serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, 
alkaline phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, 
LDH, and tumor markers are required.   
 
Radiology evaluation: For both treatment arms, radiographic studies upon which tumor 
measurements were made will be repeated every cycle (six week intervals for most patients) for 
6 cycles, and then after every two cycles of therapy (e.g. after cycles 1, 2, 3, 4, 5, 6, 8, 10, 12 
etc.), to rule out progression of disease and to determine response for measurable disease.  
Patients will remain on study until disease progression, patient withdrawal, unacceptable toxicity 
despite dose attenuation, or if the treating physician deems it is in the best interest of the patient 
following discussion with the principal investigator.  Tolerability of this regimen will be 
determined from blood test results and toxicity assessment. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1  Docetaxel (TAXOTERE®) 
For complete details, please see the package insert for further information. 
5.1.1  Description 
Docetaxel is an antineoplastic agent belonging to the taxoid family.  It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of 
yew plants.  Docetaxel is a white to almost-white powder with an empirical formula of 


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C43H53N014-3H20, and a molecular weight of 861.9.  It is highly lipophilic and practically 
insoluble in water.   
5.1.2  Preparation and Administration  
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, 
caution should be exercised when handling and preparing DOCETAXEL solutions. The 
use of gloves is recommended. Please refer to Handling and Disposal section. 
If Docetaxel Injection Concentrate, initial diluted solution, or final dilution for infusion 
should come into contact with the skin, immediately and thoroughly wash with soap and 
water. If Docetaxel Injection Concentrate, initial diluted solution, or final dilution for 
infusion should come into contact with mucosa, immediately and thoroughly wash with 
water. 
Contact of the Docetaxel concentrate with plasticized PVC equipment or devices used to 
prepare solutions for infusion is not recommended. In order to minimize patient exposure 
to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC 
infusion bags or sets, the final Docetaxel dilution for infusion should be stored in bottles 
(glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered 
through polyethylene-lined administration sets. 
Docetaxel Injection Concentrate requires two dilutions prior to administration. Please 
follow the preparation instructions provided below. Note: Both the Docetaxel Injection 
Concentrate and the diluent vials contain an overfill to compensate for liquid loss during 
preparation.  This overfill ensures that after dilution with the entire contents of the 
accompanying diluent, there is an initial diluted solution containing 10 mg/mL docetaxel. 
The table below provides the fill range of the diluent, the approximate extractable volume 
of diluent when the entire contents of the diluent vial are withdrawn, and the 
concentration of the initial diluted solution for DOCETAXEL 20 mg and DOCETAXEL 
80 mg. 
Product 
Diluent  
13% (w/w) ethanol 
 in water for injection 
Fill Range 
(mL) 
Approximate 
extractable volume of 
diluent when entire 
contents are withdrawn  
(mL) 
Concentration of 
the initial diluted 
solution 
(mg/mL docetaxel) 
 
 
 
 
Taxotere®  
20 mg/0.5 mL 
1.88 – 2.08  mL 
1.8 mL 
10 mg/mL 
Taxotere®  
80 mg/2 mL 
6.96 - 7.70 mL 
7.1 mL 
10 mg/mL 
A. Initial Diluted Solution
1. Docetaxel vials should be stored between 2 and 25°C (36 and 77°F). If the vials are 
stored under refrigeration, allow the appropriate number of vials of Docetaxel Injection 
Concentrate and diluent (13% ethanol in water for injection) vials to stand at room 
temperature for approximately 5 minutes. 


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2. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 
1.8 mL for Docetaxel 20 mg and approximately 7.1 mL for Docetaxel 80 mg) into a 
syringe by partially inverting the vial, and transfer it to the appropriate vial of 
Docetaxel Injection Concentrate. If the procedure is followed as described, an initial 
diluted solution of 10mg docetaxel/mL will result.
3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure 
full mixture of the concentrate and diluent. Do not shake. 
4. The initial diluted Docetaxel solution (10 mg docetaxel/mL) should be clear; however, 
there may be some foam on top of the solution due to the polysorbate 80. Allow the 
solution to stand for a few minutes to allow any foam to dissipate. It is not required that 
all foam dissipate prior to continuing the preparation process. 
The initial diluted solution may be used immediately or stored either in the refrigerator 
or at room temperature for a maximum of 8 hours. 
B. Final Dilution for Infusion 
1. Aseptically withdraw the required amount of initial diluted Docetaxel solution (10 mg 
docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle 
of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final 
concentration of 0.3 to 0.74 mg/mL. 
If a dose greater than 200 mg of Docetaxel is required, use a larger volume of the 
infusion vehicle so that a concentration of 0.74 mg/mL Docetaxel is not exceeded. 
2. Thoroughly mix the infusion by manual rotation. 
3. As with all parenteral products, Docetaxel should be inspected visually for particulate 
matter or discoloration prior to administration whenever the solution and container 
permit. If the Docetaxel initial diluted solution or final dilution for infusion is not clear 
or appears to have precipitation, these should be discarded. 
The final Docetaxel dilution for infusion should be administered intravenously as a 30-
minute to 60-minute infusion under ambient room temperature and lighting conditions. 
Stability: Docetaxel infusion solution, if stored between 2 and 25°C (36 and 77°F) is 
stable for 4 hours. Fully prepared Docetaxel infusion solution (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 
1 hour i.v. administration). 
How Supplied: Docetaxel Injection Concentrate is supplied in a single-dose vial as a 
sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-
pyrogenic, Diluent (13% ethanol in water for injection) vial. The following strengths are 
available: 
TAXOTERE 80 MG/2 ML 
 
(NDC 0075-8001-80) 
TAXOTERE (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 
2 mL polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in 
water for injection). Both items are in a blister pack in one carton. 


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TAXOTERE 20 MG/0.5 ML (NDC 0075-8001-20) 
TAXOTERE (docetaxel) ) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel 
in 0.5 mL polysorbate 80 and diluent for TAXOTERE 20 mg (13% (w/w) ethanol 
in water for injection). Both items are in a blister pack in one carton. 
Storage: Store between 2 and 25°C (36 and 77°F). Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs 
should be considered as per institutional guidelines.  
5.1.3  Source 
For this study, locally obtained commercial supplies of Docetaxel should be used.  
Because commercial drug will be used, accounting for Docetaxel drug supplies is not 
specifically required in this study. 
5.1.4  Safety Profile 
Principal adverse effects include neutropenia, thrombocytopenia, anemia, nausea, 
vomiting, diarrhea, ascites, mucositis, cardiac arrhythmias, hypotension, pleural effusion, 
peripheral neuropathy, rash, severe nail disorders (hypo or hyperpigmentation), 
onycholysis (loosening of the nails), alopecia, palmar-plantar dyserythroesthesia, 
hypersensitivity reaction, fatigue and fluid retention syndrome (may be irreversible). 
5.2       CISPLATIN 
For complete details, please see the package insert for further information. 
5.2.1 Description 
Cisplatin (cis-diaminedichloroplatinum, Platinol) is a heavy metal complex containing 
a central atom of platinum surrounded by two chloride atoms and two ammonia 
molecules in the cis- position. Cisplatin binds to DNA bases and produces particular 
types of cisplatin-DNA lesions or adducts. The drug is supplied in 10 and 50 mg amber 
vials. 
5.2.2 Preparation and Administration 
ARM A: Cisplatin will be given on days 1, 15, and 29 of each cycle. The drug will be 
given at a dose of 40 mg/m2 over 30 minutes on day 2 or 3 of each treatment. 
ARM B: Cisplatin will be given on days 1 and 22 of each cycle. The drug will be given at 
a dose of 75 mg/m2 over 60 minutes immediately following docetaxel administration. 
Cisplatin is available in 100mg/100 ml solution vials. The solution is then further diluted 
into saline-based solutions (preferably 100-150 ml of 0.9% NaCL for intravenous 
administration). Before drug administration the patient should be given intravenous 
hydration with at least 500 ml of 5 % dextrose in normal saline (D5W) or normal saline 
over 1-2 hours. Aluminum needles should not be used. Patients will be advised to 
maintain an oral fluid intake of at least one (1) liter per meter squared on the day of 
treatment. This regimen may be adjusted as needed, e.g., for elderly persons. 


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5.2.3 Source 
For this study, locally obtained commercial supplies of Cisplatin should be used. Because 
commercial drug will be used, accounting for Cisplatin drug supplies is not specifically 
required in this study. 
5.2.4   Safety Profile 
Cumulative nephrotoxicity associated with cisplatin is severe. Other major dose-related 
toxicities are myelosuppression, nausea and vomiting.  Ototoxicity, manifested by 
tinnitus and/or high frequency hearing loss, is significant. Anaphylactic-like reactions to 
cisplatin have been reported. Facial swelling, bronchospasm, tachycardia and 
hypotension may occur within minutes of cisplatin administration. Other side effects 
include anorexia, diarrhea, serum electrolyte disturbances (e.g., hyponatremia, 
hypomagnesemia), vascular toxicities (e.g., myocardial infarction, cerebrovascular 
accident etc.), neurotoxicity, peripheral neuropathy, autonomic neuropathy, muscle 
cramps, ocular toxicity (optic neuritis, papilledema, cerebral blindness), and 
hepatotoxicity. Other rare side effects include cardiac abnormalities, hiccoughs, elevated 
serum amylase, rash and alopecia. Local soft tissue injury has been reported following 
extravasation of cisplatin. 
 
5.3  FLUOROURACIL 
 
For complete details, please see the package insert for further information. 
5.3.1 Description 
The chemical name of fluorouracil (FU) is 5-fluoropyrimidine-2,4(1H,3H)-dione. 
Fluorouracil is also known by other names 5-Fluorouracil; Fluorouracilo; 
Fluorouracilum; 5-FU; NSC-19893; Ro-2-9757; WR-69596. Its molecular formula is 
C4H3FN2O2; it has a molecular weight of 130.1. FU is a white to almost white, 
practically odorless, crystalline powder. It is sparingly soluble in water; slightly soluble 
in alcohol; practically insoluble in chloroform and ether. A 1% solution has a pH of 4.5 to 
5.0; the USP injection has a pH of 8.6 to 9.4 and the BP injection has a pH of 8.5 to 9.1. 
Fluorouracil is commercially available, and supplied in the U.S. by ICN pharmaceuticals, 
Lyphomed, Quad Pharmaceuticals, Baxter Healthcare, Abbott Laboratories, and as 
Adrucil®hby Pharmacia & Upjohn. 
5.3.2 Preparation and Administration 
At our institution fluorouracil manufactured by Pharmacia & Upjohn (ADRUCIL®) is in 
use. It is supplied as a 50 mg/ml solution in vials of 50 ml and 100 ml. The appropriate 
volume is withdrawn into a syringe which is used for administration. No dilution is 
required. Filter ampules with aspiration needle (5µm). Compatible with D5W, 0.9% 
NaCl, D5LR. Fluorouracil will be administered as an intravenous push, usually over 1-2 
minutes followed by a 48-hour intravenous continuous infusion (further dilution is not 
required). Ensure vein patency before administration 


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Storage:  Store at room temperature and protect from light. Dark yellow color indicates 
decomposition.  Fluorouracil is stable in polypropylene syringes, and stable in PVC 
reservoirs for infusion pump usage for 12 days. Fluorouracil may adsorb to glass 
surfaces. It is stable in cellulose nitrate/acetate ester or Teflon filters. 
5.3.3 Source 
Locally obtained commercial supplies of Fluorouracil should be used. Because 
commercial drug will be used, accounting for Fluorouracil drug supplies is not 
specifically required in this study. 
5.3.4  Safety Profile 
Hematologic and gastrointestinal side effects are most frequently associated with 
fluorouracil. Hematologic toxicities of fluorouracil are leukopenia, granulocytopenia (9-
14 days), thrombocytopenia (7-14 days), and anemia. Stomatitis, gastrointestinal 
ulceration and bleeding, and diarrhea are commonly seen gastrointestinal side effects of 
fluorouracil. Nausea and vomiting, effects on the skin including rashes and 
hyperpigmentation, alopecia, ocular irritation, central neurotoxicity (notably cerebellar 
ataxia), and myocardial ischemia have been reported. A complete listing of toxicities can 
be found in the fluorouracil package insert. 
Drug Interactions 
Allopurinol may decrease efficacy of fluorouracil. Leucovorin enhances cytotoxicity of 
fluorouracil by forming a more stable tertiary complex with thymidylate synthase. 
 
5.4 LEUCOVORIN 
Please see the package insert for complete details and further information. 
5.4.1  Description 
Leucovorin calcium is commercially available, and is a stable reduced formyl derivative 
and the active form of folic acid. The following products are available: Immunex 
(formally available from Lederle): 50 mg vial, 100 mg vial, 350 mg vial. Burroughs-
Wellcome (Wellcovorin®): 100 mg vial. Chiron Therapeutics: 50 mg vial, and 100 mg 
vial.
5.4.2 Preparation and Administration 
Leucovorin may be reconstituted with Bacteriostatic Water for Injection (BWI). 
Reconstitute 50 mg with 5 ml BWI, 100 mg vial with 10 ml BWI. Both of these will yield 
a solution of 10 mg/ml. Reconstitute 350 mg vial with 17 ml BWI to yield a solution of 
20 mg/ml. Use bacteriostatic water only with doses < 10 mg/m2.  Leucovorin will be 
administered intravenously over 30 minutes prior to fluorouracil administration. 
Storage:  Unreconstituted vials are stored at room temperature and protected from light. 
The reconstituted 10 mg/ml or 20 mg/ml solution is stable for at least 7 days at room 
temperature. 


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5.4.3 Source 
For this study, locally obtained commercial supplies of Leucovorin should be used. 
Because commercial drug will be used, accounting for leucovorin drug supplies is not 
specifically required in this study. 
5.4.4  Safety Profile 
The only adverse reaction for leucovorin is a rare report of allergic reactions to parenteral 
injections of leucovorin. This is extremely uncommon. 
5.5 TRASTUZUMAB 
     Please see the package insert for complete details and further information. 
5.5.1 Description 
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that 
selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular 
domain of the human epidermal growth factor receptor 2 protein, HER2.  The antibody is 
an IgG1 kappa that contains human framework regions with the complementarity-
determining regions of a murine antibody (4D5) that binds to HER2.  
The humanized antibody against HER2 is produced by a mammalian cell (Chinese 
Hamster Ovary) [CHO] suspension culture in a nutrient medium containing the antibiotic 
gentamicin. Gentamicin is not detectable in the final product. Trastuzumabis a sterile, 
white to pale yellow, preservative-free lyophilized powder for intravenous (IV) 
administration.  Each vial of trastuzumabcontains 400 mg of tratuzumab, 9.9 mg of 
L-histidine HCl, 6.4 mg of L-histadine, 400 mg of α,α-trehalose dihydrate, and 1.8 mg of 
polysorbate 20, USP.  Reconstitution with 20 mL of the supplied Bacteriostatic Water for 
Injection (BWFI) USP, containing 1.1% benzyl alcohol as a preservative, yields 21 mL of 
a multidose solution containing 21 mg/mL trastuzumab, at a pH of ~6. 
 
   5.5.2 Preparation, Administration, and Storage  
    
Dosage 
Trastuzumab will be administered on q2wk dosing schedule, with initial loading dose of  
6 mg/kg as a 90 minute infusion, followed by trastuzumab 4 mg/kg q2wk, administered 
as a 30 minute infusion if the initial loading dose was well tolerated.  Eligible HER2-
negative patients will receive mDCF alone 
 DO NOT ADMINISTER AS AN IV PUSH OR BOLUS (see ADMINISTRATION).   
Preparation 
Use appropriate aseptic technique.  Each vial of trastuzumab should be reconstituted with 
20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a multidose 
solution containing 21 mg/mL trastuzumab .  Immediately upon reconstitution with 


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BWFI, the vial of trastuzumab must be labeled in the area marked “Do not use after” with 
the future date that is 28 days from the date of reconstitution. 
If the patient has known hypersensitivity to benzyl alcohol, trastuzumab must be 
reconstituted with Sterile Water for Injection (see PRECAUTIONS).  Trastuzumab which 
has been reconstituted with SWFI must be used immediately and any unused portion 
discarded.  Use of other reconstitution diluents should be avoided. 
Withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 
0.9% sodium chloride, USP.  DEXTROSE (5%) SOLUTION SHOULD NOT BE USED.  
Gently invert the bag to mix the solution.  The reconstituted preparation results in a 
colorless to pale yellow transparent solution.  Parenteral drug products should be 
inspected visually for particulates and discoloration prior to administration. 
No incompatibilities between trastuzumab and polyvinylchloride or polyethylene bags 
have been observed. 
Administration 
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  Trastuzumab administration 
should precede chemotherapy administration.  Patients should be observed for fever and 
chills or other infusion-associated symptoms (see ADVERSE REACTIONS).  If prior 
infusions are well tolerated subsequent doses of 4 mg/kg trastuzumab q2wk may be 
administered over 30 minutes. If chemotherapy is discontinued during the treatment 
phase, either because of completing a planned number of cycles of chemotherapy, or 
because of chemotherapy related toxicity,  trastuzumab should  be continued until disease 
progression or unacceptable toxicity related specifically to trastuzumab.    
Trastuzumab should not be mixed or diluted with other rugs. Trastuzumab infusions 
should not be administered or mixed with Dextrose solutions. 
Storage 
Vials of trastuzumab are stable at 2°C–8°C (36°F–46°F) prior to reconstitution.  Do not 
use beyond the expiration date stamped on the vial.  A vial of trastuzumab reconstituted 
with BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated 
at 2°C–8°C (36°F–46°F), and the solution is preserved for multiple use.  Discard any 
remaining multi-dose reconstituted solution after 28 days.  If unpreserved SWFI (not 
supplied) is used, the reconstituted trastuzumab solution should be used immediately and 
any unused portion must be discarded.  DO NOT FREEZE TRASTUZUMAB THAT 
HAS BEEN RECONSTITUTED. 
The solution of trastuzumab for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% sodium chloride for injection, USP, may be stored at 2°C–8°C 
(36°F–46°F) for up to 24 hours prior to use.  Diluted trastuzumab has been shown to be 
stable for up to 24 hours at room temperature 15°C–25°C; however, since diluted 
Trastuzumab contains no effective preservative the reconstituted and diluted solution 
should be stored refrigerated (2°C–8°C). 


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5.5.3 Source 
Genentech will provide trastuzumab free of charge to the patient. 
5.5.4 Safety Profile 
Cardiac Dysfunction: Signs and symptoms of cardiac dysfunction were observed in a 
number of women who received trastuzumab alone or in combination with 
chemotherapy, most often anthracycline based treatment.  Cardiac dysfunction was 
observed most frequently among patients who received trastuzumab plus AC 
chemotherapy (28%), compared with those who received AC alone (7%), trastuzumab 
plus paclitaxel (11%), paclitaxel alone (1%), or trastuzumab alone (7%).  Severe 
disability or fatal outcome due to cardiac dysfunction was observed in ~1% of all 
patients. The signs and symptoms of cardiac dysfunction usually responded to treatment.   
All patients must have a baseline evaluation of cardiac function including a measurement 
of LVEF by either MUGA or ECHO prior to entry into the study.  Only patients with 
normal LVEF should be entered into this study.  All should have regular cardiac 
monitoring throughout the study. It is suggested that the first evaluation occur 4 months 
after the initiation of trastuzumab therapy.  During the course of trastuzumab therapy, 
patients should be monitored for signs and symptoms of CHF (i.e., dyspnea, tachycardia, 
new unexplained cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal 
nocturnal dyspnea, orthopnea, peripheral edema, and rapid unexplained weight gain).  
The diagnosis must be confirmed using the same method used to measure LVEF at 
baseline (either ECHO or MUGA).     
 
Management of Symptomatic Cardiac Changes.  Patients who develop signs and 
symptoms of CHF should have trastuzumab held and should receive treatment for CHF 
as prescribed by the HFSA (e.g., ACE inhibitors, angiotensin-II receptor blockers, β-
blockers, diuretics, and cardiac glycosides, as needed;  HFSA guidelines).  Consideration 
should be given to obtaining a cardiac consultation.   
If the symptoms of CHF resolve with treatment, and cardiac function improves, 
Trastuzumab may be continued after discussion with the patient concerning the risks and 
benefits of continued therapy.  If the patient is benefiting clinically from Trastuzumab, 
the benefit of continued treatment may outweigh the risk of cardiac dysfunction.  If 
Trastuzumab is restarted, continued surveillance with noninvasive measures of LVEF 
(MUGA or ECHO) is strongly recommended until cardiac function has normalized. 
Management of Asymptomatic Decreases in LVEF.  Trastuzumab may be continued in 
patients experiencing an asymptomatic absolute decrease in LVEF of <20 percentage 
points from baseline, when the ejection fraction remains within the imaging center’s 
range of normal limits.  Repeat measures of LVEF should be obtained using the 
methodology selected at baseline.  Close follow-up of such patients is recommended.  
Patients with an asymptomatic absolute decrease in LVEF of >20 percentage points or an 
ejection fraction below the range of normal limits, should have trastuzumab held and be 
considered for treatment of incipient CHF as prescribed by the HFSA (e.g., ACE 


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inhibitors, angiotensin-II receptor blockers, β-blockers, diuretics, and cardiac glycosides, 
as needed; see HFSA guidelines).  In light of the variability inherent in the assessment of 
ejection fraction, consideration should be given to repeating the study to confirm an 
observed decline.  Repeat measures of LVEF should be obtained using the same 
methodology selected at baseline.  If trastuzumab has been discontinued for an 
asymptomatic decline in LVEF, a repeat measure of LVEF will be obtained in 1 month to 
determine if the decline has resolved. 
If cardiac function improves, trastuzumab may be restarted after discussion with the 
patient concerning the risks and benefits of continued therapy.  If the patient is benefiting 
clinically from Trastuzumab, the benefit of continued treatment may outweigh the risk of 
cardiac dysfunction.  If trastuzumab is restarted, continued surveillance with noninvasive 
measures of LVEF (MUGA or ECHO), using the methodology selected at baseline, is 
strongly recommended until cardiac function has normalized. 
 
Infusion Associated Symptoms: During the first infusion with Trastuzumab, a symptom 
complex consisting of chills and/or fever is observed in approximtely 40% of patients.  
Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, 
cough, dizziness, rash, and asthenia.  These symptoms are usually mild to moderate in 
severity, and  occur infrequently with subsequent Trastuzumab infusions. These 
symptoms can be treated with an analgesic/antipyretic such as meperidine or 
paracetamol, or an antihistamine such as diphenhydramine.  
Serious Infusion-Associated Events. Serious adverse reactions to Trastuzumab infusion 
including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently.   In rare cases (4 per 
10,000), these events were associated with a clinical course culminating in a fatal 
outcome. Serious reactions have been treated with supportive therapy such as oxygen, 
beta-agonists, corticosteroids and withdrawal of Trastuzumab as indicated. 
Hematologic Toxicity and Neutropenic Infections: In the clinical trials, an increased 
incidence of anemia was observed in patients receiving trastuzumab plus chemotherapy 
compared with patients receiving chemotherapy alone.  The majority of these anemia 
events were mild or moderate in intensity and reversible; none resulted in discontinuation 
of trastuzumab therapy.   
In the clinical trials, the per-patient incidences of moderate to severe neutropenia and of 
febrile neutropenia were higher in patients receiving trastuzumab in combination with 
myelosuppressive chemotherapy as compared to those who received chemotherapy alone.  
In the post marketing setting, deaths due to sepsis in patients with severe neutropenia 
have been reported in patients receiving trastuzumab and myelosuppressive 
chemotherapy, although in controlled clinical trials (pre- and post-marketing), the 
incidence of septic deaths was not significantly increased.  The pathophysiologic basis 
for exacerbation of neutropenia has not been determined; the effect of trastuzumab on the 
pharmacokinetics of chemotherapeutic agents has not been fully evaluated.  


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Secondary acute leukemia or myelodysplastic syndrome has been reported in 4 of 
approximately 1200 patients who participated in trastuzumab clinical trials.  Patients 
treated with chemotherapeutic agents are known to be at increased risk for secondary 
leukemia.  The observed incidence of leukemia among Trastuzumab treated patients 
appears to be consistent with the expected incidence of leukemia among patients treated 
with chemotherapy for metastatic breast cancer.  Therefore, the contribution of 
Trastuzumab to the etiology of acute leukemia or myelodysplastic syndrome in these 
cases is unclear. 
 
Management of Hematologic Toxicities. Care should be taken to carefully monitor the 
patient’s hematologic status throughout the course of the trial.  Use of hematopoietic 
growth factors to ameliorate hematologic toxicity is at the discretion of the physician 
investigator and should be in accordance with the American Society of Clinical 
Oncologists (ASCO) guidelines.  
5.6  CONCOMITANT MEDICATIONS 
5.6.1 Anticancer or experimental therapy 
No other concurrent chemotherapy or anti-cancer therapy of any kind is permitted while 
the patient is receiving study treatment.  
5.6.2 Hematopoetic Growth Factors 
Colony-Stimulating Factor (G-CSF, GM-CSF): 
ARM A 
After cycle 1 (eg. 3 treatments of mDCF), the use of colony-stimulating factor is 
permitted at the discretion of the treating physician.  However, the administration of G-
CSF in a patient who has experienced neutropenia, or its therapeutic use in patients with 
serious neutropenic complications such as tissue infection, sepsis syndrome, fungal 
infection, fever/neutropenia, etc. is recommended.  
 
 
ARM B 
Beginning with cycle 1, pegfilgrastim (Neulasta) is given subcutaneous 6 mg on either 
day 8, 9, or 10 of every cycle.  This is the preferred hematopoietic growth factor.  
Alternatively, filgrastim (Neupogen) may be given by subcutaneous injection from day 
10 to 17.  The optimal dose is as follows:   
Body weight < 60 kg:  filgastrim 300 mcg subcut daily x 7 days  
Body weight > 60 kg:  filgrastim 480 mcg subcut daily x 7 days  
 
Epoetin alfa (Procrit or Aranesp): 
Use of epoetin alfa is permitted at the discretion of the treating physician. 
5.6.3  Antiemetics and Premedications 
 


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ARM A 
The mDCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention 
and may also decrease the incidence and severity of acute hypersensitivity reactions.   
The recommended pre-medication and delayed emesis schedule for this study is as 
follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally
evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 3: 
 
 
       pre - Cisplatin 
Dexamethasone 8 mg orally or IV 
 
 
 
 
 
 
 
Palonosetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
▪ Day 4 and 5:  
 
 
 
 
Dexamethasone 4 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
 
ARM B 
The DCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention 
and may also decrease the incidence and severity of acute hypersensitivity reactions.   
The recommended pre-medication and delayed emesis schedule for this study is as 
follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally
pre-Cisplatin  -     Palonesetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
 
 
 
 
 
     evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 2 and 3:  
 
 
 
 
Dexamethasone 8 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
Both ARMS 
For patients who have persistent nausea or vomiting with palonosetron, granisetron 2mg 
po or granisetron 1mg IV may be substituted prior to chemotherapy, and then granisetron 
2 mg po may be continued on days 2 and 3.  Metoclopramide 5-10 mg po every 4 hours 
and/or prochlorperazine 10 mg every 6 hours may be used as needed for nausea/vomiting, 


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and lorazepan may be used for anticipatory nausea/vomiting or anxiety related 
nausea/vomiting.   
For patients who have no evidence of delayed emesis, the prophylaxis may be 
discontinued as tolerated as per the treating physician. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
This is a multicenter phase II study coordinated by Memorial Sloan-Kettering Cancer Center 
(MSKCC). 
 
6.1 
Subject Inclusion Criteria 
1. Patients must have histologically or cytologically confirmed metastatic or unresectable 
gastric or gastroesophageal junction (GEJ) adenocarcinoma.  GEJ adenocarcinoma 
may be classified according to Siewert’s classification type I, II, or III[43]. 
 
2.  Histological documentation of local recurrence or metastasis is strongly encouraged, 
unless the risk of such a procedure outweighs the potential benefit of confirming the 
metastatic disease.   
• If no histologic confirmation, then the metastases or recurrence will require 
documention by a 2nd radiographic procedure (eg. PET/CT scan or MRI in 
addition to the CT scan).  If the imaging procedure does not confirm recurrent or 
metastatic disease, biopsy confirmation will be required. 
 
3. Patients must have disease that can be evaluated radiographically.  This may be 
measurable disease or non-measurable disease.  Measurable disease is defined as that 
which can be measured in at least one dimension as > 20 mm with conventional 
techniques, or >10 mm by high resolution imaging.  Disease that is identified on 
radiology studies, but does not meet the criteria for measurable disease, is considered 
non-measurable– see section 12.1.1 for further details.  
4. Patients may have received no prior chemotherapy for metastatic or unresectable 
disease.  Patients may have received prior adjuvant therapy (chemotherapy and/or 
chemoradiation) if more than 6 months have elapsed between the end of adjuvant 
therapy and registration.  Patients may not have received prior docetaxel or cisplatin. 
 
5. Age 18 years or older. 
 
6. Karnofsky performance status > 70% (ECOG performance status 0-1).
7. Peripheral neuropathy < grade 1 


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8. Hematologic (minimal values) 
 
White blood cell count > 3000/mm3 
Absolute neutrophil count > 1500 cells/ mm3 
 
Hemoglobin > 9.0 g/dl 
Platelet count > 100,000 / mm3
9. Hepatic (minimal values) 
Total bilirubin < 1.5 
AST and ALT and Alkaline phosphatase must be within the eligible range as 
described by the table below.  In determining eligibility, the more abnormal of the 
two values (AST or ALT) should be used. Patients with alkaline phosphatase 
elevation secondary to the bony metastases rather than liver dysfunction may 
proceed with treatment on protocol after discussion with the principal 
investigator.  
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤1.5x ULN 
>1.5x but ≤ 5x ULN >5x ULN 
≤ ULN 
Eligible 
Eligible 
Eligible
Ineligible 
>1x but ≤2.5x  
Eligible 
Eligible 
Ineligible 
Ineligible 
>2.5x but ≤5x  
Eligible 
Ineligible 
Ineligible 
Ineligible 
>5x ULN 
Ineligible 
Ineligible 
Ineligible 
Ineligible 
10.  Kidney function (minimal values) 
serum creatinine < 1.5 mg/dl* 
* if serum creatinine is 1.2-1.5 mg/dl, the creatinine clearance (either measured or 
calculated) must be 50 ml/min or greater. 
 
 
11. The patient has a PT (INR) < 1.5 and an PTT < 3 seconds above the upper limits of 
normal if the patient is not on anticoagulation. If a patient is on full-dose 
anticoagulants, the following criteria should be met for enrollment: 
a. the patient must have an in-range INR (usually between 2 and 3) on a stable 
dose of warfarin or on stable dose of LMW heparin.   
b. the patient must not have active bleeding or pathological conditions that carry 
high risk of bleeding (e.g. tumor involving major vessels, known varices). 
12. Women of childbearing potential have a negative pregnancy test. 
13. Men and women of childbearing potential must be willing to consent to using 
effective contraception while on treatment and for at least 3 months thereafter. 
 
14. Ability to understand informed consent and signing of written informed consent 
document prior to initiation of protocol therapy. 
 


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15. Patients must have HER2-positive (FISH+ or IHC 3+) metastatic or unresectable 
gastric or gastroesophageal junction (GEJ) adenocarcinoma to be eligible for 
trastuzumab. For the purposes of this protocol, FISH+ is defined as HER2:CEP17 
ratio ≥ 2.0. Biopsy samples with cohesive IHC3+ or FISH+ clones are considered  
HER2 positive irrespective of size, i.e.<10%.  FISH+ defined as >2 HER2:CEP17. 
Note: Samples will be processed locally in the laboratory of investigational sites. The 
results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of 
HER2 status. MSK pathology review will not be required to begin therapy on the 
protocol.   Samples provided to the MSK laboratory must either be HER2 IHC slides, 
or  if FISH confirmation is necessary, a paraffin block(s) of adequate size to allow if 
possible for at least 5 slides with cuts that are 5-microns thick or if a paraffin block is 
not available, then if possible at least 5 slides with cuts that are 5-microns thick will 
be acceptable. Archived or fresh tumor samples may be used. 
 
16. Patients who are receiving trastuzumab must have a left ventricular ejection fraction 
of > 50%. 
6.2 
Subject Exclusion Criteria 
1. Patients who have received previous chemotherapy for the treatment of metastatic or 
unresectable gastric or GEJ adenocarcinoma are ineligible.  Patients who have 
received previous pre- or post-operative chemotherapy or chemoradiation are 
ineligible if therapy was completed less than 6 months prior to study registration.  
Patients must have recovered from adverse events from any previous therapy.   
2. Patients who have received previous docetaxel or cisplatin.  
 
3. Patients with a history of another neoplastic disease within the past three years, 
excluding basal cell carcinoma of the skin, cervical carcinoma in situ, or nonmetastatic 
prostate cancer. 
 
4. Patients with brain or central nervous system metastases, including leptomeningeal 
disease. 
 
5. Pregnant (positive pregnancy test) or breast feeding. 
 
6. Serious, non-healing wound, ulcer, or bone fracture. 
7. Significant cardiac disease as defined as: 
unstable angina,  New York Heart Association (NYHA) grade II or greater, 
congestive heart failure, history of myocardial infarction within 6 months 
 
8. Evidence of bleeding diathesis or coagulopathy.  
 


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9. History of a stroke or CVA within 6 months. 
10. Clinically significant peripheral vascular disease. 
 
11. Clinically significant hearing loss or ringing in the ears. 
 
12. Patients with a history of severe hypersenstivity reaction to Taxotere® or other drugs 
formulated with polysorbate 80. 
 
13. Inability to comply with study and/or follow-up procedures. 
 
14. Patients with any other medical condition or reason, in that investigator’s opinion, 
makes the patient unstable to participate in a clinical trial. 
15. For patients who are Her2 positive and will be treated on the trastuzumab + mDCF 
cohort, prior trastuzumab treatment is not allowed. 
 
16. For patients who are Her2 positive and will be treated on the trastuzumab+mDCF 
cohort, left ventricular function <50% 
 
7.0 
RECRUITMENT PLAN 
This study will be available to all patients seen at participating institutions who meet the 
eligibility criteria as outlined in section 6.0.  Memorial Hospital is a referral center for this 
disease.  In addition, the study will be placed on the MSKCC Website as well as available at 
the MSKCC satellite centers to maximize patient recruitment.  Patients will be identified from 
medical oncology clinics for treatment of their disease. 
 
 
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations.  There will be no limitation to access with regard 
to race or gender.  Patients will be required to read, agree to, and sign an IRB-approved 
informed consent form prior to registration on this trial. The registration procedure will be 
conducted as described in section 15.0. Patients will not receive payment for their 
participation on this study. The proposed study population is provided in the table below. 
 
 
Ethnic Category 
Sex/ Gender 
 
 
 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
8 
10 
18 
Not Hispanic or Latino 
28 
62 
90 
Unknown 
 
 
 
Ethnic Category: Total of all subjects 
36 
72 
108 


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Racial Category 
 
American Indian or Alaskan Native
0
0
Asian 
7 
10 
17 
Black or African American 
4 
8 
12 
Native Hawaiian or other Pacific Islander 
0 
0 
 
White 
23 
52 
75 
More than one race 
0 
0 
0 
Unknown 
2 
2 
4 
Racial Category: Total of all subjects 
36 
72 
108 
Note, the results of the recent ToGA study demonstrate that for HER2 positive gastric cancer, 
patients have a survival benefit with the addition of trastuzumab to chemotherapy (see Sect 
3.3.4).  We are therefore amending the study to include a separate cohort of 35 patients who are 
Her2 positive to receive mDCF + trastuzumab (Trastuzumab cohort) 
 
Recruitment Expectations Per Site 
Memorial Sloan Kettering Cancer Center 
10 
City of Hope 
5 
University of Pittsburgh
5
Queens Cancer Center 
2 
Long Island Jewish Medical Center 
2 
University Hospital  of Cleveland 
2 
Weill Medical College of Cornell University 
2 
Medical College of Wisconsin 
2 
Piedmont Hospital Research Institute (PHRI) 
2 
Nebraska Cancer Specialists 
2 
Memorial Cancer Institute 
1 
Total 
35 
8.0 
PRETREATMENT EVALUATION 
To be completed within 14 days of starting therapy: 
1.  History and physical examination, including height, weight, calculated body surface area, 
vital signs, and performance status.  See Appendix A for a conversion between Karnofsky 
and ECOG performance status.  
2.  Serum pregnancy test for all women of childbearing potential within 14 days of starting 
therapy. If the test result is positive, the patient will not be allowed to participate in this 
study. 


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3.  PA and lateral chest radiographs. Chest radiographs may be omitted if a baseline CT scan of 
the chest is available in the same time frame. 
 
4.  Routine urinalysis. 
 
5.  CBC with differential and platelet count, serum chemistries (Na, Cl, BUN, Creatinine, K, 
Bicarb, and glucose), LFTs (AST, ALT, alkaline phosphatase, total bilirubin), calcium, 
magnesium, phosphorus, albumin, total protein, LDH, coagulation studies, and tumor 
markers as they are available. 
 
6.  EORTC QLQ-C30 questionnaire. 
 
To be completed within 30 days of starting therapy: 
7.  A 12-lead Electrocardiogram (ECG).
 
8.  Documentation of all measurable or non-measurable disease parameters including 
radiographic imaging procedures within four weeks of study entry, and measurement of 
biochemical markers of disease (if applicable) within four weeks of study entry. The RECIST 
criteria as defined by CTEP (http://ctep.info.nih.gov/Policies) define measurable and non-
measurable disease. 
 
9.  Signed informed consent for study participation. 
 
10. Audiogram if clinically indicated. 
 
11. CT scan of the chest, abdomen and pelvis. 
 
12. Baseline PET/CT for staging.  
July 2009 Addendum: Collaborating centers that are either not able to perform the 
PET/CT at baseline (i.e., denied authorization from insurance carriers) or have opted not 
to participate in the Week 3 PET/CT may forgo performing the scan at baseline. 
To be completed at any time prior to starting therapy or during study: 
13. Placement of a MediPort, Hickman catheter or similar indwelling catheter for administration 
of continuous infusional fluorouracil chemotherapy. 
14. Paraffin stored tumor block or 15 unstained slides sent to MSKCC for planned future 
immunohistochemistry studies.
15. A baseline assessment of left ventricular ejection fraction (usually cardiac ECHO or MUGA 
scan). 


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9.0 
TREATMENT/INTERVENTION PLAN 
9.1 CHEMOTHERAPY ADMINISTRATION 
Eligible patients will be randomly assigned to receive mDCF (ARM A) or parent DCF with 
growth factor support (ARM B) as follows: 
ARM A – Modified DCF 
ARM B – Parent DCF with G-CSF
Drug
Dose (mg/m2) 
Schedule 
Drug 
Dose (mg/m2) 
Schedule 
Docetaxel 
40 
Day 1 IVPB (60 min) 
Docetaxel 
75 
Day 1 IVPB (60 min) 
Leucovorin 
400 
Day 1 IVPB (30 min) 
Cisplatin 
75 
Day 1 IVPB (60 min) 
Fluorouracil 
400 
IVP day 1 
Fluorouracil 
750 
IVCI daily x 5 days 
Fluorouracil 
1000 mg/m2/d 
IVCI daily x 2 days 
Neulasta 
6 mg 
subcut on d 8, 9, or 10 
Cisplatin 
40 
Day 2 or 3 IVPB (30 min) or Neupogen 
300 or 480 mcg* 
subcut x 7 d 10-17 
* 300 mcg for weight < 60 kg, 480 mcg for weight > 60 kg. 
Arm A is repeated every 2 weeks, and a cycle will be considered 6 weeks (eg 3 treatments).  
Arm B is repeated every 3 weeks, and a cycle will be considered every 6 weeks (eg 2 
treatments).  
December 2009 Amendment 
We have met the early stopping rule for Arm B, parent DCF with growth factor support.  
Arm A will continue to accrue until target accrual of 54 patients. In addition, we will treat 
Her2 positive patients with mDCF + trastuzumab.  Trastuzumab will be administered on an 
every 2 week dosing schedule, with an initial loading dose of 6 mg/kg over 90 minutes, 
followed by trastuzumab 4 mg/kg every 2 weeks over 30 mintues.   
A given treatment may be moved +/- 14 days for specific administrative reasons, in particular 
clinic closure for holidays.  Tumor assessments will be performed following the completion of 
every cycle for the first 6 cycles, and then every 2 cycles thereafter.  Therapy will be 
administered in an outpatient setting, under the supervision of a physician and/or chemotherapy 
nurse, as is standard for chemotherapy administration at the treating institution.  
After 6 months of therapy, cisplatin, docetaxel, and/or fluorouracil may be discontinued at the 
discretion of the treating physician.  Prior to discontinuing therapy, the treating physician will 
discuss in detail with the protocol PI.  Patients without disease progression may resume 
chemotherapy at the discretion of the treating physician, or with progression if they had more 
than a 6 month treatment free interval.  
Expected adverse events are described in Section 11.0. No investigational or commercial agents 
or therapies other than those described above may be administered with the intent to treat the 
patient’s malignancy. 
Clinical evaluation: All assessments may be performed within one day of the planned treatment.   


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ARM A – Modified DCF 
Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of cycle one (e.g. on day 1, day 15, and day 29 of cycle 1).  In cycle 2 and all 
subsequent cycles, a physician evaluation (e.g. physical examination and toxicity assessment) 
will be performed prior to treatment on day 1 and day 29 treatments.  Additional nurse or 
physician visits will be at the discretion of the treating physician.  It is encouraged that an 
oncology nurse toxicity evaluation be performed prior to each treatment, especially if the patient 
is not assessed by a physician.  
Patients treated with mDCF plus trastuzumab therapy should be monitored for signs and 
symptoms of CHF (i.e., dyspnea, tachycardia, new unexplained cough, neck vein distention, 
cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and 
rapid unexplained weight gain).   
 
ARM B – Parent DCF with G-CSF 
Patients will have a history and physical examination and assessment of toxicities prior to each 
treatment of every cycle. 
Laboratory evaluation:  
ARM A – Modified DCF 
On or within 1 day of the beginning of each cycle, a CBC with differential and platelet count, 
serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, alkaline 
phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, LDH, 
tumor markers.  A CBC with differential and platelet count is required prior to each subsequent 
treatment (eg. day 15 and day 29).  A BUN and Creatinine is required before the day 15 
treatment (treatment #2), and a serum chemistry (electrolytes, BUN, Creatinine, glucose) is 
required before each day 29 treatment (#3). LFTs are required before each treatment (#1, #2 and 
#3) of cycle 1, and before treatment #1 and #3 for each subsequent cycle.  Any patient with 
excessive LFTs abnormalities (see section 9.3) will require repeat LFTs prior to the next 
docetaxel administration. 
ARM B – Parent DCF with G-CSF 
On or within 1 day of the beginning of each treatment, a CBC with differential and platelet 
count, serum chemistries (Na, Cl, BUN, Creatinine, K, Bicarb, and glucose), LFTs (AST, ALT, 
alkaline phosphatase, total bilirubin), calcium, magnesium, phosphorus, albumin, total protein, 
LDH, and tumor markers are required.   
Radiology evaluation: For both treatment arms, radiographic studies upon which tumor 
measurements were made will be repeated every cycle (six week intervals for most patients) for 
6 cycles, and then after every two cycles of therapy (e.g. after cycles 1, 2, 3, 4, 5, 6, 8, 10, 12 
etc.), to rule out progression of disease and to determine response for measurable disease.  


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Patients will remain on study until disease progression, patient withdrawal, unacceptable toxicity 
despite dose attenuation, or if the treating physician deems it is in the best interest of the patient 
following discussion with the principal investigator.  Tolerability of this regimen will be 
determined from blood test results and toxicity assessment. 
Cardiac evaluation: For patients who are Her2 positive and will be treated on the 
trastuzumab+mDCF cohort left ventricular function will be assessed with echocardiograms or 
MUGA every 12 weeks while on study. 
A table of events to take place on this study is shown in section 10.0.   
9.2  SUPPORTIVE CARE GUIDELINES 
Concurrent supportive care is not restricted, including the use of narcotics for pain control and 
antiemetics and glucocorticoids for control of nausea, and antidiarrheal agents. Neither 
concurrent chemotherapy, immunotherapy, nor radiation therapy is permitted while on study. 
Hematopoetic Growth Factors 
Colony-Stimulating Factor (G-CSF, GM-CSF): 
ARM A
Use of colony-stimulating factor is permitted at the discretion of the treating physician. 
However, the administration of G-CSF in a patient who has experienced neutropenia, or 
its therapeutic use in patients with serious neutropenic complications such as tissue 
infection, sepsis syndrome, fungal infection, fever/neutropenia, etc. is recommended.  
 
 
ARM B 
Beginning with cycle 1, pegfilgrastim (Neulasta) is given subcutaneous 6 mg on either 
day 8, 9, or 10 of every cycle.  This is the preferred hematopoietic growth factor.  
Alternatively, filgrastim (Neupogen) may be given by subcutaneous injection from day 
10 to 17.  The optimal dose is as follows:   
Body weight < 60 kg:  filgastrim 300 mcg subcut daily x 7 days  
Body weight > 60 kg:  filgrastim 480 mcg subcut daily x 7 days  
 
Epoetin alfa (Procrit or Aranesp): 
Use of epoetin alfa is permitted at the discretion of the treating physician. 
Antiemetics and Premedications 
ARM A 
The mDCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention and 
may also decrease the incidence and severity of acute hypersensitivity reactions.   
 
 


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The recommended pre-medication and delayed emesis schedule for this study is as follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally
evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 3: 
 
 
       pre - Cisplatin 
Dexamethasone 8 mg orally or IV 
 
 
 
 
 
 
 
Palonosetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
▪ Day 4 and 5:  
 
 
 
 
Dexamethasone 4 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
ARM B 
The DCF regimen has a high emetic potential.  Additionally, the use of Dexamethasone 
decreases the incidence and severity and delays the onset of late-occurring fluid retention and 
may also decrease the incidence and severity of acute hypersensitivity reactions.   
The recommended pre-medication and delayed emesis schedule for this study is as follows: 
▪ Day prior to chemotherapy (day 0):  
          Dexamethasone 8 mg orally in the pm 
 
▪ Day of chemotherapy (day 1):     pre-Docetaxel - Dexamethasone 8 mg orally 
pre-Cisplatin  -     Palonesetron 250 mcg IVPB 
 
 
 
 
 
 
 
Aprepitant 125 mg po 
 
 
 
 
 
 
     evening - 
 
Dexamethasone 8 mg orally (pm) 
 
▪ Day 2 and 3:  
 
 
 
 
Dexamethasone 8 mg orally qd x 2d 
Aprepitant 80 mg orally qd x 2d 
Both ARMS 
For patients who have persistent nausea or vomiting with palonosetron, granisetron 2mg po or 
granisetron 1mg IV may be substituted prior to chemotherapy, and then granisetron 2 mg po may 
be continued on days 2 and 3.  Metoclopramide 5-10 mg po every 4 hours and/or 
prochlorperazine 10 mg every 6 hours may be used as needed for nausea/vomiting, and 
lorazepan may be used for anticipatory nausea/vomiting or anxiety related nausea/vomiting.   
For patients who have no evidence of delayed emesis, the prophylaxis may be discontinued as 
tolerated as per the treating physician. 
 
 


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9.3 TREATMENT PARAMETERS, DOSE DELAYS AND MODIFICATIONS 
9.3.1 Treatment Parameters 
1. Parameters for initiation of therapy (day 1) for cycle 1 are as follows: 
 White blood cell count > 3000/mm3 
 Absolute neutrophil count ≥ 1500/mm3 
 Platelet count ≥ 100,000/mm3 
 Hemoglobin > 9.0 g/dl 
 Creatinine < 1.5 mg/dl 

Total Bilirubin < 1.5 mg/dl 
AST and ALT and Alkaline phosphatase must be within the treatment range as 
described by the table below.  In determining acceptable levels for treatment, the 
more abnormal of the two values (AST or ALT) should be used. Patients with 
alkaline phosphatase elevation secondary to the bony metastases rather than liver 
dysfunction may proceed with treatment on protocol after discussion with the 
principal investigator.  
 
2
.
 
P
a
r 
2. Parameters for all subsequent treatments:
 Absolute Neutrophil count ≥ 1000/mm3 
 Platelet count ≥ 75,000/mm3.   
 Creatinine < 1.8 mg/dl  
o for Creatinine > 1.8 mg/dl and  

Total bilirubin < 1.5  (should be drawn prior to treatment on week 1, week 3, and 
week 5 of cycle 1 and again prior to treatment on week 1 and week 5 of every 
subsequent cycle beginning with cycle 2 (ie. minimum of every 4 weeks). ) 
o For total bilirubin > 1.5 but < 2x ULN, docetaxel alone may be held. 
o For total bilirubin > 2x ULN, hold all three drugs (docetaxel, cisplatin, 
fluorouracil) 
 AST/ALT* and Alkaline Phosphatase as per table below (for docetaxel dosing):  
 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤2x ULN 
>2x but ≤5x ULN 
>5x ULN 
≤ ULN 
Full Dose 
Full Dose 
Full Dose 
Hold 
>1x but ≤ 3x  
Full Dose 
Full Dose 
Reduce Dose 
Hold 
>3x but ≤ 5x  
Full Dose 
Reduce Dose 
Hold 
Hold 
>5x ULN
Hold 
Hold 
Hold 
Hold 
AST or ALT: 
ALK PHOS: 
≤ ULN 
>1x but ≤2xULN 
>2x but ≤5x ULN 
>5x ULN 
≤ ULN 
Yes 
Yes 
Yes 
No 
>1x but ≤3x  
Yes
Yes
Yes
No
>3xbut ≤5x  
Yes 
Yes 
No 
No 
>5x ULN 
No 
No 
No 
No 


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* ARM A: LFTs should be drawn prior to treatment on week 1, week 3, and week 5 of 
cycle 1 and again prior to treatment on week 1 and week 5 of every subsequent cycle 
beginning with cycle 2 (ie. minimum of every 4 weeks).  If LFTs are drawn prior to 
treatment on week 3, the above LFT treatment parameters must still be met.  Both 
AST and ALT should be drawn. If LFTs are abnormal prior to any treatment, they 
should be drawn prior to the next docetaxel treatment. The more abnormal of the two 
values (AST or ALT) should be used in determining the dose of docetaxel.   
* ARM B: LFTs should be drawn prior to each 3-week cycle 
Patients with alkaline phosphatase elevation secondary to the bony metastases rather than liver 
dysfunction may proceed with treatment on protocol after discussion with the principal 
investigator. If above parameters are not met, hold until recovered, maximum 28 days, then re-
treat as per section 9.3.2 Dose Delays and Modifications.  “Recovered” is defined as meeting the 
treatment parameters for #2 above with the exception that the ANC must be at least 1500/mm3
(ANC > 1500/mm3). 
9.3.2  Chemotherapy Dose Delays and Modifications 
Chemotherapy will be held for grade 3 or 4 non-hematologic toxicity (with the exception of 
grade 3 electrolyte abnormalities) or for not meeting treatment parameters as described above on 
the day of treatment.  If the toxicity has resolved and the patient meets treatment parameters but 
experienced interval toxicity, then for the purposes of determining dose reductions, the grade of 
toxicity should be that seen despite maximal medical management (i.e. intensive loperamide or 
tincture of opium for diarrhea).  If multiple toxicities are seen the dose administered for a 
particular drug should be based on the most severe toxicity noted.  In general, when multiple 
toxicities are experienced that can result in the dose reduction of multiple drugs, reducing 
multiple drugs at one time is the preferred approach.   Treatment may resume when the toxicity 
has resolved to < grade 2, except as indicated below. 
Generally, when therapy is held for chemotherapy related toxicity, all three drugs (cisplatin, 
docetaxel, and fluorouracil) will be held.  For hepatotoxicity, docetaxel alone should be held (ie. 
Total bilirubin > ULN but < 2x ULN, and AST/ALT and Alkphos as per table above) and 
cisplatin and fluorouracil may continue without treatment delay.  For an elevated creatinine or 
for ototoxicity (see below criteria), cisplatin alone may be held and the patient may continue with 
docetaxel and fluorouracil without treatment delay.  If all three drugs are held for more than 4 
weeks for toxicity, patients will be taken off study, unless there is a clinical benefit. If there is a 
clinical benefit, patients may be retreated at a lower dose after resolution of toxicity to ≤ NCI-
CTCAE v3.0 grade 2, except as indicated below.  Cisplatin, docetaxel, and fluorouracil may each 
be dose attenuated, either in combination, or individually.   


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ARM A: CHEMOTHERAPY DOSE ATTENUATION TABLE 
 
Dose level 0 (mg/m2) 
Dose level -1 (mg/m2) 
Dose level -2 (mg/m2) 
Docetaxel 
40 
30 
20 
Cisplatin 
40 
30 
20 
Fluorouracil (IVP)/ 
Leucovorin 
400/ 400 
300/ 300 
200/ 200 
Fluorouracil IVCI / day 
1000 
800 
600 
ARM B: CHEMOTHERAPY DOSE ATTENUATION TABLE 
 
Dose level 0 (mg/m2) 
Dose level -1 (mg/m2) 
Dose level -2 (mg/m2) 
Docetaxel 
75 
60 
50 
Cisplatin 
75 
60 
50 
Fluorouracil IVCI / day 
750 
600 
500 
Dose attenuations will be based on toxicity as described below: 
Neutropenia 
 Docetaxel dose attenuation by one dose level may occur for any treatment delay due to 
neutropenia (i.e. ANC < 1000 /cc on a treatment day following Cycle 1 Week 1).   
 For ARM A,, Neulasta or Neupogen (GCSF) should be given for subsequent treatments 
following any treatment delay due to neutropenia if a dose reduction is not required and 
not pursued.  The recommended treatment is Neulasta 6 mg subcutaneously on day 3, day 
4, or day 5 of the treatment cycle or neupogen (GCSF) for 3 to 5 days from day 9 to day 
13. 
 Grade 3 and Grade 4 neutropenia with recovery prior to next planned cycle do not require 
a dose attenuation in docetaxel with the following exceptions:  
 Grade 4, afebrile neutropenia ≥ 7 days 
 Grade 3 or 4 neutropenia associated with fever (one reading of oral temperature > 38.5° 
C, or three readings of oral temperature > 38.0° C in a 24-hour period)   
 Cisplatin and fluorouracil may be dose attenuated by one dose level at the treating 
physicians’ discretion in addition to docetaxel dose attenuation, particularly with 
persistent delays due to neutropenia. 
 
Thrombocytopenia 
 For treatment delay due to thrombocytopenia (i.e. platelet count < 75,000/cc), reduce 
docetaxel by one dose level. 
 For any platelet count of < 50,000/cc, reduce docetaxel by one dose level. 
Nausea/Vomiting 

Grade 1 nausea/vomiting does not require a dose reduction or treatment delay. 


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 Grade 2 nausea/vomiting – hold treatment for 1 week.  Reduce cisplatin by 1 dose level 
for persistent grade 2 nausea/ vomiting (eg. lasting for more than 5 days). 
 For Grade 3 or 4 nausea/ vomiting, reduce cisplatin dose by one dose level.  Docetaxel 
and fluorouracil may also be dose attenuated by one dose level at the treating physicians 
discretion. 
Anorexia 
 Grade 1 or 2 anorexia does not require a dose reduction 
 For grade 3 or 4 anorexia, reduce cisplatin and docetaxel by one dose level. 
Stomatitis 
 
If stomatitis is present on day 1 of any cycle, treatment should be held until the stomatitis 
has resolved.   
 
For ARM A: 
o If stomatitis is ≤ grade 1 prior to treatment #2 or #3 of any cycle, treat at current 
dose. 
o For interval grade 2 stomatitis prior to treatment #2 or #3, reduce fluorouracil 
infusion by one dose level without treatment delay.  For a subsequent grade 2 
stomatitis event, reduce docetaxel by one dose level. 
 For ARM B: 
o For interval grade 2 stomatitis that completely resolves prior to the next cycle, 
reduce fluorouracil infusion by one dose level without treatment delay. For a 
subsequent grade 2 stomatitis event, reduce docetaxel by one dose level. 
 If Grade 3 or 4 stomatitis occurs at any time, hold chemotherapy until resolution to <
grade 1, and then retreat with docetaxel and fluorouracil each reduced by one dose level. 
Neurotoxicity 
 
If neuropathy ≥ grade 2 is present on day 1 of any cycle, treatment should be held until 
neuropathy improves to ≤  grade 1.  
 
For ARM A (treatment #2 and 3 of each cycle): 
o If neuropathy is ≤ grade 1 on treatment #2 or #3 of any cycle, treat at current dose 
of all chemotherapy drugs. 
o
If neuropathy is grade 2 on treatment #2 or #3, reduce docetaxel by one dose level 
and treat without delay. 
 
For ARM B (treatment #2 of each cycle): 
o If neuropathy is < grade 1 on treatment #2, treat at current dose of all 
chemotherapy drugs. 
o
If neuropathy is grade 2 on treatment #2, reduce docetaxel by one dose level and 
treat without delay.
 
For Grade 3 or 4 neuropathy, treatment should be held until neuropathy returns to grade < 
1. Reduce cisplatin and docetaxel each by one dose level. 
Kidney 
 Serum creatinine must be < 1.5 mg/dl to initiate therapy 


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 For each subsequent treatment, the serum creatinine must be < 1.8 mg/dl to continue 
treatment at the current dose level. 
 If serum creatinine is > 1.8 but < 2 mg/dl, administer cisplatin at a single reduced dose 
level. A treatment delay is not required. Subsequent treatments may occur without further 
cisplatin dose attenuation if the serum creatinine remains stable at > 1.8 but < 2 mg/dl.
 If serum creatinine is > 2.0 mg/dl, cisplatin will be held. Docetaxel and fluorouracil may 
be administered without treatment delay at the treating physicians discretion. 
 Up to a 6-week treatment delay in cisplatin will be allowed. If the serum creatinine has 
not returned to less than 2.0 mg/dl within 6 weeks, then cisplatin will be discontinued. 
 Patients should be euvolemic for the determination of serum creatinine.  
 If the value of the serum creatinine is >1.8 mg/dl the value may be confirmed by a 
second serum creatinine after hydration. Treatment may resume within the next day. 
 Creatinine clearance will not be used for dose adjustments. 
 
Diarrhea 
 Grade 1 diarrhea dose not require treatment delay or dose reduction. 
 For grade 2 diarrhea, hold treatment by 1 week. 
 For grade 3 or 4 diarrhea, reduce fluorouracil by 1 dose level.  Cisplatin may be dose 
reduced as well, at the treating physicians discretion. 
 
 
Ototoxicity 
 For grade 1 or 2 ototoxicity, no dose reduction in cisplatin is required. 
 For grade 3 or 4 ototoxicity, hold cisplatin until it resolves to < grade 1, and then resume 
therapy with cisplatin dose reduced by one dose level. 
Trastuzumab related cardiac dysfunction: 
 
Symptomatic CHF 
 Hold trastuzumab, refer to cardiology for treatment  (e.g., ACE inhibitors, angiotensin-II 
receptor blockers, β-blockers, diuretics, and cardiac glycosides).  
 If the symptoms of CHF resolve with treatment, and cardiac function improves, 
trastuzumab may be continued after discussion with the patient concerning the risks and 
benefits of continued therapy. If the patient is benefiting clinically from trastuzumab, the 
benefit of continued treatment may outweigh the risk of cardiac dysfunction.   
 If trastuzumab is restarted, cardiac function should be monitored with echocardiogram 
every cycle 
 
Asymptomatic drop in LVEF 
 Trastuzumab may be continued in patients experiencing an asymptomatic absolute 
decrease in LVEF of <20 percentage points from baseline, when the ejection fraction 
remains ≥ 50%.  Such patients should be monitored with echocardiograms every cycle.   


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 Patients with an asymptomatic absolute decrease in LVEF of ≥20 percentage points or 
ejection fraction < 50%, should have trastuzumab held.   Consider cardiology referral for 
treatment of incipient CHF.   
 If trastuzumab is discontinued for an asymptomatic decline in LVEF, a repeat 
echocardiogram will be obtained in 1 month to determine if the decline has resolved. 
 If cardiac function improves, trastuzumab may be restarted after discussion with the 
patient concerning the risks and benefits of continued therapy.  If the patient is benefiting 
clinically from trastuzumab , the benefit of continued treatment may outweigh the risk of 
cardiac dysfunction.   
 
Hypersensitivity Reactions 
 Trastuzumab treatment should be discontinued for Grade 4 hypersensitivity reactions.  
There are no dose reductions for hypersensitivity reactions. 
 Docetaxel treatment should be discontinued for Grade 4 hypersensitivity reactions.  There 
are no dose reductions for hypersensitivity reactions. 
MANAGEMENT OF ACUTE HYPERSENSITIVITY 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized 
cutaneous reactions such as mild 
pruritus, flushing, rash 
· 
consider decreasing the rate of infusion until recovery from 
symptoms, stay at bedside and monitor patient 
· 
then, complete Taxotere infusion at the initial planned rate 
Moderate symptoms: any 
symptom that is not listed above 
(mild symptoms) or below 
(severe symptoms) such as 
generalized pruritus, flushing, 
rash, dyspnea, hypotension with 
systolic  
BP > 80 mm Hg  
 
· 
interrupt Taxotere infusion 
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until resolution of 
symptoms  
· 
resume Taxotere infusion after recovery of symptoms; 
depending on the physician’s assessment of the patient, 
Taxotere infusion should be resumed at a slower rate, then 
increased incrementally to the initial planned rate, (eg. 
infuse at a 4-hour rate for 3 minutes, then at a 2-h rate for 
3 minutes, then at a 1-h rate for 3 minutes, then finally, 
resume at the initial planned rate. 
· 
depending on the intensity of the reaction observed, 
additional oral or IV premedication with an antihistamine 
should also be given for the next cycle of treatment, and the 
rate of infusion should be decreased initially and then 
increased back to initial planned rate, (eg. infuse at a 4-hour 
rate for 3 minutes, then at a 2-h rate for 3 minutes, then at a 
1-h rate for 3 minutes, and finally, administer at the initial 
planned rate.) 
Severe symptoms: any reaction 
such as bronchospasm, 
generalized urticaria, systolic BP 
≤ 80mm Hg, angioedema 
· 
immediately discontinue Taxotere infusion  
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as needed; 
monitor patient until resolution of symptoms 
· 
the same treatment guidelines outlined under moderate 
symptoms (i.e. the third and fourth bullets) should be 
followed. 


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Anaphylaxis (NCI CTCAE v. 3.0 
grade 4 reaction) 
· 
NO FURTHER STUDY DRUG THERAPY 
 
Fluid Retention 
 There are no dose reductions for fluid retention. 
 Patients developing new onset edema or ascites, progression of existing edema or ascites, 
or another sign of fluid retention (eg. 2 pound weight gain) are to be treated with oral 
diuretics.  Regimens found to be effective in the management of fluid retention due to 
docetaxel are listed below: 
o 
Triamterene/hydrochlorothiazide one capsule po qd up to tid. 
o 
Furosemide 40 mg po daily if edema progresses despite 
Triamterene/hydrochlorothiazide therapy.  Potassium supplementation should be 
given as needed. 
o 
If after a two-week trial, furosemide 40 mg po qd is ineffective, the patient may 
be treated with furosemide 20 mg po daily plus metolazone 2.5 mg po daily with 
potassium supplementation as needed. 
 Further diuretic therapy should be customized depending upon the clinical situation.  The 
clinical tolerance of the patient, the overall tumor response and the medical judgment of 
the investigator will determine if it is in the patient’s best interest to continue or 
discontinue treatment.  
 
Hyperlacrimation 
 The following guidelines may be taken for patients experiencing clinically significant 
hyperlacrimation: 
 Dose reduction in fluorouracil treatment. 
 Withhold docetaxel treatment until resolution. 
 Frequent instillation of artificial tears. 
 Steroid ophthalmic solution starting the day before docetaxel administration in patients 
without a history of herpetic eye disease. 
 Ophthalmologist consult. 
 
If a dose attenuation is required in any chemotherapy drug that is already at dose level -2, the 
other chemotherapy drugs may be reduced by one dose level instead.  For cumulative toxicity, 
cisplatin, fluorouracil, leucovorin or docetaxel may be discontinued following discussion with 
the protocol principal investigator.  If more than one grade 3 or 4 event occurred, then the 
chemotherapy to be dose attenuation should be that of the most severe toxicity. 
 
For patients experiencing intolerable toxicity based on the treating physician’s clinical 
assessment, individual chemotherapy doses may be attenuation following consultation with the 
Principal Investigator.  
 
 


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9.4  CORRELATIVE STUDIES 
9.4.1 To bank tumor biopsy material for future planned correlative studies for association with 
chemotherapy efficacy and survival. 
We plan to store pre-therapy paraffin embedded tumor tissue for future tissue based correlative 
studies.  We will plan to examine this tissue bank by immunohistochemistry if markers for 
disease sensitivity or resistance to docetaxel based therapy is identified in ongoing trials.  Any 
IHC studies performed will be selected for based on clinical significance, feasibility, and 
reproducibility, in conjunction with a reference pathologist (eg. Laura Tang, MD PhD).  We will 
not require new tissue procurement for research purposes.  Prior to tissue use, we will submit a 
proposal for approval by the MSKCC Human Tissue Utilization Committee.  
 
HER2 testing will be performed in all patients to better characterize HER2-positive gastric 
cancer in US patients.  HER2 testing will be performed by the MSKCC diagnostic molecular 
laboratory on banked tumor specimens from the patients currently enrolled on the protocol and 
prospectively on all the patients screened for protocol participation.  FISH is performed using 
FDA-approved ERBB2 (HER2/NEU) PathVysion assay probes and procedure (Abbott-Vysis). 
IHC staining is performed using FDA-approved anti-Her2/neu Ventana’s PATHWAY rabbit 
monoclonal primary antibody (clone 4B5) directed against the internal domain of the c-erbB-2 
oncoprotein (Her2).  Biopsy samples with cohesive IHC3+ or FISH+ clones are considered  
HER2 positive irrespective of size, i.e.<10%.  FISH+ defined as >2 HER2:CEP17. 
Tissue samples for HER2 testing will be processed locally in the laboratory of investigational 
sites. The results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of HER2 status. 
MSK pathology review will not be required to begin therapy on the protocol.   Samples provided 
to the MSK laboratory must either be HER2 IHC slides, or  if FISH confirmation is necessary, a 
paraffin block(s) of adequate size to allow if possible for at least 5 slides with cuts that are 5-
microns thick or if a paraffin block is not available, then if possible at least 5 slides with cuts that 
are 5-microns thick will be acceptable. Archived or fresh tumor samples may be used. 
9.4.2 FDG-PET Response Assessment 
 
The primary aim of this correlative study is to examine the ability of an early FDG-PET/CT scan 
to predict treatment efficacy.  By identifying patients who are progressing early, patients 
exposure to cytotoxic therapy that is of no therapeutic value can be limited and the associated 
toxicity can be reduced.  As seen in patients who received preoperative chemotherapy, a 
significant drop from baseline in FDG uptake is associated with an improved pathologic 
treatment response and improved disease free survival (see Section 3.5.2).  However, the 
challenge in patients with locally advanced, but potentially curable disease is that surgery does 
cure some patients.  Thus, some patients who have a poor FDG-PET response, and an associated 
poor histopathologic tissue response, may still be cured with surgical resection of their tumor.  
However, for patients with metastatic or unresectable disease, this is not true.  Specifically, we 
hypothesize that patients with a good FDG-PET response will have RECIST evidence of 
response at their routine imaging time point and have a longer time to disease progression, when 


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compared with patients with a poor FDG-PET response.   If successful, we would be able to 
identify patients who are not benefiting from current therapy early, thereby allowing patients to 
minimize toxicity by minimizing exposure to ineffective therapy. 
To examine this further, we will perform a 2nd FDG-PET/CT scan on patients with FDG-avid 
primary tumors.  This 2nd scan will be performed during week 3 (following the day 15 treatment, 
but before week 4 of ARM A, and prior to the 2nd cycle of ARM B) at participating centers.  The 
PET/ CT scan is done with the patient fasting for about four to six hours, but water for hydration 
is allowed. Imaging starts about one hour after intravenous injection of a standard dose of F18-
FDG (8 to 15 mCi). Oral CT contrast is also administered for better delineation of the stomach 
and GI tract. 
 
Collaborating sites will specify at the time of study initiation if they will obtain the week 3 
PET/CT scans on all patients who have informative PET/CT scans at baseline.   
 
A low dose spiral CT is performed first, followed by acquisition of the PET images (emission 
scans only), of the neck, chest, abdomen and pelvis. The total radiation dose involved is about 1 
rem (0.5 rem from the CT and 0.5 rem from the PET).  Attenuation correction of the PET/CT 
images is then performed using the CT data. The final PET and CT image data sets are displayed 
on the fusion software for evaluation. 
 
FDG-PET/CT Data Analysis:  All images will be reviewed by a nuclear medicine physician 
independently and entered into separate data sheets.  The PET/CT images will be reviewed in all 
standard planes (3-dimensional computer display) and a maximum intensity projection. The 
images will be reviewed together with the CT and the fusion images.  Visual analysis of PET/CT 
data requires the definition of abnormal radiotracer uptake as being greater than background 
activity (on the attenuation corrected images) and outside of normal anatomic structures, which 
frequently exhibit various amount of FDG uptake (e.g., ureter, urinary bladder, bowel loops). 
Individual lesions will be graded on a scale of zero to four where 0 = definitely normal, 1 = 
probably benign, 2 = equivocal, 3 = probably malignant and 4 = definitely malignant. 
Semiquantitative analysis of tracer uptake, i.e. the standardized uptake value (SUV) will be done 
for lesions identified in the visual analysis by positioning of regions of interest (ROI) 
surrounding them. The SUV will then be calculated as below and entered into the data sheet (see 
Appendix D).  The baseline SUV value for statistical analysis will be the maximum-pixel SUV 
detected of the primary tumor.  SUVBW = decay corrected activity (mci/ml)/ injected dose (mCi)/ 
body weight (kg) 
 
9.4.3 Pharmacology and Pharmacodynamics (MSKCC patients only) 
Docetaxel is both a substrate and inhibitor of the cytochrome p450 enzyme CYP3A4, and its 
metabolism can be inhibited by CYP3A4 inhibitors such as ketoconazole, erythromycin, 
verapamil and diltiazem.  Importantly, both aprepitant and palonesetron, recently approved anti-
emetic agents for the treatment of acute and delayed nausea, are both inhibitors of CYP3A4. 
Similarly, we hypothesize that inhibition of CYP3A4 by these anti-emetic agents would result in 
reduced docetaxel metabolism, increased drug exposure, and potentially increased toxicity.  


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Pharmacokinetic blood draws will occur in patients enrolled at MSKCC only.  We will perform 
serial blood draws in approximately 20 patients (10/ arm) at the following times: 
1. 0.25 hours (15 min following initiation of docetaxel) 
2. 0.75 hours (45 min following initiation of docetaxel) 
3. 1 hour 
(end of docetaxel infusion) 
4. 1.25 hours  (15 min following the completion of docetaxel) 
5. 2 hours 
6. 4 hours 
7. 6 hours 
8. 8 hours 
9. 24 hours 
Additionally, on day 3, a CBC with differential and LFT’s (AST, ALT, Alk Phos, total Bilirubin) 
will be drawn in each of these patients.  For Arm A, these lab studies will be drawn prior to 
cisplatin administration.   
 
Amendment March 2008:  
In our initial pharmacokinetic analysis, we noted a suggestion of a difference in docetaxel 
pharmacokinetics when co-administered with cisplatin (Arm B) or without cisplatin (Arm A). 
Pharmacokinetic data are available preliminarily on 13 patients: 8 patients who were randomized 
to parent DCF (Arm B) in which cisplatin and docetaxel are co-administered on day 1, and 5 
patients who were randomized to mDCF(Arm A) in which cisplatin is administered on day 3 and 
docetaxel is administered on day 1, and . In Arm B, when cisplatin is given concurrently with 
docetaxel, dose adjusted docetaxel PK are as follows:  
AUC∞ 74.1 ng*hr/ml/mg/m2 
CL 28.9 L/hr/m2 
Vdss 27.8 L/m2
T1/2 18.8 hr 
When docetaxel is given on day 1 and cisplatin is given on day 3 (mDCF), dose adjusted 
docetaxel PK are as follows:  
AUC∞ 46.1 ng*hr/ml/mg/m2 
CL 38.1 L/hr/m2 
Vdss 17.1 L/m2
T1/2 12.1 hr 
These results appear to demonstrate that the clearance of docetaxel is reduced when it is 
administered on day 1 with cisplatin (Arm B), and this is associated with an increased exposure 
to docetaxel.  Conversely, when docetaxel is administered on day 1 and cisplatin is administered 
on day 3, docetaxel clearance appears to be higher and is associated with a lower AUC∞.  Recall 
that our hypothesis is that reduced clearance and higher exposure to docetaxel may be 
responsible for some of the increased toxicity observed with the parent DCF (Arm B) regimen.   


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We would like to expand on these initial findings.  Specifically, in up to 6 patients randomized to 
the parent DCF arm (Arm B), in addition to performing docetaxel pharmacokinetics with cycle 1 
treatment (as is already specified in the protocol), we would subsequently repeat docetaxel 
pharmacokinetics for a single cycle when cisplatin is not administered on the same day as 
docetaxel.  For example, for a single subsequent cycle, we would plan to administer cisplatin on 
a later date (i.e. day 3) and repeat docetaxel pharmacokinetic sampling.  Subsequent therapies 
would be as per protocol specification.   
9.4.4 Volumetric CT Analysis of Response to Therapy 
At MSKCC only and in collaboration with Larry Schwartz, MD, we will also initiate an 
exploratory volumetric CT analysis of Response to therapy.  This study will make use of already 
acquired image data from this clinical trial. No additional human material or CT scans will be 
needed.  The standard CT scan data (acquired either during PET/CT scanning or CT scanning) 
will be electronically transferred, via the hospital network, from the hospital PACS to the 
research PACS server, where patient identification information are de-identified.  Volumetric CT 
will be used in an exploratory way to assess tumor response during therapy to compare with 
RECIST.  The volumetric analysis, however, will not affect patient care and will not be 
communicated to the patient or clinical investigator.  To study effects of a wider range of slice 
thickness on the performance of the segmentation algorithms and reproducibility of tumor 
measurements, thinner section CT images will be reconstructed with CT raw data acquired for 
the radiographic assessment in the trial.  The volumetric CT technique used in this study may be 
able to detect asymmetric or small change in tumor size at the level that may not be possible with 
the conventional uni-dimensional RECIST criteria.   
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
The table below describes the the study plan


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TABLE 4.  STUDY CALENDAR  
 
Cycle 1 
Cycle 2 
Cycle 
3 (a) 
Off 
Study 
(j) 
Pre-
Study 
Wk 1 
Wk 2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
 
Day Number 
 
1 
8 
15 
22 
29 
35 
42 
49 
56 
63 
70 
77 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Radiology (i) 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
FDG-PET/CT (m) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Audiology Exam (k) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Collection
X 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC QLQ-C30 (n) 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Pharmacology (l) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
ARM A - mDCF 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
Toxicity check 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signs, Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Performance Status 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
CBC w/ diff, Plts 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum chemistry (b) 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
BUN, Creatinine (c) 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
LFTs (d) 
X 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
Total protein, LDH, Alb, 
Ca, Mg, PO4, tumor 
markers (e) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Echocardiogram/MUGAo 
X 
 
 
 
 
 
 
 
 
 
x 
 
 
ARB B -  
DCF + G-CSF 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Physical exam 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Toxicity check 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Vital signs, Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Performance Status 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
CBC w/ diff, Plts 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Comprehensive (g) 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
a Continues as per cycle 2, except the physical exam may be performed at the beginning of every cycle and as necessary 
and the toxicity check will be performed prior to the week 1 and 5 treatment of every subsequent cycle, and as needed. 
b Bicarbonate, BUN, chloride, creatinine, glucose, potassium, sodium   
d AST (SGOT), ALT (SGPT), Total Bilirubin, Alkaline Phosphatase.  Any abnormal LFTs require repeat LFTs prior to 
subsequent docetaxel therapy. Patients with alkaline phosphatase elevation secondary to the bony metastases rather than 
liver dysfunction may proceed with treatment on protocol after discussion with the principal investigator.  
 
b, c, d, e, f, g  May be performed on or within 1 day of treatment e Tumor markers as available. 
g Comprehensive = serum chemistry + LFTs + total protein, LDH, alb, Ca, Mg, PO4, and tumor markers as available. 
h For women of childbearing potential  i Includes CT of the chest, abdomen and pelvis within 30 days and a PA and lateral chest x-
ray unless a CT of the chest is available within 14 days of starting therapy. Tumor measurements are repeated after every cycle for 
the first 6 cycles and every 2 cycles thereafter.  May be performed earlier at physician discretion.  Radiologic documentation of 
progression is strongly recommended. j Patients will be monitored for overall survival following completion of study. Maybe 
performed by local physicians. k As clinically indicated, l Pharmacokinetic blood draws for MSKCC patients as per section 9.4.3.  m 
FDG-PET/CT scans are performed at baseline, and again during week 3 (following treatment #2 in ARM A, before treatment #2 in 
ARM B), participating sites only.  n EORTC QLQ-C30 is administered at baseline, 6 weeks, 3 months, 6 months, 9 months, and 12 
months.oFor patients receiving trastuzumab only, echocardiogram/MUGA will be done at baseline and every 12 weeks while on 
protocol.. 
 
 
10.1  FOR PARTICIPATING SITES  


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Tissue samples for HER2 testing will be processed locally in the laboratory of investigational 
sites. The results of local laboratory HER2 analysis will be required and sufficient to start the 
study treatment. The MSK laboratory will be used for subsequent confirmation of HER2 status. 
MSK pathology review will not be required to begin therapy on the protocol.   Samples provided 
to the MSK laboratory must either be HER2 IHC slides, or  if FISH confirmation is necessary, a 
paraffin block(s) of adequate size to allow if possible for at least 5 slides with cuts that are 5-
microns thick or if a paraffin block is not available, then if possible at least 5 slides with cuts that 
are 5-microns thick will be acceptable. Archived or fresh tumor samples may be used. 
 
Shipping of Specimen(s):  
 
All sites should ship specimens to MSKCC Principal Investigator: 
Yelena Y. Janjigian 
Memorial Sloan-Kettering Cancer Center 
300 E 66th Street BAIC 1033 
New York, NY 10065  
 
• Shipments should be batched. 
• A copy of the pathology report and patient signed informed consent should be included with 
the shipment. 
• At the time of shipment, a transmittal documenting patient ID and type 
of specimen sent should also be electronically submitted to janjigiy@mskcc.org and faxed to the 
Multicenter Core Project Coordinator (646-227-2482) 
• Shipments will not be received on Saturday or Sunday 
 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 CISPLATIN 
Cumulative nephrotoxicity associated with cisplatin is severe. Other major dose-related toxicities 
are myelosuppression, nausea and vomiting. Ototoxicity, manifested by tinnitus and/or high 
frequency hearing loss, is significant. Anaphylactic like reactions to cisplatin have been reported. 
Facial swelling, bronchospasm, tachycardia and hypotension may occur within minutes of 
cisplatin administration. Other side effects include anorexia, diarrhea, serum electrolyte 
disturbances (e.g., hyponatremia, hypomagnesemia), vascular toxicities (e.g., myocardial 
infarction, cerebrovascular accident etc.), renal insufficiency, neurotoxicity, peripheral 
neuropathy, autonomic neuropathy, muscle cramps, ocular toxicity (optic neuritis, papilledema, 
cerebral blindness), and hepatotoxicity. Other rare side effects include cardiac abnormalities, 
hiccoughs, elevated serum amylase, rash and alopecia. Local soft tissue injury has been reported 
following extravasation of cisplatin.  A complete list of toxicities can be found in the package 
insert. 
 


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11.2 DOCETAXEL
Principal adverse effects include neutropenia, thrombocytopenia, anemia, nausea, vomiting, 
diarrhea, ascites, mucositis, cardiac arrhythmias, hypotension, pleural effusion, peripheral 
neuropathy, rash, severe nail disorders (hypo or hyperpigmentation), onycholysis (loosening of 
the nails), alopecia, palmar-plantar dyserythroesthesia, hypersensitivity reaction, fatigue and 
fluid retention syndrome (may be irreversible). 
11.3 FLUOROURACIL 
Hematologic and gastrointestinal side effects are most frequently associated with fluorouracil. 
Hematologic toxicities of fluorouracil are leukopenia, granulocytopenia (9-14 days), 
thrombocytopenia (7-14 days), and anemia. Stomatitis, gastrointestinal ulceration and bleeding, 
and diarrhea are commonly seen gastrointestinal side effects of fluorouracil. Nausea and 
vomiting, effects on the skin including rashes and hyperpigmentation, alopecia, ocular irritation, 
central neurotoxicity (notably cerebellar ataxia), and myocardial ischemia have been reported. A 
complete listing of toxicities can be found in the fluorouracil package insert. 
11.4 LEUCOVORIN 
The only adverse reaction for leucovorin is a rare report of allergic reactions to parenteral 
injections of leucovorin. This is extremely uncommon. 
11.5 TRASTUZUMAB 
Principal adverse effects include cardiac dysfunction, infusion associated symptoms, potentiation 
of chemotherapy related hematologic side effects. A complete listing of toxicities can be found 
in the trastuzumab package insert. 
 
11.6 SUPPORTIVE MEDICATIONS 
G-CSF: common side effects include nausea, vomiting, bone pain, injection site irritation and 
influenza-like illness.  Rare side effects include vasculitis of the skin, and very rarely, acute 
respiratory distress syndrome and splenic rupture have been reported. 
Decadron: with chronic use, common side effects include hypertension, atrophic skin, impaired 
skin healing, hypercortisolism and primary adrenocortical insufficiency, irritation of the GI tract, 
increased risk of infection, osteoporosis, cataracts or glaucoma, and depression or euphoria. 
Hyperglycemia is common even with single use.   


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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT
For the purposes of this study, patients should be re-evaluated for response every cycle of 
chemotherapy, for the first 6 cycles of therapy. For patients remaining on therapy thereafter, 
patients are to be re-evaluated every 2 cycles of therapy. In addition to a baseline scan, 
confirmatory scans should also be obtained > 4 weeks following initial documentation of 
objective response. 
12.1 DEFINITIONS 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. Note:  Lesions are either measurable or non-
measurable using the criteria provided below. The term “evaluable” in reference to measurability 
will not be used because it does not provide additional meaning or accuracy. 
12.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as > 20 mm with conventional techniques (PET, CT, 
MRI, x-ray) or as > 10 mm with a high-resolution CT scan.  All tumor measurements must be 
recorded in millimeters or decimal fractions of centimeters.  A “high-resolution” CT scan is one 
in which images are recorded at least every 5 mm. 
12.1.2 Non-Measurable disease
All other lesions (or sites of disease), including small lesions (longest diameter < 20 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural / pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable.  Stomach, GEJ, or esophageal wall 
thickening is considered non-measurable. 
12.1.3 Target lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
12.1.4 Non-target lesions 
All other lesions (or sites of disease) that are not target lesions as defined in section 12.1.3 will 
be identified as non-target lesions and should also be recorded at baseline.  Non-target lesions 
include measurable lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions.  Measurements of these lesions are required when 


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feasible, since a patient may have progressive disease on the basis of larger non-target lesions. 
The presence or absence of each non-target lesion should be noted throughout follow-up. 
12.2 EVALUATION OF TARGET LESIONS 
Complete Response (CR):  Disappearance of all target lesions. Endoscopy must be without 
evidence of tumor with negative cytologic brushings and esophageal biopsies. The patient must 
be free of all symptoms of cancer.  
Partial Response (PR):  At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions taking as reference the baseline sum LD.  Positive washing, brushing or biopsy and/or 
residual tumor may still be evident on endoscopy and/or CT scan. No lesion may increase in size 
and no new lesion may appear. 
Progression (PD):  At least a 20% increase in the sum of LD of target lesions taking as reference 
the smallest sum LD recorded since the treatment started or the appearance of one or more new 
lesions. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum LD. 
12.3 EVALUATION OF NON-TARGET LESIONS 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Non-Complete Response (non CR):  Persistence of one or more non-target lesions or/ and 
maintenance of tumor marker level above the normal limits. 
Progression (PD):  Appearance of one or more new lesions. Unequivocal progression of existing 
non-target lesions. (Although a clear progression of "non-target" lesions only is exceptional, in 
such circumstances, the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the reference radiologist (or study chair). 
Note:  
1. If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
2. Cytology and histology:  If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology if possible. These 
techniques can be used to differentiate between PR and CR in rare cases (eg. residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain). The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for 


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response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
12.4 EVALUATION OF BEST OVERALL RESPONSE 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.  
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall response
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1.  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration". Every effort should be made to document the objective progression 
even after discontinuation of treatment.
2.  In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 
12.5 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
Note:  Tumor lesions in a previously irradiated area are not optimally considered measurable 
disease.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. 


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• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
• 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to the chest, abdomen, and pelvis. Head & neck 
and extremities usually require specific protocols. 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions that are clinically not easily accessible. It is 
a possible alternative to clinical measurements of superficial palpable nodes, 
subcutaneous lesions, and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination. 
 
12.6 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation:  The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed.  In cases where confirmation of response is not feasible, it should be 
made clear when reporting the outcome of such studies that the responses are not confirmed.  To 
be assigned a status of PR or CR changes in tumor measurements must be confirmed by repeat 
studies that should be performed 4 weeks after the criteria for response are first met. In the case 
of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 8 weeks. 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented, taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
13.1 DURATION OF THERAPY / CRITERIA FOR REMOVAL FROM STUDY 
In the absence of serious toxicity or complications, all patients will receive at least one cycle of 
treatment.  In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
• 
Disease progression, defined as  
(1) Appearance of a tumor > 1 cm in size at a new site, or 
(2) Reappearance of a previously completely resolved measurable tumor  
 
 
or lesion, or 
(3) An increase in tumor measurements (total longest diameter) > 20%. 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
(4) New sites of or clinical progression in non-measurable sites of disease 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), including but not limited to 
(1) grade 4 anaphylaxis 
(2) grade 4 hypertension, hemorrhage, or symptomatic grade 4 venous thromboembolism 
(3) any grade arterial thromboembolic event 
(4) grade 4 proteinuria 
(5) GI perforation or wound dehiscence (requiring medical or surgical therapy) 
• 
Patient death, 
• 
Patient decides to withdraw from the study or is lost to follow up, or 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
Patients will be discontinued from the study if they exhibit any of the following: 
• 
Dose limiting toxicity (not resolving) possibly, probably, or definitely attributable to the 
investigational agent: any Grade 3 or greater non-hematological event that does not recover 
to < grade 1. Nausea and vomiting will be dose limiting only if grade 3 despite adequate 
premedication. If a patient develops dose-limiting toxicity then the drug will be withheld 
until toxicity resolves to < grade 1, and restarted at a lower dose (Section 9.3).  
 
• 
In addition, if a patient develops an adverse experience that the Investigator feels is severe 
enough to preclude further participation, the patient will be discontinued from the study and 
receive medical treatment as determined by the Investigator.  The patient will remain under 
observation until the adverse experience is resolved.   
 
Patients will be discontinued from the study if they exhibit any of the following: 
• 
Lack of cooperation with the requirements of the study 
• 
Intercurrent illness requiring medication not allowed by the protocol 
• 
Withdrawal of consent 
The patient’s physician(s) are free to and should discontinue study treatment if this is believed to 
be in the patient’s best interest.  Furthermore, a patient is free to withdraw from study treatment 
and participation at any time for any reason.  Full documentation of the reasons and 
circumstances of all patients who withdraw must be documented in the medical record and on 
the appropriate case report forms. 
13.2  OFF-STUDY EVALUATION
• History and physical examination, including performance status and neurological exam. 
• Laboratory: Complete blood counts and chemistry tests as required at baseline 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
• Tumor Measurements: Assessment of at least one measurable lesion (in appropriate 
patients) preferably by CT scan unless within 4 weeks of last measurements. 
• Patients will be monitored for overall survival following completion of or removal from 
the study. 
14.0 
BIOSTATISTICS 
The study will be an open-label random assignment phase II therapeutic clinical trial.  The study 
population will be patients with histologically confirmed unresectable or metastatic gastric or 
gastroesophageal adenocarcinoma.  Arm A will be modified DCF and ARM B will be ‘parent’ 
DCF with growth factor support. 
The primary endpoint for both arms is progression free survival (PFS), as measured from the 
start of the treatment to the date of either documentation of disease progression or death.  We 
will define progression of disease as per RECIST criteria.  Patients with measurable disease and 
with evaluable radiographically but non-measurable disease will be eligible for study entry.  As 
per RECIST criteria, any evidence of progression in non-measurable lesions, measurable lesions, 
or the development of new lesions, would qualify as disease progression.  The 6 month 
progression free survival for 'parent' DCF is approximately 43% (see Section 3.3.2).  Using this 
as a benchmark, we propose declaring each regimen comparable to parent DCF if the 6 months 
PFS exceeds 43%, and unworthy of further investigation if it is 26% or less. Each arm will be 
evaluated separately for this purpose. We will accrue 60 patients in each arm for a total study 
population of 120 patients.  Anticipating a 10% inevaluable rate, with 54 evaluable patients 
enrolled in each arm we will be able to differentiate between 6 month PFS of 26% and 43% with 
type I and II error rates of 10% each (exact single stage binomial design) [44].  For each arm, the 
regimen is considered promising if 19 or more patients (out of 54) are progression free at 6 
months.  We will define "evaluable" patients as patients who met eligibility requirements, have 
initiated therapy, and were not removed from the study for non-compliance or patient withdrawal 
within the first 6 months.  We anticipate enrollment to be 8 patients/ month with completion of 
accrual in approximately 15 months. 
Secondary endpoints of efficacy are response rate, median PFS, overall and 1 year survival. We 
anticipate that we will enroll approximately 40 patients with measurable disease in each arm, 
from which we can establish a response rate to within +/- 15%. This is consistent with most 
Phase II studies evaluating response.  The median PFS will be estimated using the Kaplan-Meier 
method, and 95% confidence intervals will be based on the sign test [45]. The 1 year survival 
will be estimated using the Kaplan-Meier method, and Greenwood’s formula will be used to 
calculate the standard error of the corresponding Kaplan Meier estimate and 95% confidence 
interval. Survival curves will be estimated using Kaplan-Meier methodology. 
 
A secondary objective is to demonstrate improved toxicity profile of each regimen compared to 
parent DCF.  It is reported that DCF has a grade 3-4 adverse event  rate for non-hematologic 
toxicity exceeding 80%. We hypothesize that the modified De Gramont type of FU infusion and 
more frequent dosing of cisplatin and docetaxel (eg. ARM A) will be associated with less 
toxicity.  Additionally, parent DCF administered growth factor support (eg. ARM B) will also be 
associated with less toxicity.   
 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
In order to reduce patient risk, the study design includes early termination of the trial in the event 
of excessive grade 3 or 4 adverse events. We employ repeated significant testing with a constant 
significance level to monitor the grade 3/4 adverse event rate [46]. The table below provides a 
stopping boundary for this study based on an acceptable grade 3/4 adverse event rate of 50% and 
an unacceptable grade 3/4 adverse event rate of 70%.  Using this boundary, if the true adverse 
event rate is 50% then the probability of stopping early is 5%. However, if the true toxicity rate 
is 70% then the probability of stopping early increases to 87%. 
 
Stop if we observe 
12 
grade 3 or 4 adverse events in the first 
15 patients. 
21
30
 
30 
 
45  
 
35 
 
54  
Grade 3 or 4 venous thromboembolic events will not be included for the purposes of this safety 
determination. We have previously demonstrated that the majority of these events are associated 
with minimal to no co-morbidity and are likely attributable to the disease and not the 
therapy[47]. 
Total accrual will be 108 evaluable patients with a 1:1 randomization.  We will stratify based on 
center, disease (measurable vs. non-measurable), and location (gastric vs. GEJ). 
December 2009 Amendment 
Arm B will be closed because we met the above stopping rule.  Specifically, we observed 22 
grade 3-4 adverse events in the first 30 patients enrolled on Arm B. We note that there was a 
discrepancy between the two arms with regard to the rate of grade 3-4 thromboembolism (5 in 
Arm B, and 0 in Arm A).  Because of this discrepancy, we included grade 3-4 venous 
thromboembolic events in the determination of the toxicity stopping rule.  Notably, 16 patients in 
Arm B required admission due to toxicity in the first 3 months of protocol therapy.   As a result 
of this unacceptable toxicity, the standard DCF + growth factor support arm will close.   
 
As of October 23, 2009, 26 patients are evaluable for toxicity in Arm A (mDCF). We’ve 
observed 16 grade 3-4 adverse events attributable to treatment in the first 3 months, and 8 
hospitalizations.   
Note, the results of the recent ToGA study demonstrate that for Her2 positive gastric cancer, 
patients have a survival benefit with the addition of trastuzumab to chemotherapy (see Sect 
3.3.4).  We are therefore amending the study to include a separate cohort of 35 patients who are 
Her2 positive to receive mDCF + trastuzumab (Trastuzumab cohort) 
.  
Total patient accrual to this protocol is fixed at 120 patients.  Arm B has closed with 31 patients 
enrolled in total.  Arm A will remain with a target accrual of 54 eligible patients.  For the 
remaining 35 patients, we will open a Trastuzumab Cohort in which Her2 positive patients with 
metastatic gastric/GEJ adenocarcinoma will receive mDCF + trastuzumab.  With 35 HER2-
positive patients, we will be able to differentiate between 6-month PFS of 43% and 64% with 
type I and II error rates of 10% each (exact single stage binomial design). The modified DCF 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
plus trastuzumab regimen will be considered promising if 19 or more Her2 positive patients (out 
of 35) are alive and progression free at 6 months.  
For the Trastuzumab Cohort, we will employ a similar early stopping rule for safety, as we have 
done for Arm A and Arm B. The table below provides a stopping boundary for this study based 
on an acceptable grade 3/4 adverse event rate of 50% and an unacceptable grade 3/4 adverse 
event rate of 70%.  Using this boundary, if the true adverse event rate is 50% then the probability 
of stopping early is 5%. However, if the true toxicity rate is 70% then the probability of stopping 
early increases to 87%. 
 
Stop if we observe 
12 
grade 3 or 4 adverse events in the first 
15 patients. 
 
21 
 
30  
 
For the FDG-PET/CT correlative study (section 9.4.2), the change between baseline and 2nd PET 
scan (change in SUV) will be correlated with response, time to tumor progression, and overall 
survival.  These associations will be assessed using a t-test for response (comparing the means 
between responders and non-responders), and Cox regression for overall survival and time to 
tumor progression. 
 
Another secondary objective is to explore the differences in docetaxel pharmacology between the 
two study arms.  Serial blood draws will be performed in approximately 10 patients in each arm, 
as explained in section 9.4.3.  Some patients in Arm B may have repeat docetaxel pharmacology 
tests without cisplatin administration. Standard pharmacokinetic parameters including Cmax, 
Tmax, and AUC will be estimated for each patient using non-compartmental methods, and a 
Wilcoxon rank sum test will be used to compare the distribution of levels for the two groups. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES
15.1   RESEARCH PARTICIPANT REGISTRATION 
All centers must register patients through MSKCC.  No patient can be treated unless they are 
registered through MSKCC.   
For MSKCC patients: 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations can be phoned in or faxed. The completed signature page of the written 
consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
For  Participating Centers: 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center.
Patient registration must be initiated at Memorial Sloan Kettering Cancer Center within 48 hours 
of the patient signing the informed consent. 
To complete registration and enroll a patient from another institution, the study staff at that site 
must contact the Multicenter Core Project Coordinator  to notify him/her of patient registration. 
The study staff then needs to fax registration/eligibility documents to the Multicenter Trials Core 
at MSKCC at 646-227-2482. 
The following documents must be sent within 24 hours of informed consent form being signed 
for each enrollment:  
• 
The completed or partially completed MSKCC eligibility checklist  
• 
The signed informed consent and HIPAA Authorization form (Research    
Authorization)  
• 
Supporting source documentation for eligibility questions (laboratory results,  
pathology report, radiology reports, MD notes, physical exam sheets, medical 
history, prior treatment records, and EKG report).  
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.   If the eligibility checklist is not complete, the patient will be 
registered PENDING and the site is responsible for sending a completed form within 30 days of 
the consent.  
 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSKCC, the MSKCC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as stated 
in section 15.1.  The participant will be registered. 
 
15.2 
PROTOCOL PATIENT NUMBER 
Once eligibility has been established and the patient is registered, the patient will be assigned an 
MSKCC Clinical Research Database (CRDB) number (protocol patient number). This number is 
unique to the patient and must be written on all data and correspondence for the patient. This 
protocol patient number will be relayed back to study staff at the registering site via e-mail and 
will serve as the enrollment confirmation. 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
15.3 RANDOMIZATION 
After eligibility is established and immediately after consent is obtained and a patient number is 
assigned patients will be registered and randomized using the Clinical Research Database 
(CRDB).  Patients will be 1:1 randomized to the two arms.  Randomization will be accomplished 
by the method of random permuted block.  We will stratify based on center, disease (measurable 
vs. non-measurable), and location (gastric vs. GEJ). 
 
December 2009 Amendment 
Due to excessive toxicity, Arm B has been closed. Patients will no longer be randomized 
between two arms of the study.  Instead, patients will be assigned to Arm A.  If they are Her2 
positive and are eligible for trastuzumab, they will be assigned to the Trastuzumab cohort.   
 
August 2010 Amendment 
Arm B remains closed due to toxicity and target accrual has been reached for Arm A.   
Accordingly, eligibility criterion has been expanded to include Her2.  Patients eligible under 
these criteria will be assigned to the Trastuzumab cohort.   
 
16.0 
DATA  MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team.  
The data collected for this study will be entered into a secure database (Clinical Research 
Database – CRDB).  Source documentation will be available to support the computerized patient 
record.  Standardized Case Report Forms (CRFs) that meet the requirements for MSKCC data 
reporting have been generated for this study.  Adverse events, including all toxic effects of 
treatment, will be tabulated individually, and summarized by body system and to severity or 
toxicity grade.  Laboratory data will be tabulated and summarized by descriptive statistics, as 
well as on the basis of MSKCC specified normal ranges.   
16.0.1 Data Management Requirements for Participating Sites  
 
Data 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements have been 
generated for this study. Blank case report forms will be sent to the study staff at each 
participating site for use. The participating Site PI is responsible for ensuring these forms are 
completed accurately, legibly and in a timely manner.  
Please see Appendix C for the data collection schedule that each pariticipating center is expected 
to adhere to. 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and evaluations 
that are subsequently recorded as data. Source documentation should be consistent with data 
entered into CRFs. Relevant source documentation to be submitted throughout the study includes 
but is not limited to:  
 
• Baseline measures to assess pre–protocol disease status (ex. CT)  
• Treatment records  
• Grade 3-5 toxicities/adverse events  
• Response designation  
 
16.0.2  Data and Source Documentation Submission for Participating Sites 
 
Participating sites should fax CRFs and source documentation to MSKCC to the contact provided 
below. Submissions should include a cover page listing all CRFs enclosed per participant.  
 
FAX: To the attention of Multicenter Trials Core at 646-227-2482 
 
16.0.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according to guidelines 
specified in Appendix A-C.  
 
SAE Reporting: 
Hospitalization requiring Serious Adverse Event Reporting must be reported within three 
calendar days. 
Please see Section 17.2.1 regarding the requirements for SAE reporting.  
Off-Study Requirements: 
When a patient is taken off-study all CRFs with required source documentation are required to 
be sent to MSKCC not later than 14 calendar days after the off-study date. Failure to submit 
required forms in the timelines requested will result in suspension of accrual privileges at a given  
site until data is updated, and/or withholding of contract payments if applicable. 
16.0.4 Data Review and Queries for Participating Site Data 
Research staff at MSKCC will review data and source documentation as it is submitted. Data will be 
monitored against source documentation and discrepancies will be sent as queries to the participating 
sites. Queries will be sent by MSKCC Research staff twice a month. 
 
Participating sites should respond to data queries within 14 days of receipt.


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
16.1 QUALITY ASSURANCE 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. Random-sample data quality and protocol 
compliance audits may be conducted by the study team, at a minimum of two times per year, 
more frequently if indicated.   
16.1.1 Site Auditing 
Each site participating in the accrual of patients to this protocol will be audited by the staff of the 
MSKCC study team for protocol and regulatory compliance, data verification and source 
documentation. Audits may be accomplished in one of two ways: (1) selected patients records 
can be audited on-site at participating sites or (2) source documents for selected patients will be 
sent to MSKCC for audit. Audits will usually be determined by patient accrual numbers and rate 
of accrual, but can also be prompted by reported SAEs or request of Lead PI.  
 
Audits will be conducted at least once shortly after initiation of patient recruitment at a site, and 
if possible, at the end or closeout of the trial at a site and during the trial if the trial lasts 3 or 
more years. At a minimum, audits will be conducted once a year or more frequently, if indicated. 
The number of patients audited will be determined by available time and the complexity of the 
protocol.  
 
The audit will include a review of source documentation to evaluate compliance for:  
• 
Consent documents and procedures  
• 
Adherence to eligibility criteria  
• 
Protocol defined treatment  
• 
Required baseline, on study and follow-up protocol testing  
• 
IRB documents (submitted amendments, annual continuing review reports, SAEs)  
• 
Required specimen submission  
• 
Pharmacy review, if applicable  
• 
Case Report Form submissions to MSKCC: timing and accuracy  
 
A wrap-up session will be conducted at the outside site and preliminary findings will be 
discussed with the outside site PI and research team. The preliminary results will be sent to the 
MSKCC PI.  


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating 
institution within 30 days of the audit. The report will include a summary of findings, patient by 
patient case review, specific recommendations on any performance and/or shortcomings and 
request for corrective action, when necessary. When corrective action is required, the 
participating institution must reply within 45 days of receipt of audit report with their corrective 
action plan. 
A copy of the audit report and corrective action plan (if applicable) submitted by the outside site 
must be sent to the MSKCC IRB, CRQA and maintained in the department’s protocol regulatory 
binder.  
16.1.2 Response Review  
Since therapeutic efficacy is a stated primary objective, all sites patient’s responses are subject to 
review by MSKCC’s Therapeutic Response Review Committee (TRRC). Radiology, additional 
lab reports and possibly bone marrow biopsies and/or aspirates will need to be obtained from the 
outside sites for MSKCC TRRC review and confirmation of response assessment. These 
materials must be sent promptly upon request to MSKCC. 
16.1.3 Adherence to the Protocol 
The study will be conducted as described in the approved protocol, except for an emergency 
situation in which proper care for the safety of the patient requires alternative treatment.  Any 
deviation from the protocol will be reported, explained and documented in the patient's medical 
record. 
16.2 DATA AND SAFETY MONITORING 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.  The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The MSKCC 
Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Quality%
20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality.  There are institutional processes in place for quality assurance (eg. protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control, plus there are two 
instutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
During the protocol development and review process, each protocol will be assessed for it’s level 
of risk and degree of monitoring required.  Every type of protocol (eg. NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will bee addressed and the 
monitoring procedures will be established at the time of protocol activation. 
For Multicenter studies, standardized Case Report Forms (CRFs) have been generated from this 
study that meet the requirements of CTEP and MSKCC data reporting. A set of CRFs will be sent to 
each center (for photocopying and use) following local activation.   
16.3 ETHICAL AND ADMINISTRATIVE ISSUES 
The investigator will agree to personally conduct and supervise the proposed investigations 
according to recognized principles of good clinical practice (GCP). 
16.4 INSTITUTIONAL REVIEW BOARD APPROVAL 
This protocol and the informed consent form will be reviewed and approved by the IRB before the 
study is initiated.  The Investigator is then responsible for informing the IRB of the completion of the 
study and will provide the IRB a final study status report.  The Investigator/Study Coordinator will 
inform the IRB of all serious adverse events. 
 
 
16.5  REGULATORY DOCUMENTATION  
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MSKCC 
Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this protocol at the 
participating sites, approval for the MSKCC IRB/PB approved protocol must be obtained from the 
participating site’s IRB.   
 
The following documents must be provided to MSKCC before the participating site can be initiated 
and begin enrolling participants:  
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical license for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 
• 
Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant permission 
to proceed with enrollment.  


Memorial Sloan-Kettering Cancer Center 
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                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
 
16.5.1 Amendments 
Each change to the protocol document must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 
immediately distribute all non expedited amendments to the participating sites, for submission to 
their local IRBs. 
 
 
Participating sites must obtain approval for all non expedited amendments from their IRB within 90 
calendar days of MSKCC IRB/PB approval. If the amendment is the result of a safety issue, sites will 
not be permitted to continuing enrolling new participants until the participating site IRB approval has 
been granted. 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines:  
• 
Participating Site IRB approval  
• 
Participating Site IRB approved informed consent form and HIPAA  authorization 
 
16.5.2  Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of study 
activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who does not 
meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in their study plan. 
If a deviation from this protocol is proposed for a potential or existing participant at MSKCC or a 
participating site, approval from the MSKCC IRB/PB is required prior to the action. Participating 
sites should contact the MSKCC PI who will in turn seek approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are identified 
after they occur, the participating site should report to MSKCC as soon as possible. The MSKCC PI 
will in turn report the violation to the MSKCC IRB/PB.  
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the participating 
site IRB for protocol deviations and violations should be submitted to MSKCC as received.  
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to local 
guidelines, and submit copies of that correspondence to MSKCC. 
 
16.5.3 Document maintenance 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to enable 
the implementation of the protocol to be fully documented and the data to be subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB approval letters 
referencing protocol version date and amendment number, IRB approved protocol, appendices, 
informed consent forms, deviations, violations, and approval of continuing reviews) is maintained in 
the regulatory binder on site and sent to MSKCC. 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper or 
electronic. 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 7 years. 
 
16.6 NONCOMPLIANCE  
 
If a participating site is noncompliant with the data and regulatory requirements set forth in section 
16.0 -16.5 accrual privileges may be suspended and/or contract payments maybe withheld (if 
applicable), until the outstanding issues have been resolved.   
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. All patients will be required to sign a statement of informed 
consent, which must conform to IRB guidelines. 
Inclusion of Women and Minorities:  Memorial Sloan-Kettering Cancer Center has filed forms HHS 
441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 680 (age 
discrimination); we also take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. Patients of all races, both male and female, will be 
accepted into the protocol. The proposed study population is as described in section 7.0. 
Exclusion of Lactating or Pregant Women:  Children have been excluded from this study. Gastric 
and GEJ adenocarcinoma is an adult cancer. Thus, the relevance of this drug to the pediatric 
population has not been established. Lactating and pregnant women are also excluded because of 
potential anti-proliferative effects of chemotherapy that may be harmful to the developing fetus or 
nursing infant. 
Benefits: It is possible that this treatment will result in shrinkage of the gastric tumor or in a 
stabilization of an otherwise progressing disease. It is not known, of course, whether these or any 
other favorable events will occur. It is not known whether this treatment will affect the overall 
survival of the patients. 
Costs: The patient will be responsible for the costs of standard medical care, including all drug 
administration fees and all hospitalizations, even for complications of treatment.  The laboratory 
correlative studies and week 3 FDG-PET/CT scans will be performed without charge to the patient. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
                           IRB#: 06-103 A(17)
Amended:  08/03/15 
 
Incentives:  No incentives will be offered to patients/subjects for participation in the study. 
 
Alternatives:  For patients with metastatic gastric cancer alternative treatments may include other 
chemotherapy regimens as well as palliative radiation therapy, and/or surgery. At present, no specific 
chemotherapy regimen represents standard treatment for the disease. Patients may be eligible for 
other investigational studies. 
Confidentiality:  Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. Patient’s name or any other personally identifying information will not be 
used in reports or publications resulting from this study. The Food and Drug Administration or other 
authorized agencies (eg, qualified monitors from MSKCC or collaborating institutions, the NCI, 
Sanofi-Aventis etc.), may review patients records and pathology slides, as required. 
17.1 PRIVACY 
It is the responsibility of the Research Staff to ensure that protocol subjects received the Center’s 
Notice of Privacy Practices.  If the subject has not received one, MSK personnel must provide a 
Notice of Privacy Practices and obtain acknowledgment before the subject participates in the study. 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form.  The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form.  A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board. 
 
17.2 SERIOUS ADVERSE EVENT (SAE) REPORTING 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the 
following information: 
 
Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of    
• 
MSKCC)  
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 


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• 
Detailed text that includes the following information: 
o       A explanation of how the AE was handled 
o       A description of the subject's condition 
o       Indication if the subject remains on the study 
o    If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
All adverse events, whether observed by the investigator, elicited from the patient, or volunteered by 
the patient, will be recorded The  MSKCC PI (Yelena Janjigian, MD) will report all SAE’s to the 
MSKCC IRB and to Sanofi-Aventis Pharmaceuticals and Genentech via the CRDB AE report .  
17.2.1 ADVERSE EVENT REPORTING DEFINITIONS 
Adverse Event: An adverse event is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic functions, as indicated by physical signs, symptoms, and/or laboratory 
changes occurring in any phase of the clinical trial, whether or not considered drug related. All of the 
following are to be considered adverse events:   
•  an exacerbation of a pre-existing condition. 
•  an intercurrent illness. 
•  any drug interaction. 
•  any event related to a concomitant medication. 
• 
development of an abnormal laboratory value or a significant change from baseline in a 
laboratory value within the range of normal, considered by the investigator to be clinically 
important. 
•  an unexpected significant worsening of the cancer under treatment.  Anticipated day-to-day 
fluctuations in the activity of the cancer or the anticipated progression of the cancer (other than 
death) should not be considered an adverse event. 
 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability / incapacity, or is a congenital anomaly / 
birth defect. 
 
The definition of serious adverse event (experience) also includes important medical event.  Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above.  These should also usually be 
considered serious.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
 
The definition of “related” is that there is a reasonable possibility that the drug caused the adverse 
experience. 
 


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Life-threatening: A life-threatening adverse event implies an immediate risk of death from the 
reaction as it occurred.  Life-threatening does not include a reaction that, had it occurred in a more 
serious form, might have caused death.  For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug-induced 
hepatitis can be fatal. 
 
 
ASSESSMENT OF SEVERITY  
This study will utilize the Cancer Therapy Evaluation Program Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0 for toxicity and Adverse Event reporting. A copy of the 
CTCAE Version 3.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). 
ASSESSMENT OF RELATIONSHIP TO STUDY MEDICATION 
The following definitions of relationship to study medication should be used in assessing the 
suspected causality of an adverse event: 
Definite:  The adverse event is clearly related to the chemotherapy or investigational agent. 
Probable: The adverse event is likely related to the chemotherapy or investigational agent. 
Possible: The adverse event may be related to the chemotherapy or investigational agent. 
Unlikely: The adverse event is doubtfully related to the chemotherapy or investigational agent. 
Unrelated: The adverse event is clearly NOT related to the chemotherapy or investigational agent. 
 
17.2.3 
REPORTING 
ADVERSE 
EVENTS 
ASSOCIATED 
WITH 
TRASTUZUMAB
(GENENTECH)  
With the occurrence of an adverse event, the first concern will be for the safety of the subject.  
Investigators are required to report to Genentech Drug Safety any serious adverse event, whether 
expected or unexpected, and which is assessed by the investigator to be reasonably or possibly 
related to or caused by trastuzumab.  All events meeting these criteria will be reported for the time 
period beginning with any amount of exposure to trastuzumab through the protocol-defined follow-
up period.  Serious criteria, definitions, and guidance for reporting follow. 
 
Reporting Serious Adverse Events Associated With Trastuzumab  
All SAEs that are serious and reasonably or probably related to the use of Trastuzumab (this applies 
to both expected and unexpected events) should faxed to: 
Genentech Drug Safety Contact Line 
Tele: 1-888-835-2555 
Fax:  (650) 225-4682/ (650) 225-4683  
AND: 
Study Coordination Center/Principal Investigator 
Contact Information 
AND: 
IRB Contact information 


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17.2.4 SANOFI –AVENTIS REPORTING GUIDELINES 
All SAEs are to be reported as soon as possible to Sanofi-Aventis.   Reports by FAX should be sent 
to Aventis Pharmaceuticals Global Pharmacovigilance and Epidemiology Department (908-231-
4827), within 24 hours of receipt by investigator / sponsor.  FAX transmission should include the 
following on the provided IIT SAE REPORT, fax cover form (Appendix E): 
Reports by E-MAIL should be sent to: GPEmailbox@aventis.com , within 24 hours of receipt by 
investigator / sponsor.  E-Mail transmission should include the following:  
Investigator-Initiated (IIT #) study number:___________________  
Study Title:____________________________________________ 
Name of Principal Investigator:____________________________ 
 
17.3 SERIOUS ADVERSE EVENT REPORTING FOR OUTSIDE CENTERS 
Responsibility of Participating Sites 
Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail 
within 3 calendar days. 
Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
 
Participating sites should use the SAE Report Template (appendix E) to report SAEs to MSKCC. 
  
SAE contact information for the Coordinating Center is listed below:  
PI: Yelena Y. Janjigian, MD 
Tel: 646-888-4186 
Email: janjigiy@mskcc.org  
Multicenter Core Project Coordinator 
Fax: 646-227-2482 
Responsibility of MSKCC 
• The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC 
IRB/PB as specified in 17.2 [and to the funding entity as described in 17.2.3 and 17.2.4] 
• The MSKCC PI is responsible for informing all participating sites about unexpected 
SAEs within 30 days of receiving the stamped SAE from the MSKCC IRB/PB.  
• Any report pertaining to a grade 5 event will be distributed to the participating sites as 
soon as possible. 
17.4 SAFETY REPORTS  
 


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• 
MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt.  
• 
MSKCC must submit safety reports to the MSKCC IRB/PB according to institutional 
guidelines. 
• 
Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines. 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information.  
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
18.1 For Participating Sites 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be given 
to the participant to be retained for their personal records. One copy will be maintained on file at 
the MSKCC. The third copy will be confidentially maintained by the participating institution. 
 


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A note should be placed in the medical record documenting that informed consent was obtained 
for this study, and that the participant acknowledges the risk of participation. 
 
 
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26. Lorenzen, S., J. Duyster, N. Weigert, et al. Docetaxel (T) plus Cisplatin (P) and 
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20.0 
APPENDICES 
Appendix A:  KARNOFSKY / ECOG PERFORMANCE STATUS SCALES 
Appendix B:  TISSUE TRANSMITTAL SHEET 
Appendix C:  SERIOUS ADVERSE EVENT REPORT FORM FOR NON-MSKCC SITES 
    Appendix  D:  EORTC QLQ-C30