Conditions: Squamous Cell Carcinoma of the Oral Cavity Squamous Cell Carcinoma of the Soft Palate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 928
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine whether LI administered in combination with cyclophosphamide, indomethacin and zinc in a multivitamin (CIZ) combination prior to standard of care therapy (surgery followed by radiotherapy or concurrent radiochemotherapy) is safe and will increase the overall survival of subjects with previously untreated locally advanced primary squamous cell carcinoma of the oral cavity or soft palate at a median of 3 to 5 years

Detailed description:
Head and neck carcinomas constitute about 5% of all cancers annually worldwide. In the US there are about 65,000 new cases annually. Ninety percent are squamous cell carcinoma of the head and neck (SCCHN). Approximately 2/3 of SCCHN patients present on their first visit with locally advanced disease. The median 3 year overall survival (OS) for these patients with existing standard of care (SOC) therapies - surgery followed by radiotherapy or concurrent radiochemotherapy - is estimated to be between 52 and 55%; the 5 year OS is approximately 43%. There are clearly many of SCCHN patients not well served by available modalities.

Regional intra or perilymphatic and/or intratumoral or peritumoral low dose cytokine therapy may have important therapeutic effects in SCCHN patients and constitute an additional anti-tumor mechanism of action different and distinct from current SOC. Leukocyte Interleukin Injection (LI) \[Multikine\] contains a defined mixture of naturally derived cytokines and chemokines with demonstrated safety and immunomodulatory activity in animals and in man in Phase I and Phase II clinical trials. LI is administered prior to SOC and in combination with low non-chemotherapeutic doses of cyclophosphamide, indomethacin, and zinc (CIZ) in studies with LI. The results of these studies indicate that the local/regional injection of mixed interleukins (LI) with CIZ prior to SOC can overcome local immunosuppression, break tumor tolerance to tumor antigens and allow for a sustainable and effective anti-tumor immune response.

LI was tested in this large, global, multinational Phase III clinical trial to develop definitive proof of its efficacy and safety in treating SCCHN. The trial is an open-label randomized multi-center controlled study of LI + CIZ + SOC in subjects with advanced primary SCCHN of the oral cavity/soft palate vs. SOC \[the comparator arm\]. OS is the primary efficacy endpoint.

Arms:
arm 1: LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). arm 2: SOC for previously untreated SCCHN patients is currently surgery (with curative intent) followed by either radiotherapy or combined radiochemotherapy depending on the patient's risk status for recurrence as determined at surgery. arm 3: LI was administered without CIZ to determine the contribution of CIZ to the effects of LI.

Interventions: intervention 1: LI intervention 2: Cyclophosphamide intervention 3: Indomethacin intervention 4: Zinc intervention 5: Surgery intervention 6: Cisplatin intervention 7: Radiotherapy
Intervention descriptions: intervention 1: LI 400 IU (2.0mL total daily) 1.0 mL peritumoral, 1.0 mL perilymphatic 5x weekly x3 consecutive weeks administered as neoadjuvant therapy prior to SOC, (surgery followed by radiation or concurrent radiochemotherapy with cisplatin 100 mg/m\^2 intravenously x3) to determine if LI plus CIZ affects the 3-5 year overall survival. intervention 2: Cyclophosphamide was administered IV bolus (one time only) at a dose of 300mg/m\^2 three days prior to beginning treatment with LI. Standard of care (SOC) for previously untreated squamous cell carcinoma of the head and neck is currently surgery followed by radiotherapy (60-70Gy in 30 to 35 fractions over 6 to 7 weeks) for higher risk subjects (subjects determined at surgery to have adverse features per the National Comprehensive Cancer Network (NCCN) guidelines, such as, positive surgical margins, 2 or more clinically positive nodes or extracapsular nodal spread, etc. that would pre-dispose them for higher risk of recurrence) radiotherapy is combined with concurrent chemotherapy (cisplatin 100mg/m\^2 intravenously on day 1 of weeks 1, 4 and 7 of radiotherapy. intervention 3: One 25mg capsule of indomethacin was self administered orally (BID) beginning on day one of LI treatment daily until the day before surgery. intervention 4: One capsule daily self administered beginning on day one of treatment with LI until one day before surgery intervention 5: Excise tumor and nodes intervention 6: Cisplatin was administered 100mg/m\^2 IV concurrent with radiotherapy. The chemotherapy agent (cisplatin 100mg/m\^2) was administered intravenously on day 1 of weeks 1, 4 and 7 of radiotherapy. intervention 7: Total 60 to 70 Gy (2Gy per day) in 30 to 35 fractions over 6 to 7 weeks to subjects determined at surgery to be at lower risk for recurrence (per NCCN guidelines). For subjects determined at surgery to be at higher risk for recurrence due to having positive surgical margins, 2 or more clinically positive nodes or extracapsular nodal spread etc. (per NCCN guidelines), radiotherapy (as above) is combined with concurrent chemotherapy (cisplatin 100 mg/m\^2) intravenously on day 1 of weeks 1, 4 and 7 of radiotherapy.

Protocol document:
SAP_002.pdf: 







SAP_004.pdf: 





SAP_006.pdf: 





SAP_003.pdf: 





Prot_000.pdf: 
A Phase lll, Open-label, Randomized, Multi-center Study of the Effects of
Leukocyte lnterleukin, lnjection [Multikine] Plus Standard of Care (Surgery +
Radiotherapy or Surgêr! + Çe¡surrent Chemoradiotherapy) in Subjects with
Advanced Primary Squamous Cell Carcinoma of the Oral Gavity / Soft Palate
Versus Standard of Gare Only
Regulatory
Sponsor:
Funding
Sponsor:
Study
Product:
Protocol
Number:
IND
Number:
EudraCT
Number:
CEL-SCl Corporation
8229 Boone Boulevard
Suite 802
Vienna, Virginia 22182 U.S. A.
Phone: 703-506-9460 Fax: 703-506-9471
CEL-SCl Corporation
8229 Boone Boulevard
Suite 802
Vienna, Virginia 22182 U.S. A.
Phone: 703-506-9460 Fax: 703-506-9471
Leukocyte lnterleukin, lnjection [Multikine]
cs001 P3
BB IND 5677
2010-019952-35
I
This material is the property of CEL-SCI Corp Do not disclose or use except as author¡zed in writ¡ng by the study sponsor
Original Protocol
Final. 30 Jun 2010
Amendment #l
Version 2.0, 19 December 2011
Amendment #2
Version 3.0, 15 May 2013
Amendment #3
Version 4.O,27 June 2014
Amendment #3 Protocol: 27 June 2014, Version 4.0


Medical Monitor:
Sponsor Representatives
Authorized to sign the Protocol
And Protocol Amendments:
Lead Medical Monitor
Gene Resnick, MD
Aptiv Solutions
Tel: +1 9147333488
Fax: +1 914 696 0988
Email: gene. resnick@aptivsolutions.com
John Cipriano, RPh, MSc.
and/or Eyal Talor, PhD
CEL-SCl Corporation
8229 Boone Boulevard
Suite 802
Vienna, Virginia 22182 U.S. A.
Phone: 703-506-9460 Fax: 703-506-9471
Central Pathology Laboratory:
Prof. Dr. Jozsef Timar, MD, PhD, DSc
Professor of Pathology and Director
2nd Department of Pathology
Semmelweis University,
Ulloi93, Budapest, 1091 Hungary
CONFIDENTIAL
Th¡s document is conf¡dential and the property of the CEL-SCI Corporat¡on. No part of ¡t may be transmitted, reproduced,
published, or used by other persons w¡thout prior wr¡tten author¡zat¡on from the study sponsor.
ii
This material is the property of CEL-SCI Corp. Do not disclose or use except as authorized in wril¡ng by the study sponsor
Amendment #3 Protocol: 27 June 2014, Version 4.0


Sponsor Signature Page
I have read and understood the contents of thís protocol entítled:
"A Phase lll, Open-label, Randomized, Multi-center Study of the Effects of
Leukocyte lnterleukin, lnjection [Multikine] Plus Standard of Care (Surgery +
Radiotherapy or Surgery + Goncurrent Ghemoradiotherapy) in Subjects with
Advanced Primary Squamous Gell Carcinoma of the Oral Cavity / Soft Palate
Versus Standard of Gare Only" and dated 27 June 2014.
Protocol approved by:
/J
'1rÐ t
n Cipriano,
, MSc.
Date
Senior VP - Regulatory
CEL-SCl Corporation
8229 Boone Boulevard
Suíte 802
Vienna, Virginia 22182
USA
I
7+ - Jo*-- zÐtL(
EYa
lor, P
Date
ch
Officer
CEL-SCI Corporation
8229 Boone Boulevard
Suite 802
Vienna, Virginia 22182
USA
llt
This material is the property of CEL-SCI Corp. Do not disclose or use except as aulhori¿ed in writing by the study sponsor
Amendment #3 Protocol: 27 June 2014, Version 4.0


lnvestigator Signature Page
I have read and understood the contents of this protocol entitled:
"A Phase lll, Open-label, Randomized, Multi-center Study of the Effects of
Leukocyte lnterleukin, lnjection [Multikine] Plus Standard of Gare (Surgery +
Radiotherapy or Surgery + Concurrent Chemoradiotherapy) in Subjects with
Advanced Primary Squamous Cell Carcinoma of the Oral Cavity / Soft Palate
Versus Standard of Care Only" and dated 27 June 2014
I understand that the information contained in this protocol is confidential and is
provided to me, my staff, and the IRB/IEC for purposes of conducting a clinical trial
I have also read and understood the contents of the lnvestigators' Brochure.
I agree to conduct this clinical trial in accordance with the protocol and all applicable
regulatory req uirements.
Signature of lnvestigator
Date
Name and Address of lnvestigator
lnvestigator's Name City, State (or country)
This material is the property of CEL-SCI Corp. Do not discloseïr use except as authorized in writing by the study sponsor
Amendment #3 Protocol: 27 June 2014, Version 4.0


TABLE OF CONTENTS
TABLE OF CONTENTS
I. LIST OF ABBREVIATIONS.......
II. LIST OF TABLES
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III. LIST OF FIGURES
IV. STUDY SUMMARY..
1. 
INTRODUCTION
1 1 BACKGRoUND .........
1.2 I uvesrcRrrou¡- Aceur
1.2.1 Description
1 2.2 Manufacture
1 3 Pnecul.¡lcAl DATA.......
1.3.1 lmmunopharmacologyStudies
1.3.2 Efficacy Studies
1.3.3 Toxicity Studies
1 .4 MULTTKTNE Cur.¡rcRl DRrn ................
1.5 DosE RnïouLe ¡ruD RrsdBENEFrrs 
.
2. 
STUDY OBJECTIVES
2. 1 PRTMARY Oe¡ecrve ......
2. 2 SEcor.¡oanY OBJ EcrvES
2.3TERTTARY Oe¿ecrves ...
3. 
STUDY DESIGN
3.'1 Geruennl DEsrcN......
3.1.1 Pr¡marystuovrnJJo¡;|.............:.
3.1.2 Secondary Study Endpoints.........
3. 1. 3 Tertiary Study Endpoints ...................
3 1 4 
Quality of Life (QOL).
3.1.4.1 Background and Rationale
3.1.4.2 Quality of Life Objectives...
3.1.4.3 Quality of Life Assessment
3.1.4.4 Assessmentlnstruments..
4. 
SUBJECT SELECTION AND WITHDRAWAL
4 1 lNcLUsroN CRrreRn.....
4.2ExcLUsroN CRTTERTA ....... ... .. . .. ....::........ .
4.3 PRoHIBITED TREATMENTS AND MEDICATIoNS,..............,.....
4.4 SuBJEcr RECRUTTMENT Rruo ScReerurruc...........................,
4.4.1 Recruitment . ...........
4.4.2 Screening ................
4.5WlrHDRAWAI Rlto DrsconlNUAroN oF SuBJEcrs
4. 5. 1 Subject Discontinuation...................
4 5 2 Study Discontinuation by the Sponsor
4.5.3 Data Collection and Follow-up for Withdrawn Subjects
5. 
STUDYDRUG
5.1 DescnrproN.....
5.2 Tnenrrr¡Er.rr Recrn¡Eru . . . . . ..
5.3 METHoD FoR AssrcNrNc Sue.Jecrs ro TneRrrr¡e¡¡r Gnoups....
This mater¡al is the property of CEL-Scl Corp Do not disclose Xr use except as author¡zed in writ¡ng by the study sponsor
Amendment #3 Protocol: 27 June 2014, Version 4 0
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5 4 PREPARATIoN AND ADMINISTRATIoN oF STUDY DRUG............
5. 5 MoNrroRrNG SuBJEcr CollplrRruce.
5.6 Pnlon Rruo Cor'¡corr¿trRnr THERApy.......
5.7 Pncxncr¡rc .. ........
5.8 Br-rr.rorr'rc or Sruov Dnuc ............
5.9 RECEIVING, SroRnce, DISPENSING n¡¡o RETuRN/DESTRUCTIoN oF DRUGS.
5.9.1 Receipt of Drug Supplies
5.9.2 Storage
5.9.3 Dispensing Study Drug. . .
5.9.4 Return or Destruction of Study Drug . ....
6. 
STUDYPROCEDURES
6.lAssESSMENrANDTesrs(Gnoues1,2nruo3).. 
...........35
6.2 ADMrNrsrRAroN oF PRorocol ReeurReo MEDrcAroNs Ano Sruoy DRUG (GRoups 1 , 2, 3) ...... ....... 36
6 2.1 The following medications and study drug are to be administered as per protocol to subjects
randomized to the Multikine + CIZ + SOC group (Group 1):.................
6.2.2 Study Drug Administration (Group 2). .. .
6.2.3 The following medications are given to subjects randomized to SOC only group (Group 3)
6 3 Posr-MULTTKTNE TREATMENT EvALUATToNS ..
6.3.1 Tumor measurements (to be performed at baseline and one day prior to surgery)
6.4 STANDARD oF CARE
6 4 1 Dental Care.............
6 4 2 Surgery
6.4.2.1 T1 and T2 Disease
6.4.2.2 T3 and T4 Disease...
6.4.3 Radiotherapy ...........
6.4.3 1Treatment.. .
6.4.3 2 Primary Treatment Fields Tumors by Site
6.4. 3. 3 Radioprotective Agents
6.4.3.4 Technical Factors.........
6.4.3.5 Radiation Treatment lnterruptions for Toxicity....
6.4 3 6 Appropriateness of Radiation Therapy.....
6 4.4 Chemotherapy: Cisplatin (U S.P. or equivalent) lV Bolus lnfusion
6.4.4. I Administration (Cisplatin)
6 4.4.2 Formulation (Cisplatin)
6.4.4.3 Storage (Cisplatin).....
6.4.4.4 Preparation (Cisplatin) .
6 4 4.5 Pharmacology and Pharmokinetics (Cisplatin)
6.4.4.6 Toxicity (Cisplatin)
6.4.4.7 Supplier.....
6.4 4.8 Chemotherapy Dose Modifications (Cisplatin).....
6.4.4.9 Antiemetic Regimen for Cisplatin Administration..................
6.4.4.10 Renal Toxicity
6.4.5 Safety follow-up
6.5 LoNG-TERwT Follow-up
6.6 SnrerynnD EFFrcAcy INTERVALS oF INTEREST
6.7 GENoMrc MTcRoARRAy - A Srnruo ALo¡lE cor-LesoRArvE sruov (wrrn rne US NIH/NCl) THAT DERTvES
ITS SAMPLES FRoM THE SUBJECTS oF THIS PHASE III STUDY ..........,
6.7.1 Rationale for DNA Collection......
6 7 2 DNA Sample Disposition Procedures for Genomic Microarray Testing....
6 8 Bu¡¡olr.¡c or CerurRnl L¡e SpEcl[¡Et'¡s AND IMAGING DATA ....
6.9 UN¡eLrNorNc or CerrRR¡- L¡e Specrtrer.rsAND IMAGTNG DATA.............
7. 
STATISTICALCONSIDERATIONS
7,1 STUDY DESIGN
7.2 Pnlunnv HyporHESts AND ANALysEs.
vl
This material is the property of CEL-SCI Corp Do not disclose or use except as authorized in writing by the study sponsor
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Amendment #3 Protocol: 27 June 2014, Version 4.0


7.3 Secoruonnv HvpornEses AND ANALysEs.
7.4 TERTIARY HYPoTHESES R¡Io AunIvSES.
7.5 RANDoMrzAroN..............
7.6 SAMPLE Srze RnïoruRlE..........................
7.7 AssuMpïoNs AND Cnr-cuuïo¡¡s
7 8 Sruov PopuLRrorrrs
7. 9 MrssrNG Dnrn Co¡¡ve¡rïoNs ...................
7 9 1 Statistical Analysis Strategy
7.10 SrersrcAL SrGNrFrcANcE.. ..
7.1 1 lNrERrM ANALYSTS
7.12 ANALYSIS APPRoAGH
7. 12. 1 Subject Disposition....
7.12.2 Descriptive Statistics..... ...
7. 12.3 Subject Demographics .....................
7 .12.4 Tumor Response.. .. .
7.12.5 Progression ...
712.6fime to Event Outcomes....
7.12.7 Qualily of Life.
7.12.8 Safely
8. 
SAFETY AND ADVERSE EVENTS
8. 1 DErlrullo¡rs. . . ... 
.- .. ........... ...67
8.1.1 Adverse Eueni : . : .::::: . :.... .. . 
. .. 07
8.1.2 Serious Adverse Event . 
........ 67
8.1.3 Unexpected Adverse Event.... 
..... 68
S.I.4EXPECTEDADVERSEEVENTSRELATEDToTREATMENTSINTHISPROTOCOL 
.. ,..,............69
8.1.4.1 Medication Related Toxicities 
...... ..........69
8.1.4.2lnvestigational Agent - Multikine (Leukocyte lnterleukin, lnjection) Possible Toxicities...69
8.1.4.3 Surgery Related Toxicities...... 
....................70
8.1.4.4 Radiation Associated Toxicities 
. .. .....-.-.....71
8.1.4.5 Cisplatin Related Toxicities...... 
.................71
8.1.5 Severity of Adverse Events 
...........72
8 '1 6 Causal Relationship to Study Drug..... 
...... . ...72
8.2 AovEnse EvENr RgpoRrrruc PeRroo. 
. . .73
8.3 PRE-EX|SïNG CoNDrroNS................... 
.................... 73
8.4 PHysrcAL EXAMTNATToN F|NDINGS....... 
. ........................ 73
8 5 Posr-sruov AoveRse Eve¡rr ..... 
.... ...... 73
8.5.1 Pregnancies. ... 
- ........ ....74
S.6Aer.JonMnLL¡eoRAroRvVALUEs 
......74
8.7 HosprrnuzATroN, PRolorrrcEo HosprnuznÏoN................ 
. ... . ...74
8.8 RECoRDTNG oF ADVERSE EvENTs......... 
..............75
8.9 Reponr¡¡e or SeRrous AoveRsE Ever'¡rs....... 
. ...... .75
8.9.1 Study Sponsor Notification by lnvestigator....... . . 
...........75
8 9.2 EC/IRB Notification by lnvestigator . .... . 
. .. -.. ..76
8.9.3 FDA, Health Canada and other Regulatory Agencies Notification by Sponsor...........................76
8.9.4 Pregnancies. . .. . 
....... .. . .. 77
8.10 UN¡erNorNG PRoCEDURES ...... . 
.. . . 77
8.'l 1 SToPPTNG RULES 
.. ...77
8.'t2 Meolcnl MoNrroRrNG By |NVESTIGAToRS............... 
.......... 78
8. 13 INDEPENDENT DArA MoNrroRrNG Coururrree (|DMC) 
...............78
8.13.1 lnterim Safety Analys¡s............ 
. -............. ...79
9. 
DATA HANDLING AND RECORD KEEPING 
............80
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9. 1 Corunoerl¡TtAltry...........
9.2 souRcE Do.rrr*rå"'.. .. .. : ... . .... . . .. . .
9.3 Cnse REpoRr FoRMs.
vll
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Amendment #3 Protocol. 27 June 2014, Version 4.0
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9 3.1 Electronic Case Report Form (eCRFs)
9.3.2 Paper CRFs (CRFs)
9 4 Reconos RETENTToN
9.5 lruspecr¡oN oF REcoRDs
10. 
STUDY MONITORING, AUDITING, AND INSPECTING
10 1 STUDy MorurroRrxc PL¡ru . .. .. . . ..
1 0.2 Auorruo AND 1NspEcrNG...................
12 1 FuruolNo Sounce..
'12.2 FrrunrucnL DrsclosuRE/Corurlrcr op lrureRESr.
12.3 Sue.Jgcr Srpexos oR Pnvuerurs
14.1 Cycr-opHospHAMrDE (USP oR EourvALENr)..
1 4. 2 I NDoMETHACTN (USP oR EeurvALENr)..................
14 3 NurnrroNnl Supplerr¡eNTATroN - MulrvrrnurNs wrrH zrNc. . . .... ...
'14 4 CrspurN lV BoLUs lrupusrol¡ (USP on EourvALENr) (Secrroru 6 4-4).
APPENDIX 1. TABLE OF SCHEDULED EVENTS
APPENDIX 7. MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS
APPENDIX 8. NCI COMMON TOXICITY CR¡TERIA VER. 4.0, MAY 28, 2OO9
APPENDIX 9.
QUALITY OF LIFE INSTRUMENT. EORTC QLQ-C3O AND EORTC QLQ-H&N 35.........................
APPENDIX 10. RECIST RESPONSE CRITERIA VERS¡ON I.0...............
APPENDIX 11. ¡NVESTIGATIONAL DRUG THAW PROCEDURE
15. 
REFERENCES
Th¡s material is the property of CEL-SCI Corp. Do not ¿¡sclosevåÏuse except as authorized in wr¡ting by the study sponsor
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1 1. 1 Wnrrreru INFoRMED Conserur..........
1 '1 .2 Geuoulc MTcRoARRAy Sruov ..... ....
1 1.3 ErHrcs REV|EW.........
11.4 Ernrcru Coruoucr or rnE Sruov.....
12. 
STUDY F|NANCES... 
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PUBLICATIONPLAN........
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14. 
REQUIREDCONCOMITANTMEDICATIONS
APPENDIX 2A. TECHNIQUE FOR PERI-TUMORAL, SUBEP¡DERMAL INJECTION OF MULTIKINE.93
APPENDIX 28. TECHNIQUE FOR PERI-TUMORAL, SUBEPIDERMAL INJECTION OF MULTIKINE.94
APPENDIX 3. JUGULAR REGION PERILYMPHATIC ADMINISTRATION OF MULTIKINE
95
APPEND¡X 4. CLINICAL LABORATORY TESTS OBTAINED IN THE PROTOCOL REGIMEN...........96
GENoMtc MtcRoARRAySTUDY ..... ...
APPENDIX 5. KARNOFSKY PERFORMANCE STATUS
APPENDTX 6. AMERTCAN JOTNT COMMTTTEE ON CANCER (AJCC) STAGTNG, 7TH EDITION 2010
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Amendment #3 Protocol: 27 June 2014, Version 4.0


l. List of Abbreviations
AE
ALT
ANC
AST
BSA
BUN
cBc
CHF
caz
CNS
CRA
CRF
CR
CTCAE
CRT
CSF
CT
CTLL.2
CrCl
DCFs
DM
DMC
DNA
EC
EKG
ELISA
EMEA
EORTC 30
ESR
FDA
FNA
FNAB
GCP
GEE
GLP
GMP
GM.CSF
H&E
H&N
HBV
Hct
EORTC H&N 35
adverse event
alanine aminotransferase
absolute neutrophil count
aspa rtate am inotra nsferase
body surface area
blood urea nitrogen
complete blood count
Congestive heart failure
Cyclophosphamide, lndomethacin, Zinc
central nervous system
Clinical Research Associate
Case Report Form
complete response
Common Toxicity Criteria for Adverse Events
Chemoradiotherapy
Colony stimulating factor
Computed Tomography
Cytotoxic Tlymphoid cell line
creatinine clearance
data clarification forms
data management
Data Monitoríng Committee
deoxyribonucleic acid
Ethics Committee
electrocardiogram
Enzyme Linked lmmunosorbant Assay
European Medicines Agency
European Organization for Research and Treatment of
Cancer QLQ (Questionnaire)
European Organization for Research and Treatment of
Cancer Head and Neck QLQ (Questionnaire)
Erythrocyte sedimentation rate
Food and Drug Administration
fine needle aspiration
fine needle aspiration biopsy
Good Clinical Practice
generalized estimating equations
Good Laboratory Practice
Good Manufacturing Practice
Granulocyte Macrophage Colony Stimulating Factor
Hematoxylin and Eosin
Head and Neck
hepatitis virus type B
hematocrit
tx
This material ¡s the property of CEL-SCI Corp Do not d¡sclose or use except as authorized in writing by the study sponsor
Amendment #3 Protocol: 27 June 2014, Version 4.0


HCV
Hb
HIPAA
List of Abbreviations (continued)
hepatitis virus type C
hemoglobin
Health lnsurance Portability and Accountability Act of
1 996
human immunodeficiency virus
human leukocyte antigen
head and neck cancer
human papilloma virus
human T-cell Lymphotropic Virus
informed consent
lnternational Conference on Harmonization Guidelines
lmmunohistochemistry
lnterferon gamma
lnterleukin type I,2,6,8
lntense modulated radiation therapy
lnvestigational New Drug Application
lnstitutional Review Board
i ndependent radiotherapy quality assurance
immunotherapy
lntent to Treat
lnternational unit
intravenous
lnteractive Voice Response System
Karnofsky performance status
longest diameter
Loco-regional control
missing completely at random
milligram
micromolar
Major H istocom patibility Complex
Macrophage inhibitory factor 1 alpha, 1 beta
magnetic resonance imaging
maximum tolerated dose
Nucleic Acid Testing
National Cancer lnstitute
Natural Killer cell
overall survival
Oral Squamous Cell Carcinoma
posterior-anterior
Peripheral Blood Mononuclear Cells
Polymerase chai n reaction
Positron Emission Tomography
progressive disease
progression-free survival
HIV
HLA
HNC
HPV
HTLV
tc
tcH
tHc
IFN-y
lL-l ,2,6,8
IMRT
IND
IRB
IRTQA
IT
ITT
IU
IV
IVRS
KPS
LD
LRC
MCAR
mg
pM
MHC
MIP-1c, p
MRI
MTD
NAT
NCI
NK
os
oscc
PA
PBMC
PCR
PET
PD
PFS
This mater¡al is the property of CEL-Scl Corp. Do not disclose är use except as author¡zed in wr¡ting by the study sponsor
Amendment#3 Protocol: 27 June 2014, Version 4.0


PHA
PHI
PID
PO
PORT
PR
PT
QLQ
QOL
RANTES
RBC
RECIST
RT
RTOG
SAE
SAP
SCCHN
scR
SD
SGOT
SGPT
soc
SOPs
STDs
Th1,2
T¡d
TNF-c, p
TNM
TSH
TTP
US
USP
wBc
List of Abbreviations (continued)
Phytohemaglutinin
Protected Health I nformation
personal identification data
per os (by mouth)
postoperative Radiation Therapy
partial response
prothrombin time
Quality of Life Questionnaire
Quality of life
An 8kD Protein belonging to the PF4 (Platelet
Activating Factor 4) Super Family of chemoattractants,
attracting CD4+, CD45RO+ T-cells and Monocytes at
the inflammatory site
red blood cell
Response Evaluation Criteria in Solid Tumors
Radiotherapy
Radiation Therapy Oncology Group
serious adverse event
Statistical Analysis Plan
squamous cell carcinoma of the head and neck
serum creatinine
stable disease
serum glutamic oxaloacetic transaminase (AST)
serum glutamic pyruvic transaminase (ALT)
standard of care
standard operating procedures
sexually transm itted diseases
T-cell mediated immune response - Type 1, type 2
Three times daily
Tumor necrosis factor alpha, beta
tumor, lymph nodes, metastasis
Thyroid stimulating hormone
Time To Progression
United States
United States Pharmacopeia
white blood cell
x1
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ll. List of Tables
Table 1
Table 2
Table 3
Table 4
Methodology: Randomization and Treatment of Enrolled Subjects
Protocol Treatment Regimen....
TNM Categories and Corresponding Tumor Stage
Summary of Surgery, Radiotherapy and Chemotherapy (SOC)....
,XV
19
31
42
lll. List of Figures
Figure 1. Diagrammatic representation of Multikine's mode of action.......................... 6
Figure 2. 
Effect of Multikine treatment on tumor growth in one subject with terminal
Stage lV squamous cell carcinoma. ......... 
............... 10
Figure 3. Cell cycle marker (Ki67) in Multikine treated Oral Squamous Cell Carcinoma
(oscc) 
....... 15
Figure 4. Histological appearance of necrosis in oral squamous cell carcinoma (H&E
staining) 
........ 15
Figure 5. Schematic representation of subject randomization and treatment... . . .... 18
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lV. Study Summary
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Title
A Phase lll, Open-label, Randomized, Multi-center Study of the Effects
of Leukocyte lnterleukin, lnjection [Multikine]Plus Standard of Care
(Surgery + Radiotherapy or Surgery + Concurrent Chemoradiotherapy)
in Subjects with Advanced Primary Squamous Cell Carcinoma of the
Oral Cavitv / Soft Palate Versus Standard of Care Onlv
Short Title
A Phase lll Study of the Effects of Multikine on Cancer of the Oral
Cavitv.
Protocol Number
cs001 P3
Phase
Methodology
Open label, randomized, three group study. See Table 1
Study Duration
45-60 months (15-18 (or 24) months accrual and 30-36 months follow-
uo).
Study Cente(s)
Multi-center. Approximately 90 sites, globally
Objectives
The primary objective is to determine the efficacy of peri-tumoral and
peri-lymphatic injection of Multikine (400 lU, as lL-2) given prior to
Standard of Care (SOC) as measured by overall survival. The
secondary objectives are to evaluate the effects of Multikine treatment
on the cumulative incidence of loco-regional control, progression-free
survival, tumor response, tumor histopathology, and quality of life, while
confirminq Multikine safetv.
Number of Subjects
784 (completed subjects)
Diagnosis and Main
lnclusion Criteria
Untreated tumors of the oral cavity to include ONLY the oral tongue
(not the base of tongue), floor of mouth, cheek and soft palate that are
scheduled for SOC (surgery and radiotherapy or surgery and
concurrent chemo- radiotherapy). Other key inclusions: primary tumor,
and if present, clinically positive lymph node(s) measurable in two
dimensions, normal immune function, no immunosuppressive drugs
within the past year, Karnofsky Performance Status (KPS) > 70, age >
18 vrs.
Study Product,
Dose, Route,
Multikine Regimen
Study drug name: Leukocyte lnterleukin, lnjection (Multikine) totaldaily
dose: 400 lU (as lL-2); Route: one half delivered peri-tumorally, one
half delivered peri-lymphatically (daily) by percutaneous injection,
Sx/week for 3 weeks.
Two treatment groups will get Multikine injections. Gro=up I will receive
Multikine preceded on Day minus 3 only by 300 mg/m'
cyclophosphamide (1.V. bolus), 25 mg indomethacin po tid daily from
Day I to one day prior to surgery, plus daily Zinc supplementation as
found in a standard multivitamin formulation (hereinafter referred to as
Multikine + "ClZ Treatment) followed by SOC (surgery of tumor and
involved lymph nodes + radiotherapy or surgery + concurrent
chemoradiotherapy). Group 2 will get Multikine without *ClZ (referred to
as Multikine w/o *ClZ) followed bv SOC. Group 3 will receive SOC only.


3 weeks
Duration of
administration
Reference therapy
Standard of Care (control): surgical excision of tumor and involved
lvmph nodes followed bv radiotheraov +/- concurrent chemotheraov
Statistical
Methodology
Statistical analysis of the Kaplan-Meier life tables, log rank tests, and
proportional hazard models comparing Multikine treatment regimen
(plus CIZ) plus SOC vs. SOC alone for overall survival (primary), loco-
regional control and progression-free survival over a 24 month
enrollment phase and a subsequent 30-36 month follow-up phase for
all randomized subjects. Additional evaluations of treatment on tumor
response using a longitudinal growth model and quality of life using
generalized estimating equations (GEE). Further assessment of the
prognosis of risk status, post-surgical therapy (radiation only,
chemoradiotherapy), tumor location (tongue, floor of mouth, cheek, and
soft palate), tumor stage (T1 N1-2, T2N1-2, T3 N0-2, T4 N0-2), and
geography upon treatment, including treatment interactions, using
proportional hazards models.
' CIZ = Cyclophosphamide 300
po daily
lV Bolus + lndomethacin 25 mg po tid + Zinc (as Multivitamin)
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CONFIDENTIAL
Table l. 
Methodology: Randomization and Treatment of Enrolled Subjects
. CIZ: Cyclophosphamide 300 mg/m2 (x1 ,lV bolus, Day -3); lndomethacin 25mg tid, po (Day I to approximately 24 hrs prior to surgery) + Zinc
(as Multivitamin) po id (daily, from Day 1 to approximately 24 hours prior to surgery )
** Surgery: complete surgical resection of primary tumor and any positive lymph nodes.
*** Radiotherapy is to be given per protocol at a total of > 60 Gy to <70 Gy (in 30-35 fractions over a 6-7 week period)
...* H¡gh risk subjects are defined as those with: positive surgical margins, 2 or more clinically positive nodes, or extracapsular nodal spread
(any or all of the above)
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aJ
I
3
Group l:
Multikine 5)Uweek X 3 weeks
+ clz*
Group 2:
Multikine@ 5)Uweek X 3 weeks
wlo ÇlZ*
s**
U
R
G
E
R
Y
Group 3:
Standard of Care Group
R
A
N
D
o
M
I
z
E
E
N
R
o
L
L
M
E
N
T
RTx
Radiotherapy ô0-70Gy,
30 fraclions over ô-7 Weeks'*
-oR-
GRTx
*'LllqtLSÞK: Concurent
radiochemolherapy 60-70 Gy, 30-35
fractions, over 6-7 weeks + lV
cisplalin (100 mg/m2) 1)Vweek X 3
reeks (resk 1 , 4 and 7) on days 'l,
22, and 43 of radiolherapy @urse
g¡ven wilhin +t 3 days for each
scheduled day of adminislralion of
chemo during the rad¡otherapy
period


1. lntroduction
This document is a protocol for a human research study. This study is to be conducted
according to US and international standards of Good Clinical Practice (FDA Title 21 Part
312 and lnternational Conference on Harmonization guidelines), which have their
origins' and are based on the Helsinki accords, and applicable government regulations
and lnstitutional research policies and procedures.
l.l Background
Head and neck (H&N) carcinomas constitute 5%o of all new cancers diagnosed annually
worldwide and approximately 37,000 new cases annually in the United Statesl. These
lesions tend to metastasize first to regional lymph nodes, and loco-regionalcontrol
traditionally has been the greatest obstacle to the cure of these tumors. Approximately
ninety percent of all oral cancers are primary squamous cell carcinomas (SCCHN)
arising from the lining 
nly the tongue and floor of the
mouth2 3'4. Carc¡nom 
the mouth represent about 65% of
all oropharyngeal can 
of all H&N cancer patients) of
patients with SCCHN present with locally advanced disease6'7, at their first visit
(diagnosis), and have poor to very poor prognosrs.
Although the use of current therapy (surgery, radiotherapy and chemotherapy) results in
a very high (>70 - 9O%) cure rate for early primary disease, review of the scientific
literature for clinical trials conducted with patients having locally advanced squamous
cell carcinoma of the head and neck, which have been treated with any or all available
treatment modalities (surgery, radiation therapy, chemotherapy, immunotherapy and
any combinations thereof) published in peer-reviewed journals between 1987 and 2006
indicates that, the median 3 year overall survival (OS) for locally advanced patients is
52o/o and the 5 year OS is 39%. A review of only the more recently (2004 - 2006)
published clinical trials (from the same data above) indicates that, the median 3 year OS
is 55% and the 5 year OS is 43%. Thus, there is a large number of locally advanced
squamous cell carcinoma of the head and neck cancer patients that are not well served
by the currently available treatment modalities.
Until recently 
ve
tumor followe 
)t.
by the Radiat 
by
for Research 
xp
and sequential chemotherapy and radiotherapy regimens to improve outcomes in the
head and neck cancer patient population. As a result of these and other studies,
multimodality therapy is now a well-established strategy for the improved control of
these tumors.
I
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CONFIDENTIAL
Protocol No: CS001P3
The strategy of using concurrent chemoradiotherapy (with cisplatin as the
chemotherapeutic agent) following surgery in "High-Risk" patients was tested in two
clinical trials for which interim analyses were recently reported by the RTOG (RTOG
9501/lntergroup) and the EORTC (EORTC trial22931) in the New England Journal of
Medicines n. The RTOG study reported a 10o/o increase in the 2-year rate of local and
regional control (p= 0.0t). An 11% increase in the S-year rate of disease-free survival
was reported by the EORTC (p=0.02). Further the EORTC also demonstrated an
increase in survival (53% in the combined-therapy group vs. 40% on the post-operative
radiotherapy group alone (p=9.04). Neither trial reported a decrease in distant
metastases. ln addition, the incidence of severe early adverse events was significantly
increased by the addition of concurrent chemoradiotherapy. Grade 3 toxicity or greater
occurred in 77o/o of patients who received concurrent chemoradiotherapy as compared
to 34% of patients who received radiotherapy alone (p=<0.001) in the RTOG study, and
in 41% vs.21% (p=0.01) in the EORTC study.
Despite the encouraging findings using the concurrent chemoradiotherapy approach
following surgical resection, further improvements in treating patients with loco-
regionally advanced squamous cell carcinomas of the head and neck are needed.
Support for this conclusion comes from the study outcomes reported by the RTOG and
EORTC '' n. The estimated five-year cumulative incidence of local or regional relapses
was 31% in the radiotherapy group and 18% in the combined-therapy group in the
EORTC study. Similarly, local or regional recurrence as the first sign of treatment failure
occurred in 61 of 210 patients who received radiotherapV Q9%) and in 33 of 206
patients given combined therapy (16%).
lntra-tumoral and peri-tumoral immunotherapy with cytokines has been studied
extensively in animal models. Anti-tumor responses have been associated with the
development of an inflammatory response localized to the tumor mass. This therapeutic
approach has also been shown to overcome tumor-induced suppression of host
immune response. ln animal models, the local or peri-lesional administrations of
interferons, TNF and lL-2 have all shown objective regression of experimental tumors. lt
has been demonstrated that host reactivity is required for this response to occur, and
that the effectiveness of local therapy can be abrogated by treatment with cyclosporine,
a host immunosuppressant. lmmunotherapy with cytokines has also been studied in
and used successfully to treat human cancers.
Many human tumors have tumor-specific or tumor-associated antigens, which may be
recognized by the host's defense mechanisms. Anti-tumor host defenses play an
important role in the course of malignant disease. Both cell-mediated and humoral anti-
tumor immunity are involved in this process. ln addition, a variety of approaches to
cancer treatment based on host defense mechanisms have also been developed.
These are currently referred to as immunotherapy or biologicaltherapy. Effective
biological therapies approved for cancer treatment include interferon-o for malignant
2
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CONFIDENTIAL
Protocol No: CS001P3
melanoma, Hairy Cell Leukemia, AIDS-related Kaposi Sarcoma, and lL-2 for metastatic
renal cell carcinoma and malignant melanoma.
lmmunotherapy is being explored as therapy for chronic myelogenous leukemia,
malignant lymphoma and carcinoid tumors, as well as for a variety of other
malignancies. These treatment modalities have direct anti-tumor activity and anti-cancer
effects via the modulation of host defense mechanisms. lnterferon-a and lL-2 fall into
the broad category of cytokines. Cytokines with known anti-tumor activity in either
animal or human systems include interferon-cr, -B and -y, TNF-u, TNF-P, lL-1, lL-2 and
'L-4.
Regional intra-lymphatic or intra-tumoral low-dose cytokine therapy may have important
therapeutic effects. One group reported that squamous cell head & neck cancer
responds to peri-lymphatic low-dose natural lL-214. Others have established the
rationale for local cytokine therapy and the safety of the preparationls. ln humans, there
is good evidence for the activity of local / regional cytokine therapy of cancer in a
number of sites, including skin, genitalia, peritoneum, pleural cavity, brain, head & neck,
liver, and bladderl6' 17' 1a' 1s'20'21'22' " These data provide a part of the rationale for the
use of Leukocyte lnterleukin, lnjection (Multikine) in multiple solid tumors, and
encourage further studies not only of recombinant lL-2, but also of mixed natural
cytokine preparations, such as Multikine (an extensively characterized mixture of
naturally occurring human cytokines).
ln head & neck cancer subjects, injection of lL-2 at 200 units (qd/10 days) into the
regional lymph node drainage (in the head & neck area) induced remission in squamous
cell carcinomal0. When tumors from these treated subjects were examined
histologically, cellular infiltrates were observed. Twelve subjects treated with I x 10s
units of lL-2 in the peri-tumoral area before surgery exhibited marked cytotoxicity to the
tumor cells11. ln another trial, 8 x 105 units of rlL-2 were administered directly into the
tumor area in 20 head & neck cancer subje ,ts daily for 4 weeksl2 Three responses
were seen, including two complete remissions. ln another study with rlL-2, four
responses were observed in 46 head & neck cancer subjectsr3.
The presence of both Thr and Th2 type cytokines induced by a vaccination regimen is
analogous to the injection of Multikine peri-tumorally and in the regional draining lymph
nodes. Multikine, which contains biologically active, naturally occurring mixture of both
Thr and Th2 type cytokines, has induced both tumor reductions gnd lymphocytic
infiltrations into the tumors of subjects with head & neck cancer'". lt also appears to be
effective in improving pre-cancerous cervical lesions, as determined by both visual
(colposcopy) and histopathological methods2s. These findings further support the use of
Multikine as an immunotherapeutic agent for cancer.
Multikine neoadjuvanVadjuvant immunotherapy modulates both the tumor and host
antitumor immune response when administered peri-tumorally26 or both peri-tumorally
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CONFIDENTIAL
Protocol No: CS001P3
and peri-lymphatically to advanced primary oral squamous cell carcinoma (OSCC)
patients, prior to conventional therapy2T. Multikine promotes a number of putative
beneficial immunologic effects:
f . induction of tumor cell entry into the pool of dividing cells increasing their
sensitivity to follow-on treatment with radiotherapy,26 chemotherapy or combined
chemoradiotherapy,
2. the inversion of the CD4+/CD8+ T-cell ratio in the mononuclear cells infiltrating
the tumor 27, and
3. a decrease in both the tumor and tumor-stroma macrophages 27' 28'. The
reduction of Macrophages in the tumor site has recently been correlated with a
marked decrease in lung-metastases of mammary tumors (and a general
decrease in the tendency of mammary tumors to metastasize)2s.
ln addition, in a recent Phase ll trial of Multikine in advanced primary OSCC patients
MHC ll (HLA Class ll) expression of the OSCC tumor cells was completely absent in
tumors from patients responding to Multikine treatment (having >30o/o tumor reduction
from baseline) (n=6), while the Multikine treated but non-responding group (n=11) and
the disease matched pathology study historical controls (n=20) had similar HLA Class ll
expression on their OSCC tumor cells (pcO.05)28. MHC Class ll expression on tumor
cells has been correlated with poor prognosis in melanoma patients3o'31.
These potentially beneficial immunologic effects have been achieved with no added
toxicity in all clinical trials of Multikine, and support the rationale for the use of Multikine
as adjuvanVneoadjuvant immunotherapy in primary OSCC of the head and neck.
Multikine (developed by CEL-SCI Corporation) contains a defined mixture of naturally
derived and naturally-occurring human cytokines and chemokines with demonstrated
immunomodulatory activity in-vitro and in vivo in animals and man. lt has been
administered as a neo-adjuvant peri-tumorally and peri-lymphatically in various dosage
schedules in Phase I and Phase ll clinical trials conducted in patients with advanced
loco-regional squamous cell head and neck cancer (See Sec 1.4). Multikine
administration was welltolerated and was found to be safe in allthe studies at allthe
doses administered by whatever route. ln addition, data from these studies suggest
Multikine pre-treatment may impact the rate of tumor recurrence and/or delay the time to
recurrence in patients with primary advanced disease.
Based on the clinical and pathology data collected and the fact that Multikine imparts
anti-tumor immune activation, which constitutes an additional anti-tumor mechanism of
action different and distinct from radiotherapy, chemotherapy, or chemoradiotherapy
with little to no toxicity, Multikine has the potentialto increase the effectiveness
associated with follow-up radiotherapy or concurrent chemoradiotherapy in patients with
primary advanced head and neck cancer.
4
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CONFIDENTIAL
Protocol No: CS001P3
ln this Phase lll trial of Leukocyte lnterleukin, lnjection (Multikine) in locally advanced
oral squamous cell carcinoma, overall survival (OS) at 3 years is the primary end point
and local regional control (LRC) at 2 years and progression-free survival (PFS) at 3
years are the secondary end points. The trial will test the hypotheses that Multikine
adjuvant (or neoadjuvant) immunotherapy administered prior to surgical resection of
tumor and involved lymph nodes followed by radiotherapy or chemoradiotherapy in
patients with advanced squamous cell carcinoma of the oral cavity will:
. extend the time of overall and progression free survival
. enhance local/regional control
. improve quality of life
Collection of survival data for 3 years is expected to allow sufficient comparison of the
treatment groups. The studies conducted by the RTOG and EORTC t't demonstrated
overall survival curves whose slopes decrease in the initial 2-3 year interval and are
nearly flat (after the 3 year mark) to 5 to 6 years and to 10 years.
1.2 lnvestigationalAgent
1.2.1 Description
Multikine is a biological product that contains a defined mixture of naturally derived and
naturally occurring human cytokines with immunomodulatory activity. lt may be used as
an adjuvant or neo-adjuvant immunotherapy in treating cancer, with broad-spectrum
application for this disease and also for other diseases that might benefit from
immunomodulation.
It has been shown that the local instillation of interleukins in the region of the tumor, or
the actual transfection of interleukin genes into a tumor, markedly augments anti-tumor
immune response and results in tumor regression32.
Results of animal studies demonstrated that different interleukins have
immunomodulatory and immunostimulatory activity in-vitro and in vivo33 and the
observed immunoincompetence status of patients with cancer provided the rationale for
the development of Multikine. The hypothesis for the product's development is that the
local/regional injection of "mixed interleukins" (Multikine) would overcome local immune-
suppression (induced by the tumor), break tolerance to tumor antigens, and allow for an
effective local anti-tumor immune response to occur.
Multikine's proposed mechanism of immune augmentation is depicted in Fig. 1 below:
5
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CONFIDENTIAL 
ProtocolNo:Cs001P3
Figure l. 
Diagrammatic representation of Multikine's mode of action
Irnrnune^",r"IråHol;"#*¡"ñlelnterleukin,lni.
Tumoricidal I Turnoristatic kfor,
.1,
ted¡oúytË
Interhlchthj.
fp'ihrr+hdicÌ
NecrosiS
(e,9., T{Føl
Oellç
O.'D'
l{eutrophlls
(D('OID
lfr*¡i.Gl¡é
lñtetler*hi hj.
1¡prrr.lwl)
rþ
+ T Cêlls
-{D (D
G08 * T Cell
I
ar'-
Ghemotactic
{êü.ilL-6, iLt}
Ly,mphoprultfurative
le_u.;ll,Zl
CEL-SCI believes that Multikine mode of action is due to its unique and proprietary
composition of matter. Multikine is a naturally derived cytokine product containing,
among others, three major "families" of bioactive molecules. Each cytokine has a
distinct effect on the host and the tumor, and the sum of all effects synergistically impact
solid tumor destruction (i.e., regression / necrosis) in cancer patients.
Multikine, injected peri-tumorally and in the region of the local/regional draining lymph
nodes contains (1) tumoricidal/tumoristatic cytokines (e.9., TNFcr,, TNFP, lFNy), (2)
chemotactic cytokines and chemokines (e.9., RANTES, lL-8, MIP-1c¿, MIP-1P) and (3)
lymphoproliferative and pro-inflammatory cytokines (e.9., lL-1, lL-2 and lL-6, TNF).
CEL-SCI and the authors of a recently published article depicting the results of a
Multikine phase ll trial (Timar et al, JCO, 23(15): May 2OO5)28 hypothesize that Multikine
mode of action is due to the combined activity of the different cytokines present which
induce a cascade of events as follows:
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CONFIDENTIAL
Protocol No: CS001P3
1. tumor necrosis factors present in Multikine (such as TNF-o) attack the tumor to
release tumor antigens
2. antigen presenting cells (e.9., dendritic cells) transport the newly released tumor
antigens to lymph nodes
3. lymphoproliferative cytokines (present in Multikine administered peri-tumorally
and peri-lymphatically, e.9., lL-1 ,lL-2) induce a marked polyclonalexpansion of
tumor specific T-cells - primarily in lymph nodes
4. Multikine (cytokines/chemokines) recruits CD4+ T-cells from local lymph nodes
via chemotactic factors, and reverts the balance of intra-tumoral CD4+|CD8+
cells in favor of CD4+ T-cells, which further upregulate the antitumor immune
response, resulting in tumor cell necros¡s,
5. Multikine recruits neutrophils from the circulation (via GM-CSF, also present in
Multikine), which propagate the destruction of the tumor cell nests
6. Multikine -derived cytokines or the de novo cytokine production by the tumor
infiltrating cells induce massive local fibrosis26'28
1.2.2 Manufacture
Multikine is prepared under Good Manufacturing Practices (GMP) manufacture from
human peripheral blood mononuclear cells, including T-cells, B cells and macrophages.
The cells are separated by centrifugation from human donor "buffy coats" obtained
under contract from the American Red Cross, and subjected to tests for viruses,
bacteria, and parasites, and all other tests mandated by the U.S. FDA for blood for
transfusion and blood derived products (including HlV, HBV, HCV, HTLV, STDs, West
Nile Virus, ALT and NAT testing). All buffy coats must be negative for alltests in order
to be accepted for Multikine manufacture. ln addition, all units are obtained only from
repeat-donors who were not in any deferral category, either at the time of current or
past donation. Viable PBMCs are cultured with PHA for 24 hours. Subsequently, the
culture supernatant is aseptically harvested. The supernatant is clarified, subjected to a
commercialvirus exclusion process, concentrated (approximately 10 times) by
ultrafiltration, and subjected to microfiltration. Subsequently, Human Serum Albumin, lnj.
USP or equivalent is added, the concentrate is buffered to physiological pH and brought
to a target lL-2 concentration of 200 lU/ml, then subjected to a second microflltration
(0.22 micron-rated filter). lt is then aseptically dispensed into a sterile serum vial and
labeled by its content of lL-2.
Product potency is measured by the incorporation of radiolabeled thymidine by a
cytotoxic T-lymphoid line (CTLL-2). The final injectable agent is further tested (by
ELISA) for the presence of five marker cytokines: lL-2, lL-1B, TNF-o, IFN-y, and
GM-CSF. Leukocyte lnterleukin, lnjection is subject to quality control tests for identity,
sterility, bacterial endotoxins, pH, and total protein concentration. Each vial is inspected
for particulate contamination and appearance. ln addition, data is collected on the
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CONFIDENTIAL
Protocol No: CS001P3
concentrations of residual DNA, PHA and ciprofloxacin contained in each lot of the
injectable drug.
Multikine is provided frozen in a borosilicate glass serum vial containing 2.2 mL of drug
at2O0lU (as lL-2) per mL for peri-tumoral, intra-tumoral, peri-lymphatic or percutaneous
administration. The preparation has a total protein content of 3 mg/mL.
The drug is supplied sterile and pyrogen free. DNA (approximately 20 ng/ml), PHA
(approximately 0.004 pg/mL), and ciprofloxacin (approximately 2 pg/mL) are currently
known to be present in the preparation. The manufacturer has assigned an expiration
date of twenty-four (24) months from date of manufacture when the drug is stored at
-200c.
1.3 Preclinical Data
Extensive studies in animal models have demonstrated antitumor effects of intra-
tumoral and peri-tumoral cytokines. Alone or in combination with interferons,'o intra-
tumoral or peri-tumoral administration of tumor necrosis factor3s and interleukin-210, 36
induced objective regressions of a variety of experimental tumors. ln other experimental
models, interleukin-137,38 and interleukin-432 inhibited tumor growth. These effects were
associated with the development of an inflammatory type reaction in the tumor3e. Host
immune reactivity seems to be required for antitumor responses as the effectiveness of
the local therapy can be abrogated by treatment with cyclosporine.oo ln addition to the
local instillation of interleukins directly in the region of the tumor, other means of local
therapy, including cell therapy wlth tumor cells transfected with interleukin genes also
markedly augmented the antitumor immune response and resulted in tumor
regressional. C¡okine combinations had synergistic effects on cellular immune cell
activity in in-vitro models, as in the effect of lL-7 on lL-1 induced murine thymocyte
proliferation3T and the augmentation of murine CD4+ and CD8+ thymocytes by low
doses of combined administration of lL-1 and lL-2.37
lnterleukins and other cytokines are produced by antigen or mitogen stimulation of
various human leukocytes. 14'25'40 Mitogen-stimulated leukocytes produced a mixture of
interleukins and other cytokines that had immunomodulatory and immunostimulatory
activity in-vitroao,a2. When administered to guinea pigs, low-dose mixed interleukins had
immune stimulating effects on regional lymph nodes.a3 Low-dose mixed lymphokines
prolonged survival in cyclophosphamide pretreated-melanoma bearing miceoo. The use
of cyclophosphamide is based on the demonstration that cyclophosphamide
pretreatment abrogates suppressor cell activityas and augments the response to specific
immunotherapy,46 as well as non-specific immunotherapyaT.
1.3.1 lmmunopharmacology Studies
A series of in-vitro experiments and whole animal studies have been performed with lL-
2. These studies demonstrate that lL-2:
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Protocol No: CS001P3
1. Serves as a second signal for mitogenic action in mature T-cells but also as
a regulator of proliferation and maturation of immature T-lymphocytes
2. lL-1 and lL-2 act synergistically to induce prothymocyte and immature
thymocyte proliferation
Multikine contains both ll-l and lL-2 as well as other cytokines such as gamma
interferon, and it has been demonstrated that it may be more effective than recombinant
lL-2 in inducing proliferation of mature functionally responsive thymocytes o'. Studies
have demonstrated that it produces the same magnitude of proliferative and
differentiation affects as rDNA lL-2 in athymic nude mice at1l1O the doseas.
1.3.2 Efficacy Studies
ln-vitro and in vivo studies in mice and in-vitro studies with Multikine with human
PBMCs demonstrated significant (p<0.01) increases in natural killer cell (NK) and
cytotoxic T-lymphocyte (CTL) responses with low doses of the drug administered by
multiple routes. NK cell activity remained elevated for over 5 days following only one
treatment, and multiple in vivo treatments did not lead to a depression of NK cell
activityas.
1.3.3 Toxicity Studies
Preclinical animal toxicity studies were conducted in accordance with the FDA's Good
Laboratory Practice (GLP) regulations in beagle dogs, mice and guinea pigs. A repeat
dose 14 day sub-acute toxicity study administered Multikine subcutaneously 5 times a
week for 2 weeks at a dose as high as approximately 10 times the human dose, to
beagle dogs, and was not associated with significant local or systemic toxic response.
The studies undertaken in mice and guinea pigs were General Safety Tests conducted
on bulk material as described in 21CFR610.11. Mixed results were obtained in these
studies. While no toxicity was observed in mice, adverse effects noted in guinea pigs
were determined to be the result of the presence of residual human insulin in the bulk
product, which was derived from the culture medium used for in-vitro cell culture. A
group of expert consulting toxicologists concluded that the adverse events noted in
animals were due to the exquisite sensitivity of the species to human insulin and that,
the very low level of insulin that would be present in the final drug product does not
present any serious human safety concerns. ln vivo human insulin titration experiments
conclusively demonstrated that the effects seen were due to the residual human insulin
(and not due to the investigational drug) present in the concentrated Bulk Solution used
in these General Safety Tests.
1.4 Multikine Clinical Data
To date, a number of Phase I and Phase ll clinical studies have been conducted with
Multikine injected into and around tumors. These studies are summarized below.
9
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CONFIDENTIAL
Multikine Phase I (Head & Neck - U.S.l
Protocol No: CS001P3
Hadden and co-workers completed a clinical pilot study with Multikine combined with
low-dose cyclophosphamide (to reduce T suppressor activity), indomethacin (to reduce
macrophage suppression via inhibition of prostaglandin synthesis), and zinc (to
augment T-cell function via stimulation of thymulin production). Multikine was injected
peri-tumorally and peri- or intra-lymphatically in the neck on the contra-lateral side of the
measurable recurrent local metastatic head & neck squamous cell cancer. Four terminal
subjects were treated; three subjects were reported by the authors to have measurable
tumor regression. Biopsy of residual tumor showed increased infiltration of lymphocytes
and tumor cell lyses. The fourth treated subject failed to respond. The results were
achieved without demonstrable toxicity2a.
Gonclusion: Three of four terminal subjects who were refractory to all conventionally
available treatment (stage lV) were reported (by the authors) to have had rapid tumor
regressions following Multikine administration with no Multikine treatment-related side
effects. One subject, with a plum-sized metastasis behind the ear (see below) at the
onset of a 21-day Multikine treatment course, had a marked (near complete) clinical
response.
Figure 2
Day I 
Day21 
Day 42
Effect of Multikine treatment on tumor growth in one subject with
terminal Stage lV squamous cell carcinoma.
l0
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Protocol No: CS001P3
Multikine Phase l/ll (Head & Neck - lsrael)
Multikine was administered peri{umorally to subjects with head & neck cancer in an
attempt to augment local/regional anti-tumor immune responses and achieve local
tumor control.
Twelve subjects with previously untreated, primary (stages ll to lV) squamous cell
carcinoma of the oral cavity (9 subjects), facial skin (2 subjects) and a neck lymph node
metastasis with an unknown primary tumor (1 subject) were given a treatment regimen
that included peri-tumoral injections (10 subjects - 800 lU lL-2 equivalence and 2
subjects - 1600 lU) of Multikine daily, 5 days/week for 2 weeks, and had surgical
resection of the residual tumor within one week following the last injection of Multikine.
Subjects also received pretreatment with cyclophosphamide (300 mg/m2 on Day -3 only,
indomethacin, 25 mg po tid, and zinc supplementation, 50 mg po qd) for 18 days
immediately following pretreatment. At the completion of the treatment regimen (before
surgery), the subjects displayed one or more anti-tumor responses consisting of
reduction in tumor surface dimensions, including one complete clinical response of aT2
retromolar trigone tumor and a neck lymph node metastasis with an unknown primary
response and four with tumor reductions (of >50%), reduction in tumor thickness,
resolution or reduction in size of tumor ulceration, subsidence of local pain and increase
in tongue mobility (in tongue tumors). There were no tumor progressions or other
adverse local changes, nor evidence of systemic toxicity. Recovery after operation and
wound healing were normal. Microscopic examination of surgical specimens showed
cellular immune infiltration into the tumor and tumor necrosisas.
Gonclusion: This well-tolerated, short-term local regimen resulted in 6/10 responders,
four (4) of which had >50% tumor reduction and one (1) had a complete clinical
response, while the other complete responder had a complete reduction in an affected
neck node - with an unknown primary. The treatment may impact the rate of tumor
recurrence and/or delay the time to tumor recurrence (see below) in subjects who are
subsequently treated by surgical resection and/or radiation therapy49. Two subjects
who refused surgery (following Multikine treatment) had no reported recurrence of
disease 1-3 years post-treatment (personal communication, Dr. R. Feinmesser,
Principal lnvestigator).
Multikine Phase ll (Head & Neck - Poland I Czech Republic)
ln a multi-center Phase ll dose escalating study conducted at four centers located in
Poland and the Czech Republic, 30 subjects received six (6) administrations of
Multikine (x3/week) over 2 weeks, plus a one week wait period before surgical resection
of the residualtumor and any effected lymph node. ln contrast to the lsraeli study,
subjects received half of each dose peri-tumorally and half peri-lymphatically in the
vicinity of the jugular lymphatic chain.
ll
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Protocol No: CS001P3
Conclusion: Atthe mid-dose leveltested (1600 lU, as lL-2),70o/o(7110) of the subjects
had tumor reductions after completion of treatment prior to surgery or radiation, 3 of
whom had partial responses (reductions >50%). At the lowest dose (800 lU, as lL-2)
group, 60% (6110) of the subjects had tumor reductions, 2 of which were >50%. No
partial responses were observed in the high dose (3200 lU, as lL-2) group.
Multikine Phase I lHead & Neck - US / Ganadal
CEL-SCl has completed a Phase l-ll multicenter, randomized, dose-response, open
label trial of Multikine plus cyclophosphamide, indomethacin and zinc sulfate (ClZ) in
biopsy confirmed advanced head and neck cancer patients, who had failed prior
therapy. The objective of the trial was to demonstrate clinical safety, evaluate pilot
efficacy and explore a possi ble M ultikine dose-response relationshi p.
The study was conducted under BB-lND 5677 and Canadian IND 033575. Patients
initially received monotherapy with Multikine at one of four escalating doses (200, 400,
800 or 1600 lU as lL-2) subcutaneously in a peri-tumoral, intra-tumoral, or perilymphatic
location at the discretion of the investigator. Depending on their response to the therapy
patients could receive up to 5 subsequent cycles of therapy consisting of Multikine in
combination with cyclophosphamide injection (300 mg/m'), oral indomethacin (25 mg po
tid) and oral zinc sulfate (142 mg po qid). The first treatment course was 26 days and
subsequent courses were 29 days. The last day of the previous course was also the
first day of the subsequent course. During the first treatment course Multikine was
administered once daily on Days 1-5 and 8-12, in subsequent courses it was
administered once daily on Days 4-8 and 11-15 of each course.
One patient completed all 6 courses of therapy, three completed 5 courses, three
completed 4 courses, ten completed 3 courses, fourteen completed 2 courses and all
sixteen completed the initial course of treatment. One patient began treatment course 2
but did not complete it, and 1 patient who entered treatment course 4 did not complete
it. Fifteen patients discontinued participation in the study, 13 because of progressive
disease and 2 as a result of death.
Thirteen severe adverse events were reported during the study. None of these were
attributed to the treatment regimen by investigators. Only two adverse events were
considered "possibly related" to therapy: moderate hyponatremia and mild asthenia.
Seven deaths occurred during the study. The deaths were not unexpected, given the
advanced nature of the patients' disease and were not drug-related. Five were related
to the patient's malignancy and two were unrelated.
Currently available information indicates that none of the patients in the low dose group
had a complete response or partial response, but therapy did result in decreased or
t2
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Protocol No: CS001P3
stable tumor size in about half of patients assessed after two courses of treatment. lt
was not possible to demonstrate a dose-response relationship for Multikine in this trial,
perhaps due to small sample size.
Conclusion: Multikine when administered alone and as part of the regimen including
cyclophosphamide injection, daily indomethacin and oral zinc sulfate was safely
administered and well tolerated at all doses administered in this trial. A final report of the
efficacy results is pending, however, given the improvement or stabilization of most
patients who received two courses of therapy and the safety of Multikine when given
alone or in conjunction with ClZ, additional studies are warranted in the group studied
and other patient groups.
Multikine Phase ll (Head & Neck - Canada)
CEL-SCI enrolled 28 patients in a multi-center, Phase ll dose escalating clinical trial in
subjects with previously untreated, advanced primary squamous cell carcinoma of the
oral cavity.
This study was a Phase l-ll trial of Leukocyte lnterleukin, lnjection (Multikine) in patients
with head and neck cancer. The study was conducted primarily to determine the safety
of a 3-week dosing regimen of Multikine in combination with cyclophosphamide,
indomethacin, and zinc (CIZ) in patients with advanced disease (Multikine was given
three times weekly in two of the dosing weeks), and to evaluate indications of efflcacy.
The study had an open label, multicenter, ascending dose design. Following screening
and at least three weeks before tumor treatment by surgical resection or the
commencement of radiation therapy, each patient was given a single injection of
cyclophosphamide 300 mg/m2 lV, an 18-day regimen of indometh acin 25 mg orally
three times daily, zinc sulfate monohydrate 142 mg orally daily, and alternate day peri-
tumoral injections of leukocyte interleukin for a total of six injections during a two week
interval. The first seven patients received the low Multikine dose 200 lU lL-2 equivalent.
lf safeÇ was observed, i.e., no unacceptable toxicity as defined by the investigator or
patient, the second seven patients received the Multikine dose 400 lU lL-2 equivalent,
the third seven received the Multikine dose 800 lU lL-2 equivalent, and the last seven
received the high Multikine dose 1600 lU lL-2 equivalent.
Patients were typical of those with advanced cancer of the head and neck. Most had a
history of alcohol consumption and long term tobacco use. The mean age was 60.1
years and the majority (85.7Vo) were male. Most patients (89.3%) had stage ll or lll
disease.
Almost all patients were stable in terms of primary tumor growth following treatment with
Multikine. Clinically positive lymph node size changes were variable, and changes in
l3
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Protocol No: CS001P3
size did not appear to be dose-related. Tumor characteristics did not change in most
patients following treatment, though pain/tenderness was decreased in those patients
who did have a reduction in tumor surface area. Both the patients and medical staff
assessed well-being as stable or improved, and other health assessments as stable in
most patients.
Multikine was found to be safe and well tolerated. No deaths or serious adverse events
occurred during the study regimen. The most common drug-related adverse events
were local effects of mild severity. No clinically significant toxicity, changes in laboratory
values or other safety measures occurred during the study.
Conclusion: No serious adverse events attributable to Multikine were reported in this
trial. Multikine is safe for use in this patient population, and indications of potential
efficacy suggest that further studies with Multikine are warranted.
Multikine Phase ll (Head & Neck - Hunqarvl
The results of a fully enrolled, multi-center, dose escalating Phase ll clinical study in
advanced primary head & neck subjects conducted in Hungary are summarized as
follows: Twenty-seven (27) disease matched tumor tissue samples were obtained from
the National Oncology Center (Hungary), the lead center of this multi-center clinical trial,
and served as the control group for a follow-on histopathology study. Multikine was
administered peri-tumorally six times over a two week period to the first three groups of
advanced primary OSCC patients [8 subjects -200|U, as lL-2 (per day), and to 12
subjects - at 400 lU/day and to 7 subjects - 800 lU/dayl for a total of ten times over a
two week period, peri-lymphatically plus a one-week wait period before surgical
resection of the residual tumor. Preliminary safety data corroborates the lack of toxicity
seen in previous studies. Furthermore, preliminary results (from one site, The National
Cancer lnstitute, Hungary) demonstrated the lack of recurrence in the first eight (8)
sequentially treated patients at 24 months + post treatment with Multikine (which was
followed by surgery and radiation therapy). At the same clinical site, approximately 50%
of these type of patients (undergoing surgery for the primary tumor and affected lymph
nodes - followed by radiotherapy) are expected to present with recurrence of disease at
18-24 months post treatment. Histological data suggested that Multikine pre-treatment,
in addition to its direct anti-tumor effect, significantly (p<0.05) increases the number of
residual tumor cells that enter into the cell-cycle mode (Fig 3), thereby making these
tumor cells more susceptible to follow-on therapy with radiation or radiation and
chemotherapy26'
This study was expanded to include 20 additional advanced primary OSCC patients
receiving the drug (800 lU/day) 1/2 peri{umorally and 112 peri-lymphatically. ln this later
study, Multikine was administered Sx/week for 3 weeks, and 20 additional disease
matched controls (selected as described above) were used for the pathology portion of
the study. Safety data corroborate the lack of toxicity seen in the previous studies.
t4
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Protocol No: CS001P3
Histopathology results indicate a marked anti-tumor response resulting in necrosis,
marked lymphocytic infiltration and fibrous collagen deposition in the tumor bed (Fig 4)
ln situ HLA class ll expression of OSCC tumor cells from patients responding to
Multikine immunotherapy (>30% reduction) showed a complete absence of HLA ll
marker as compared to Multikine non-responder group (p<0.05). Multikine neoadjuvant
immunotherapy decreased the number of macrophages in the tumor (p<0.0Q-2) in the
Multikine responder group as compared to control (non-Multikine treatment)28.
Gonclusion: Multikine treatment induced a shift from stromal T-cells to tumor epithelial
T-cell infiltrate (p<0.05), increased intra epithelial CD3+, CD4+, CD28+ T-cells and
decreased CD8+ T-cells (p<0.05). As a result of tumor cell death and necrosis and
CD4+ T-cell infiltration into the tumor, tumor stroma/cancer nest ratio decreased in the
Multikine pre{reatment group (p<0.005) as compared to a control population (in this
pathology study). The^gbjective response rate in this study was 21Yo and the overall
responsé was 42%o27'28
Figure 3. 
Cell cycle marker (K¡67) in Multikine treated Oral Squamous Cell
Carcinoma (OSCC)
+@odb
+strq¡d @ü9
ff
fn
(@briEd@)
A. Morphometry of Ki-67+ cells in OSCC.
Data are means+/-SEM, *p<0.05
0 = Control Untreated Grou
B. Visualization of cycling cancer cells
in OSCC by Ki-67+ (Histopathology)
Figure 4. 
Histological appearance of necrosis in oral squamous cell carcinoma
(H&E staining)
l5
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Protocol No: CS001P3
Panel A
Panel B
Panel A: Control - Lack of necrosis in the epithelial nests of Oral Squamous Cell Carcinoma.
Panel B: Multikine treatment - Entire cancer nest is necrotic and filled with debris and leukocytes
ln this Phase I dose escalation study, 200 lU/day (as lL-2) was administered by
endocervical / peri-lesional injections (S></wk, for 2wks, 2 wks "rest", and a repeat of the
injection regimen) over a 6 week period to 5 HIV-1 / HPV co-infected subject volunteers
(women) and following safety assessments of this group, Multikine was given at 400
lU/day (as lL-2) to 3 additional HIV-1/HPV co-infected study volunteers (women). All
subjects tolerated the injections well without any investigational drug associated serious
adverse reactions. Five of eight (5/8) showed clinical improvement by colposcopic
visualization, 3/8 had improvement in PAP smear and on colposcopically guided biopsy
(by pathology examination) taken 7-8 weeks after the final Multikine injection. Three of
eight (3/8) remained unchanged , and 218 had disease progression. One patient was
withdrawn from the study, due to a severe adverse reaction (severe pancreatitis), which
was related (exclusively) to the anti-retroviral medication she was taking. Multikine
treatment of HIV/HPV co-infected women had a direct effect on HPV virus infection of
the cervix (reduction in the number of HPV viral types by 75o/o), as measured by PCR
(tested in the first three patients enrolled in this trial).2s
1.5
Dose Rationale and Risk/Benefits
Previous dose escalation studies in animals and humans have tested Multikinedoses
up to 3200 lU/day for 2 weeks when administered by peri-tumoral and peri-lymphatic
injection. There was no evidence of systemic or local toxicity. Analysis of tumor tissue
post treatment has shown infiltration of tumor by CD3+, CD4+ and CD25+ T-cells, tumor
necrosis and a dose dependent, cell cycle activation of tumor cells in the tumor bed,
which is characteristic of cells' becoming increasingly sensitive to chemotherapy and
radiation therapy.
ln total, over 200 patients treated with Multikine had no reported serious adverse events
associated with Multikine neoadjuvant / adjuvant immunotherapy in clinical trials
conducted in the US, Canada, Europe and lsrael. Because antitumor activity has
consistently been demonstrated at the proposed dose (between 400-800 lU, as lL-2)
with concomitant activation of tumor cells in the tumor, a dose of 400 lU was chosen for
this phase lll study. Although not the maximum dose tested, this dose is safe, well
tolerated, and achieves antitumor effects (T-cell infiltration, tumor necrosis and
regression, and cell cycle activation of tumor cells). A maximum tolerated dose (MTD) is
not being sought, in this trial, as this type of therapy is not anticipated to have a toxicity-
based limit.
t6
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CONFIDENTIAL
2. Study Objectives
2.1 Primary Objective
The primary objective is to compare overall survival in the Multikine + CIZ + SOC group
to that in the SOC alone group for superiority of the former.
Overall survival will be accessed via a Kaplan-Meier life{able and compared using a log
rank test and confirmed further with stage-, location-, and geographic-stratified log rank
tests. The unstratified logrank test constitutes the primary analysis. Further details on
the statistical analyses can be found in section 7.9.
2.2 Secondary Objectives
The following secondary comparisons are also planned
(1) Overall survival in Multikine + SOC vs. SOC
(2) Progression Free Survival in Multikine + CIZ + SOC vs. SOC
(3) LRC in Multikine + CIZ + SOC vs. SOC
(4) OOL in Multikine + CIZ + SOC vs. SOC
(5) Examination of the histopathological nature of cellular tumor infiltration
stimulated by Multikine injection vs SOC
2.3 Tertiary Objectives
The tertiary objectives of the study include
(1) Equivalence between overall survival in the Multikine + CIZ + SOC vs
Multikine + SOC
(2) Tumor response in Multikine + CIZ + SOC vs. SOC
3. Study Design
3.1 General Design
This is a Phase lll, open-label, randomized, multi-center study of Multikine given peri-
tumorally and peri-lymphatically to subjects with cancer of the oral cavity and soft palate
scheduled for surgical excision of tumor followed by radiotherapy or chemoradiotherapy.
The control group will receive standard of care only (surgery followed by radiotherapy or
concurrent chemoradiothera py).
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Protocol No: CS001P3
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CONFIDENTIAL
Protocol No: CS001P3
An interim safety analysis will be performed after the first 40 subjects have been treated
with Multikine and completed surgery (see 8.13.1). Subsequent interim analyses will be
performed to confirm sample size and to conduct futility analyses.
Figure 5. 
Schematic representation of subject randomization and treatment.
* CIZ: Cyclophosphamide 300 mg/m2 (x1, lV, Day -3); lndomethacin 25mg tid, po (Day 1 to approx¡mately 24 hrs pr¡or to surgery) +
zinc (as Multivitamin) po id daily (from day I to approx¡mately 1 day prior to surgery)
** Surgery: complete surgical resection of primary tumor and any positive lymph nodes.
"'* Radiotherapy is to be g¡ven per protocol at a total of > 60 Gy to S70 Gy (in 30-35 fractions over a 6-7 week period)
..'. H¡gh risk subjects are def¡ned as those w¡th: positive surgical marg¡ns, 2 or more clinically positive nodes, or e)ûracapsular
nodal spread (any or all of the above).
l8
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r'
aJ
.4>
I
\
3
E
N
R
o
L
L
M
E
N
T
R
A
N
D
o
M
I
z
E
Group 1:
SXweek X 3 weeks
+ clz*
Multikine@
Group 2:
Multikine@ S)Uweek X 3 weeks
wlo ClZ"
Group 3:
Standard of Care Group
S*
U
R
G
E
R
Y
RTx
Radiotherapy 60-70 Gy,
30 fraclions over6-7 Weeks'-
-oR-
CRTx
""tllqLBlgk: Concurenl
rad¡ochemlherapy 60-70 Gy, 30-35
fracl¡ons, ovor 6-7 re€ks + lV
cisplalin ('100 rE/mÐ 1/\,/reek X 3
weks (reek 1, 4 and 7) on days 1,
22, and 43 of râd¡olh€rapy course
g¡ven within +\- 3 days for each
scheduled day of administral¡on of
chemo during lhe rad¡otherapy
period
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CONFIDENTIAL 
protocolNo:CsQQ1P3
A Phase lll, Open-label, Randomized, Multi-center Study of the Effects of Leukocyte lnterleukin, lnjection [Multikine] Plus Standard of Care (Surgery +
Radiotherapy or Surgery + Concurrent chemoradiotherapy) in Subjects with Advanced Primary Squamous cell Carcinoma of the Oral Cavity/Soft Palate
Versus Standard of Care Only
Table 2
Protocol Treatment
lmen
Notes: l. Cyclophosphamide given on Day -3 prior to Multikine injection. Dose: 300
lV (bolus) xl
2. Multivitamins with zinc supplementat¡on started on Day 1, continued daily until one day prlor to surgery.
3. lndomethacin 25 mg tid po with food starting on Day 1 until one day prior to surgery.
4. Multikine injection-Daily Dose: 400 lU; % dose peri-tumorally, % dose peri-lymphatically Sx/week for 3 weeks.
by the lnvestigator)
6. Radiotherapy initiated no more than 56 days (8 weeks) post surgery: 60-70Gy, 30-35 fractions; 2Gy 5x/ week for 6-7 weeks.
chemotherapy during the radiotherapy period) to start on day one of radiotherapy if indicated (i e. in high risk subjecls)
l9
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Surgery
Week 5-
6
Radiation theraov, initiated no later than 56
days (8 weeks) post surgery +/- concurrent
chemotheraDv
Days
29-38
x
ffiffi
X
ffi
X
x
x
x5
x
x
Week
4
Days
22-26
x
x
Week
3
Days
15-19
x
X
x
Week
2
Days
8-12
x
x
X
1
Week
Days
1-5
x
x
x
Day
-3
x
Treatment Groups
Multikine Treatment
(Groups 1and2l
Cyclophosphamide 
1 (Group I only)
Multivitamin with zinc
supplementation2 (Group I onlv)
lndomethacin 'lGroup 1 only)
Multikine lnjection o(Groups 1, 2)
Surgery'lcroups 1 and 2)
Radiotherapy u lcroups I and 2)
Chemotherapy tl Groups 1 and 2)
Standard of Care Treatment
(Group 3)
Surgery 
5
6
Radiotherapy
Chemotherapy'
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Protocol No: CS001P3
3.1.1 Primary Study Endpoint
The primary endpoint of the study is OS. After Multikine injection (with or without
CIZ) followed by SOC treatment, subjects will be monitored on a regular basis by
clinical and radiographic criteria and will be followed for 30-36 months after
completion of study drug + SOC until the required number of deaths are
observed. Subjects will be subjected to assessments as described in Section 6.3.
3.1.2 Secondary Study Endpoints
The secondary efficacy endpoints of the study are
1. Progression-free survival (defined as survival without tumor recurrence,
new disease or distant metastases) and on the rate and distribution of
distant metastases.
2. Disease progression defined as loco-regionalfailure, i.e. the
reappearance (recurrence) of disease, progressive disease (but not
distant metastases), or any new disease above the clavicle not present at
baseline.
3. Quality of life assessments on subjects receiving Multikine treatment and
standard of care.
4. Histopathological nature of cellular tumor infiltration stimulated by
Multikine injection.
3.1.3 Tertiary Study Endpoints
1. Equivalence between overall survival in the Multikine + CIZ + SOC vs
Multikine + SOC
2. Tumor response in Multikine + CIZ + SOC vs. SOC
3.1.4 Quality of Life (aOL)
3.1.4.1 Background and Rationale
It is now widely recognized that Squamous Cell Carcinoma of the Head and
Neck (SCCHN) and its treatment may significantly affect patients'functioning in
basic areas such as eating, speaking and socializing, alLoJwhich may, in turn,
have a profound influence on overall quality of life50's1' 52' 53' 54. Particularly in
advanced disease, treatment is aggressive, multimodal and confers significant
acute toxicity and functional impairment. Perhaps of even greater concern, are
20
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sponsor
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CONFIDENTIAL
the potential late effects, which may
well as overall quality of life.55's6'57
Protocol No: CS001P3
interfere long term, with specific functions as
Suroery: Treating head and neck cancer (HNC) by primary surgical resection
may result in disfigurement, voice loss, and difficulty chewing and/or swallowing.
ln addition, some patients experience excessive drooling, choking, respiratory
problems, impaired vision, and a decreased sense of taste and smellsT'ut. All of
these side effects have been associated with moderate to severe distress,
negative self-image and disturbed interpersonal relationships5s'60'61'62. A review
of the literature suggests that the most commonly cited late effects of surgery
include (percentage reflects % of patients reporting moderate to severe
problems) : disfigurement (-50%); voice loss/disturbance (-50%); difficulty eating
(chewing, swallowing) (30%-40%); decreased activity (-3970); pain (25%-50%);
these percentages are derived from various studies63'64' 65' 66of heterogeneous
groups of HNC patients treated with surgery + radiation therapy. Other data also
suggest that larger tumors and more extensive surgery, which generally result
from a larger tumor, confer even greater morbidity6Y' oel bg' zo' zt'72'zs.
Radiation Therapv: Radiation therapy (RT) has long been used alone or in
combination with surgery to treat HNC and both the severe acute and long-term
sequelae are widely recognized. The literature documents oral toxicities and
compl ications, fu nctional and performance impai rments, patient reported
symptoms and side effects as well as consequences to QOL. The following list
summarizes the most commonly cited late effects of radiation therapy and the
percentage of patients reporting moderate to severe problems in that area.
These percentages are derivedfrom various studies56'7a'75'76'77of heterogeneous
groups of HNC patients treated with radiation alone: xerostomia (dry mouth)
>66%; difficulty eating/ swallowing 350/o-680/o; sticky saliva -33o/o; decreased
sense of taste 25o/o-50%o; dental problems 33%; pain 15o/o-30o/o; appearance
20%o-25o/o. ln one study of 240 oro- and hypopharyngeal cancer patients treated
with an aggressive investigational regimen,2SVo of patients were still feeding
tube dependent 2 years after treatment 77 to 95% of patients had a dry mouth
after six months, while 66% had not recovered at one year; a finding, which is
consistent with many radiation therapy type studies.
Adding chemotherapy to radiation regimeng-tçnds to exaggerate both the acute
and long term impact of the radiotherapyTs'7s'80. Most patients recovered from
acute toxicities, but some problems (e.9., dry mouth, diet restriction) persisted
years after treatment cessation.
Multikine: ln general, the addition of any furthertherapy, particularly in the
induction phase, prior to scheduled definitive therapy, has the potential to: a)
increase subsequent therapy related toxicities and worsen quality of life, b)
2t
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Protocol No: CS001P3
decrease subsequent toxicities by shrinking tumor (and either minimizing tumor
related impairments or leading to tumor downstaging and in turn, a possible
reduction in subsequent surgical resection, radiation fields or dose) or c)
effecting no change in immediate or long term toxicities. ln addition, one needs to
address the potential impact of the additional treatment itself. As proposed in this
protocol, Multikine will be administered by injection daily 5 days/week for three
weeks prior to surgical resection. As presented in Section 1.4, limited data
suggest that Multikine is well tolerated without substantial acute or long term side
effects or sequelae. However, further data are needed to more fully document
the impact of Multikine on QOL and performance both in and of itself as well as
an adjunct to further therapy. Questions related to pain at the injection site,
possible downstaging or possible aggravation of subsequent therapy, require
further evaluation. Thus, while traditional efficacy endpoints are undeniably
critical considerations, assessment of the patient's QOL and performance is
important to the comprehensive evaluation of the success of this new treatment
regrmen.
3.1.4.2 Quality of Life Objectives
The proposed treatment regimen aims to improve overall survival, loco-regional
tumor control, disease free survival and possibly impact distant metastases while
minimizing performance and QOL deficits. Thus, QOL and performance
assessment are also important treatment objectives. The objective is to describe
these dimensions prospectively, pretreatment, through treatment, to long-term
follow-up. QOL specific aims are to:
. Evaluate changes in QOL and performance as affected by Multikine
treatment compared to SOC.
. Document patient's experience of treatment effects.
. Determine extensiveness and persistence of QOL and function-related
treatment effects.
. Describe the pattern, timing and extent of recovery of function and QOL.
3.1.4.3 Quality of Life Assessment
Quality of life assessments will be performed for the first time prior to
randomization (but following enrollment and signing of the informed consent by
the subject volunteer), and then following Multikine administration up to 1 day
prior to surgery and at about, 6, 12, 18, and 36 months after completion of
therapy.
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Protocol No: CS001P3
For SOC subjects, assessments will be at baseline prior to randomization - as
above and then again prior to surgery, and at about 6, 12, 18 and 36 months
after completion of therapy.
3.1.4.4 Assessment lnstruments
The EORTC QLQ - C30 version 3 core questionnaire will be used in combination
with EORTC QLQ-H&N3S specific to head and neck cancer. Both the core
questionnaire and H&N35 are validated instruments used in multi-cultural setting.
The instrument has demonstrated ability to assess the functional, performance
and quality of life domains germane to SCCHN, and sensitivity to change over
time.
The EORTC QLQ-C3O consists of 30 questions covering general health aspects
in cancer patients. The disease-specific EORTC QLQ H&N35 consists of 35
questions covering aspects of head and neck cancer. The core questionnaire
and disease-specific questionnaire in totalwill contain 65 questions. The
instrument is self-administered by the subjects (or can be completed by subjects
with the assistance of a qualified healthcare provider). Validated translations for
EORTC QLQ-C3O and EORTC QLQ-H&N35 are available in most major
languages such as English, Spanish, Hungarian, Ukrainian, Portuguese, French,
Polish, Russian, Mandarin, Cantonese, Hebrew and many lndian languages
(Bengali, Gujarathi, Hindi, Kannada, Malayalam, Marathi, Punjabi, Tamil,
Telugu).
A scoring manual will be provided with details on scoring procedure for the
subject's responses to the questions posed by the EORTC QLQ-C3O and
EORTC QLQ-H&N35 Questionnaires.
4. Subject Selection and W¡thdrawal
4.1 lnclusion Criteria
1. Previously untreated primary squamous cell carcinoma of the oral cavity
inclusive of the tongue (but not the base of the tongue), floor of the mouth,
cheek (buccal mucosa) and soft palate only, confirmed by biopsy, with or
without regional lymph nodal metastases, deemed curable by and
scheduled for definitive treatment by surgical resection and postoperative
radiation therapy or surgical resection and postoperative concurrent
chemoradiotherapy (standard of care). Tumors in other locations (and
those in other locations of the head and neck) are excluded.
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Protocol No: CS00'lP3
The primary tumor class must be T1, T2 or T3 and must NOT measure
more than 6 cm in greatest dimension. T4 is allowed if invasion of the
mandible is minimal (defined as <0.5cm as confirmed by CT,-and/or MRI
with the use of CT imaging being mandatory) and can be salvaged by
marginal mandiblectomy (retention of function and having intact mandible
post surgery).
The class of clinically positive lymph node(s) must be N1 or N2 and must
not measure more than 6 cm in greatest dimension.
Clinical tumor stage must be lll or lV. For stage lV, only subjects treatable
by surgical resection or surgical resection followed by postoperative
radiation/ radiochemotherapy are eligible:
Eligible TNM Categories:
T1 N1-2 M0
T2 N1-2 M0
T3 N0-2 M0
T4* N0-2, M0
. T4 is allowed if invasion of the mandible is minimal (defined as <0 5cm as
confirmed by CT, and or MRI with CT imaging mandatory) and can be
salvaged by marginal mandiblectomy (retention of function and having
intact mandible post surgery).
2. Primary tumor and, if present, clinically positive lymph node(s) with at
least one measurable lesion as defined by the RECIST criteria (Appendix
10) and measurable in two dimensions by physicalexamination.
3. ¿18 years of age.
4. lf female, is neither pregnant nor lactating.
5. lf subject is of reproductive potential they must be willing and able to
utilize effective methods of contraception (e.9. barrier methods with
spermicide).
6. Hemoglobin: >9gm/dl; WBC: > 3000/mm3; platelets: > 100,000/mm3,
bilirubin < 1.0 mg/dl; creatinine < 1.2 mgldl'
7. No prior therapy with lL-2, lL-1 or any other biological response modifier
(e.9., interferon ü,, 0 or y, G-CSF, GM-CSF) in past one year.
8. Negative reaction to intradermal test with ciprofloxacin (a fluoroquinolone
antibiotic).
L No immune depressive drugs, e.9., corticosteroids, cyclosporine,
methotrexate, or anticancer agents, in past one year. Subjects on topical
corticosteroids to treat dermatological conditions covering not more than
5% of body surface area are considered eligible.
10. Life expectancy greater than six months.
11. Karnofsky score 70 or greater.
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a
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Protocol No: CS001P3
12.Able to take oral medication.
13. Able to provide informed consent.
14. Must have normal immune function, i.e., must not be known to be HIV
infected or have any other disease or condition causing significant
immunodeficiency.
4.2 Exclusion Criteria
1. Subjects other than those to be treated by surgery, followed by radiation
therapy +/- chemotherapy and/or those for whom surgery would be
scheduled prior to Day 8 from enrollment /randomization.
2. Tumor invasion of bone as detected by a suitable imaging technique MRI
and/or CT or by physical examination, except for mandibular invasion (as
described above for T4 Tumor).
3. Any T1N0 or T2N0 stage tumors and all tumors classified as T4, N3
and/or any TN classification with Ml or greater (Note: only M0 is allowed
in this study), or in locations other than those specified in lnclusion Criteria
#1 (Section 4.1).
4. Active peptic ulcer disease despite ongoing adequate medical therapy.
5. Prior surgical resection of the jugular lymph nodes on the ipsilateral neck
that the injection is to be administered.
6. Any acute or chronic viral, bacterial, immune or other disease in a stage
usually associated with abnormal cellular immunity (e.9., HIV infection,
hepatitis, nephritis, lung disease, rheumatoid arthritis or other autoimmune
disease).
7. Subjects on hemodialysis or peritoneal dialysis.
8. Prior history of asthma.
9. Prior completion of one or more courses of therapeutic irradiation,
excluding such treatment of the extremities.
10. History of allergic reaction to fluoroquinolone antibiotics (e.9.,
ciprofl oxaci n, ofloxacin).
11. History of any other malignancy, excluding basal cell carcinoma of the
skin and in-situ carcinoma of the cervrx.
12. History of congestive heart failure (CHF) and other heart conditions that in
the opinion of the investigator would cause the subject to likely be unable
to participate in the study or tolerate the study's protocol regimen
(including the surgical procedure).
13. The opinion of the investigator that the subject may be unable to tolerate
the protocol regimen or that participation in the trial may compromise the
subject's preparation for tumor treatment.
14. Failure to meet the lnclusion Criteria.
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ProtocolNo:Cs001P3
4.3 Prohibited Treatments and Medications
The following medications are prohibited during study participation:
. Any investigational agent other than Multikine.
. Routine use of hematopoietic growth factors.
. lmmunotherapeuticagents.
. Chemotherapeutic agents other than those specified in the protocol.
. Radiation therapy other than that given postoperatively per this
protocol.
. Surgery for cancer management or treatment other than that planned
for definitive treatment of the primary head and neck cancer.
. Full-dose (therapeutic) anticoagulation therapy, aspirin >325 mglday,
or any other platelet inhibitory agent.
. Medications and treatments other than those specified in the above
list, including palliative and supportive care for disease-related
symptoms, are permitted during the study.
4.4 Subject Recruitment and Screen¡ng
4.4.1 Recruitment
Subjects will be recruited from oncology centers having the demonstrated
expertise to treat head and neck cancer. All advertising (if any) will be reviewed
and approved by the IRB/EC of that institution and a letter indicating review and
approval of the advertising will be supplied. Subjects will receive and be asked to
sign an informed consent that fully describes the study procedures in lay
language. The subject will have an opportunity to have all questions regarding
the study answered and will understand that their participation is voluntary.
4.4.2 Screening
The following assessments and tests should be performed within 2-4 weeks prior
to randomization (unless otherwise specified in the Protocol):
1. Measurements of the target lesions in longest diameter (LD) by either
CT/MRI or clinical examination. For clinical examination the LD should be
assessed using calipers and documented by color photography including
a ruler. Clinically positive regional lymph nodes will be measured in short
axts.
2. Bi-dimensional measurements of the primary tumor and bi-dimensional
measurement(s) of clinically positive regional lymph nodes by CT or
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Protocol No: CS001P3
gadolinium - enhanced MRI scan. Note: The radiologist performing the
MRI should provide an original copy of the scan(s) and a data tape or
diskette to the clinical investigator for inclusion in the subject study
documentation (Section 9.2). These measurements must be taken prior to
biopsy.
Note: RECIST criteria (Appendix 10) will be used to evaluate the
response of the tumor to Multikine treatment and for the SOC population
prior to surgery and during the course of the study.
3. Punch Biopsy of the primary tumor may be obtained up to four (4) weeks
prior to subject randomization in the trial. The specimens obtained must
be diagnostic of squamous cell carcinoma and be sufficient to allow
grading of tumor cell activity and evaluation of peripheral blood white
blood cell infiltrate and other immunological markers. Tumor samples
available from the biopsy (H&E slides) will have to be sent to both the
local and central pathology laboratories participating in this study for
examination. lf these samples are unavailable or insufficient to allow the
additional testing required by these laboratories then an additional biopsy
must be performed at study entry. FNA biopsy will be performed on any
affected clinically involved regional lymph node. Consultation with a
pathologist should occur to ensure that the biopsy sample will be
adequate for this evaluation. Specific instructions for sending specimens
to the central pathology laboratory for this study are provided in Appendix
4 of this protocol.
4. Subjects electing to participate in the genomic microarray study described
in section 6.7 will be required to provide an additionalfine-needle
aspiration (FNA) sample (frozen) and an additional 25-50mL of blood for
collection and preparation of PBMCs for the microarray study at
screening.
5. Medical history (including betel nut, tobacco and alcohol use) and physical
examination.
6. Vital signs.
7. Height and body weight.
8. Chest X-ray (PA and lateral) and EKG. CT of chest may be substituted for
chest X-ray.
9. Complete blood cell count (CBC), including platelets and white blood cell
differential, and erythrocyte sedimentation rate (ESR) (Appendix 4).
10. Urinalysis (Appendix 4).
11. Blood chemistry tests (Appendix 4).
12. Clinical staging of the primary tumor and regional lymph nodes.
13. Photographs of the primary tumor with adjacent metric scale (color
electronic media capture - Digital Photography).
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Protocol No: CS001P3
14. Scoring of skin test response to ciprofloxacin.
15. Appropriate evaluations of intercurrent diseases (HlV test).
16. Review of previous and current medications.
17. Serum pregnancy test (within 3 days of start of Multikine treatment).
1 8. Adverse Event recording.
4.5 Withdrawal and Discontinuat¡on of Subjects
4.5.1 Subject Discontinuat¡on
This study will be conducted under the intent-to-treat-principle (lTT). This means
that once a subject is randomized to a treatment group, he or she will remain in
that treatment group and should follow his or her protocol defined sequence of
visits regardless of whether the subject receives the assigned study medication,
and regardless of the extent of the subject's compliance with dosing. A subject
may be discontinued from study medication for a number of reasons, some of
which are listed below, but this does not automatically mean the subject is
discontinued from study follow-up. Reasons for discontinuing study medication
include the following:
1. lf a subject has documented evidence of progressive disease or
symptomatic tumor progression after administration of SOC or Multikine
followed by SOC.
2. lf the investigator thinks a change of therapy would be in the best interest
of the subject.
3. lf the subject requests discontinuation, withdraws consent for any reason,
or is unwilling or unable to comply with study requirements.
4. lf the study drug exhibits unacceptable toxicity that does not respond to
dosage modifications.
5. lf a subject becomes pregnant after enrollment in the trial, or fails to use
adequate birth control (for those subjects who are able to conceive).
Study personnel should make every reasonable effort to åncoutage subjects to
continue with the follow-up schedule even if the subjects are not receiving study
medication, or did not receive a full regimen of study medication.
Subjects who need to withdraw from the study for a period of time, but are willing
to resume should be encouraged to do so. Likewise, subjects who are unable to
attend all protocol visits but may be able to attend a subset of visits should be
encouraged to do so. Subjects who miss a visit should be contacted and
encouraged to continue with thelr treatment (if applicable) and follow-up.
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Protocol No: CS001P3
The study will be closed once the targeted number of deaths are observed; this
is expected to take place 30-36 months (the duration of follow-up is event driven)
after SOC (as defined in this protocol) has been administered to the last enrolled
subject. lnvestigators will collect survival information after study closure for all
subjects who have been involved in the study and have not withdrawn their
consent for three (3) years following randomization.
4.5.2 Study Discontinuat¡on by the Sponsor
The sponsor has the right to terminate this study and/or any investigative site at
any time. Reasons for terminating the study and/or investigative site may include
the following:
1. The incidence or severity of an adverse event (AE/SAE) in this or other
studies indicates a potential health hazard to subjects.
2. Subject enrollment is unsatisfactory.
3. Data recording is inaccurate or incomplete.
4. Good Clinical Practice (GCP) procedures are not being followed.
The sponsor will not have access to, or base the decision to terminate a clinic on
unblinded data. Subjects from a site where enrollment has been terminated will
continue to be followed under the intent-to-treat principle, at the terminated site
or at an alternate site.
4.5.3 Data Gollect¡on and Follow-up for Withdrawn Subjects
All subjects must be followed for safety evaluation (Section 8) until the time of
study discontinuation or study closure (Sections 4.5.1 and 4.5.2 respectively). At
the time of discontinuation, all procedures and evaluations scheduled for the last
visit of the study must be performed (Section 6.3 and as indicated). The reason
and date of study discontinuation will be recorded for all subjects. As noted
above, it is essential that all subjects be followed as long as possible, and as
completely as possible even if they have not received Multikine, or have only
received a partial regimen, unless they have withdrawn consent.
WHILE COLLECTING CONPLETE DATA FOR ALL STUDY
ENDPOINTS IS CRUCIAL, IT ffi,isT BE AN ESPECALLY HIGH
PRIORITY TO OBTAIN SURWUAL DATA ON ALL SUBJECTS FOR 3
YEARS.
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5. Study Drug
5.1 Description
Protocol No: CS001P3
Multikine (Leukocyte lnterleukin, lnjection) is provided frozen in a borosilicate
glass-serum-vial containing2.2 mL of drug at 200 lU (as lL-2) per mL for peri-
tumoral, intra-tumoral, peri-lymphatic or subcutaneous administration. The
preparation has a total protein content of 3 mg/ml. The drug is stored frozen in
the pharmacy at -20oC until needed. The vial contents may be thawed at
ambient temperature just before use, and the drug is allowed to reach ambient
temperature before injection. lf thawed at ambient temperature, the drug must be
injected within 4 hours.
Multikine may also be thawed at refrigerator temperature (2'-8oC) one day
before use, and allowed to come to ambient temperature just prior to injection -
either way of thawing the drug vial, is acceptable. However, the overnight thaw at
2"-8oC temperature is preferable as the drug may be kept for up to an additional
24 hours at 2'-8oC temperature after thawing, if the subject did not arrive in the
clinic - once the drug is brought to ambient temperature it must be used within 4
hours (of reaching ambient temperature) or be disposed of. See Appendix 11 for
speciflc instructions on Drug Vial Thawing Procedure.
5.2 Treatment Regimen
Subjects randomized to one of the Multikine treatment groups are scheduled to
be treated with or without ClZ. Multikine, 400 lU (2 mL) is injected each day of
study drug administration,l12 dose (1 mL) peri-tumorally and 1/2 dose (1 mL)
peri-lymphatically at the jugular lymphatic chain ipsilaterally to the injected tumor
site inferior to the tip of the mastoid process in the area of the sternomastoid
muscle (See Appendix 3) sequentially and during the same visit. Both injections
(peri-tumorally and peri-lymphatically) are administered 5 times per week for 3
weeks. lf scheduled to receive ClZ, subjects will also receive 300 mg/m2
cyclophosphamide (lV bolus on Day -3 of flrst Multikine injection) and 25 mg
indomethacin (tid po daily with food from Day l to one day prior to surgery).
Additionally, a multivitamin supplement containing zinc is given from Day 1 to the
day before surgery for immune system/nutritional support. These medications
are to be recorded on the concomitant medication Case Report Form (CRF). At
the discretion of the investigator, a local anesthetic may be administered prior to
Multikine injections.
5.3 Method for Assigning Subjects to Treatment Groups
The entry criteria of eligible subjects will be reviewed upon enrollment and a
study number and treatment group (Multikine +l- CIZ plus SOC or SOC alone)
will be assigned via randomization. Upon acceptance, the study site will be
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Protocol No: CS001P3
notified of the treatment assignment. Subjects randomized to Groupl and 2
(Multikine +l- CIZ plus SOC) must begin treatment within 7 days of study
randomization.
An lnteractive Voice Response System (IVRS) will be used for randomization
and stratification. Randomization sequences will be computer generated and
maintained by the IVRS. Subjects, who meet all eligibility requirements and
complete screening evaluations, will be randomly allocated in a 3:3:1 allocation
with Multikine + SOC (without CIZ) being the treatment group to be assigned
least often in contrast to Multikine + CIZ + SOC and SOC alone. The IVRS will
employ a dynamic randomization procedure to ensure balanced treatment
assignment within the arms of the trial for each of the following stratification
factors: tumor location (tongue, floor of mouth, cheek, and soft palate) and tumor
stages lll and lV (Table 3 below), within each country, such that each group
(Multikine + SOC and SOC alone groups, respectively) will have as near to as
the same number of subjects that are in each of the prospectively stratified sub-
groups throughout the whole study. The dynamic algorithm (Pocock and Simon
1975: Taves 1974) 81'82'is designed to balance treatment assignment along the
marginal distribution of each factor.
Table 3. 
TNM
and Corres
d¡
Tumor Sta
Note: Stage lvb (T4b primary and all N3 disease) are not eligible.
NE = Not Eligible.
5.4 Preparat¡on and Administration of Study Drug
Pharmacy instructions will be provided separately. Multikine is supplied sterile
and pyrogen free in 5 mlvials containing2.2 mL,400 lU (as lL-2)lvial and is
stored frozen at -20oC. Prior to use, the pharmacist will remove the vial from the
freezer and place it in the refrigerator to thaw overnight (Appendix I 1). After
thawing of the investigational drug, the appropriate protocol and subject
identification information are entered onto a label, which is then affixed to the
vial, recorded on the drug accountability record and the CRF for each subject.
The drug is then ready for use by the clinical staff.
3l
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Primary Tumor
T3
T4
Nodal
lnvolvement
T1
T2
NO
NE
NE
Staqe lll
Staqe lVa
NI
Staqe lll
Staqe lll
Staqe lll
Staqe lVa
N2
Staqe lVa
Staqe lVa
Staqe lVa
Staqe lVa
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Protocol No: CS001P3
When a subject is in the clinic and is being prepared (readied) to receive the
injections of Multikine, the clinical staff shall prepare two separate sterile syringes
each containing no less than 1 mL of Multikine (A vial of Multikine contains
approximately 2.2 mL of drug) and each syringe will have a separate sterile
needle (needle size at the discretion of the administering physician.
Note: Recommended needle size smaller or equalto G-25).
Multikine is injected (one half the daily dose) 200 lU (as lL-2) into the submucosa
at the peripheral margin of the tumor (peri-tumorally), and peri-lymphatically (one
half the daily dose) 200 lU (as lL-2) at the jugular lymphatic chain ipsilaterally to
the injected tumor site inferior to the tip of the mastoid process into the
sternomastoid muscle (sequentially and at the same visit) (Appendix 3). An
approximately equally subdivided volume [e.9., 1 ml (112 dose)] is injected in a
minimum of four equally spaced sites: i.e., near either extent in the longest
dimension of the tumor and near either extent at right angles to and at the
midpoint of the longest dimension of the tumor [Appendix 2A: Technique of Peri-
tumoral, Subepidermal lnjection of Leukocyte lnterleukin (Multikine), Figures 1
and 21. When the anatomical location of the tumor does not allow injections to be
made completely around the tumor (e.9., bone adherence or invasion), Multikine
is injected in approximately equal volumes at a minimum of four sites around the
injectable accessible portion of the tumor margin (Appendix 28, Figure 3). lf
Leukocyte lnterleukin, lnjection (Multikine) is observed to leak out of the needle
channel, the number of sites injected may be increased and volume per site
reduced (e.g., 8 sites at 0.125 mL for 200 lU peri-tumoral dose, Appendix 24,
Figure '1) to ensure drug retention. Peri-lymphatic injections are administered as
described in Appendix 3: Jugular Region Peri-lymphatic Administration of
Multikine (200 lU peri-lymphatic).
5.5 Monitor¡ng Subject Compliance
Except for administration of concomitant medications required per protocol
(multivitamin supplementation and indomethacin self administered by subjects),
alltreatments are to be administered by authorized clinical staff. Compliance with
concomitant medication administration by subjects will be monitored by drug
accountability and notation in the CRF.
5.6 Prior and Concomitant Therapy
All concomitant medication for subjects will be recorded on appropriate case
report forms. There is no prohibition on medications administered to subjects for
normal medical care except administration of any immunosuppressant drugs
(e.9. Cyclosporine), or administration of concomitant anticancer therapies.
Corticosteroids used to control edema or inflammation post surgery or to treat
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Protocol No: CS001P3
dermatological conditions topically during the protocol regimen [<5% of Body
Surface Area (BSA)I are permitted as per investigator clinicaljudgment. Drugs
for analgesia may be used during Multikine injection. Subjects may also receive
nutritional support and drugs to control nausea and vomiting to be used as
indicated.
Cytokines, biological response modifiers and growth factors may not be used for
six (6) weeks prior to and during the protocol regimen as these may be
confounding to the interpretation of the results. However, if it becomes necessary
to use these agents to treat toxicity induced by radiotherapy or
chemoradiotherapy as part of normal medical care of the subject, they may be
used. Use of these agents will be documented including the specific indication for
use in the CRF.
5.7 Packaging
Multikine is packaged in 5 ml vials containing 2 mL of Multikine (200 lU/mL) and
is stored frozen at approximately -20oC C a "C). lt is thawed and administered
as described in Appendix 1 1. An overage of 0.2 mL is also contained in each
vial.
Multikine is packaged in bulk in 50 vial/ boxes for use in creating a "Subject Kit"
(by the international drug distribution center). Packaged treatment kits contain 15
vials of drug/carton ("Subject Kit"). Two (2) extra vials are shipped for each kit (of
15 vials to be used per subject) - for a total of 17 vials per Subject Kit, shipped to
the institutional pharmacy. This is done as a precautionary measure in the event
of a mishap with a vial. The number of "Subjects Kits" shipped (all via courier) to
the institutional pharmacy will be a sufficient quantity of study drugs to treat the
number of subjects anticipated to be enrolled at each investigational site. Kits will
be contained within an outer shipping carton containing cool-frozen packs (U-
Teck or a validated equivalent) for shipping of drug at -20oC (or below, for
shipment only, +/- 5"C allowed).
Each "Subject Kit" will be labeled with the name of the study drug, protocol
number, IND number, unique subject and IVRS number and FDA mandated (if
applicable) warning(s) and any specific or unique to country information
mandated by country/local laws for such an investigational drug (if any) . The
"Subject Kit" label will also have space for the subject's unique lD and unique
IVRS number to be entered at each site.
5.8 Blinding of Study Drug
Not applicable. This is an open label Phase lll study
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5.9 Receiving, Storage, Dispensing and Return/Destruction of
Drugs
5.9.1 Receipt of Drug Supplies
The study drug distributor will store study drug frozen and ship the "Subject Kits"
to each investigative site upon written instruction from the sponsor. Prior to drug
receipt, each site must have completed a pre-study site assessment (conducted
by sponsor or designee), signed a clinical trial agreement, and have IRB
approval for the study protocol and informed consent.
Upon receipt of the "Subject Kits" and other supplies an inventory must be
performed and a drug receipt log filled out and signed by the person accepting
the shipment. Study drug (Multikine, "Subject Kits") must be stored at -20oC
immediately upon receipt. lt is important that the designated study staff counts
and verifies that the shipment contains all the items noted in the shipment
inventory at each institution. Copies of the drug receipt accountability sheets will
be faxed to the sponsor or designee within 24 hours of drug receipt. The receipt
of any damaged or unusable study drug in a given shipment will be documented
in the study files at each participating site. The investigator must notify the study
sponsor of any damaged or unusable study drug that is supplied to the
investigator's site immediately by telephone and fax. Damaged drug will
immediately be segregated and placed under "Quarantine" (at each site) and so
labeled. Damaged or unusable supplies will be replaced via IVRS notification.
5.9.2 Storage
Multikine is stored at -20"C for long-term storage (+l- 1oC preferred, however, +/-
3oC excursions are allowed). Only transient temperature excursions are allowed
and all are required to be documented on a temperature execution log. Multikine
is shipped at -20'C (or lower temperature for shipment only, +/- 5oC allowed).
The investigational drug is thawed just prior to use as described in Section 5.4
and administered within 4 hours.
5.9.3 Dispensing Study Drug
Study drug will be dispensed by the investigational pharmacist on a subject-by-
subject basis (controlled by the IVRS system). Each subject will use one (the
same) drug kit for the duration of the treatment. After a subject is enrolled, the
subject's identifying information, subject lD number and subject's initials will be
fonruarded to the pharmacy by research personnel as described in Section 5.4
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Protocol No: CS001P3
above. The pharmacist will designate a kit for treatment for a specific subject by
entering the subject identifiers (given by the IVRS system) on the kit label. That
kit will be used for the exclusive treatment of that subject. The pharmacist will
dispense study drug on a daily basis for the subject (from the subject specific kit),
as required per protocol.
5.9.4 Return or Destruction of Study Drug
At the completion of the study, there will be a final reconciliation of all study drug
shipped, drug consumed, and drug remaining. This reconciliation will be logged
on the drug reconciliation form, signed and dated by the investigational
pharmacist at each investigative site. Any discrepancies noted will be
investigated, resolved, and documented prior to return or destruction of unused
study drug to the local/central drug depot for complete drug accountability in this
study. Drug destroyed on site will be accounted for and documented in the study
files and will be as per study site standard operating procedures (provided both
drug and drug labels are completely destroyed). A copy of each institution's drug
destruction protocol will be collected. lf directed by the sponsor, study drug may
also be returned to the sponsor or its designee. Separate instructions will be
provided for study drug returns by the designated supplier of study drug.
6. Study Procedures
6.1 Assessment and Tests (Groups l, 2 and 3)
1. Day minus three (-3) or the same day of treatment regimen with
cyclophospham ide (if scheduled) but before cyclophosphamide
administration (Group I only) and also for Groups 2 and 3 not receiving
cyclophosphamide (i.e., for all groups) at study randomization day:
a. CBC and ESR (Appendix 4)
b. Blood chemistry test (Appendix 4)
c. Vitalsigns (Blood pressure, temperature, pulse, respiratory rate) before
and 30 minutes after administration of cyclophosphamide
d. QOL assessment (as specified in Section 3.1.4.3)
e. Recording of Adverse Events
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2. Treatment regimen Days 1-19 (Groups 1 and 2)
a. Vital signs for Multikine treated group, Days 1-5, 8-12 and 15-19, before
and 30 minutes after administration of Multikine
b. Tumor measurements Day 1 and 15
c. CBC with differential , ANC Day 1
d. ESR Day 1
e. Recording of Adverse Events at all visits
For Groups 1,2 and 3:
3. Tests and examinations requested by the Principal lnvestigator for further
evaluations of symptoms described in the Daily Health Assessment Forms
and in other inquiries concerning the subjects' health status. Long term
follow-up (Section 6.5)
4. Record all concomltant medications received by subjects.
All medications [prescription, over-the-counter (OTC) medications, or
herbal preparationsl taken before enrolment into the study and continued
after screening visit must be documented on the concomitant medication
section of CRF. Medications started during study and different from
protocol-specified medication must be documented on the concomitant
medication section of CRF.
6.2 Administration of Protocol Required Medications and Study
Drug (Groups 1,2,31
6.2.1The follow¡ng medications and study drug are to be
administered as per protocol to subjects random¡zed to the
Multikine + CIZ + SOC group (Group 1):
1. Cyclophosphamide 300 mg/m2 (USP-grade or equivalent, commercially
available) administered as intravenous bolus on Day minus 3 of the
protocol regimen.
2. lndomethacin, 25 mg capsule (USP-grade or equivalent, commercially
available), administered orally three times daily (with food) on Days 1
through one day prior to surgery of the protocol regimen. Subjects should
bring bottles to each visit for counting to monitor compliance. Unless there
is a problem (i.e., <80% compliance), counts should be performed at a
minimum on Days 4, 8, 11, 15, 18 and between Days 22-28. lf non-
compliance is noted, the reasons should be identified and efforts made to
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Protocol No: CS001P3
rectify the problem. This should be documented on the subject's record
and on the CRF.
3. Multivitamin tablet(s) and/or capsule(s) with zinc (commercially available),
taken orally once daily on Days I through one day prior to surgery, and as
indicated for nutritional support (amount of zinc should be >15 mg and no
more than 40 mg per day).
4. Multikine 400 lU (as lL-2, total daily dose) (2.0 mL), one half (1 mL)
injected peri-tumorally (200 lU) and the other half (1 mL) injected peri-
lymphatically (2001U) on Days 1-5, 8-12 and 15-19 for a total of 15 daily
treatments, for all subjects randomized to receive Multikine treatment
(Appendix 2a, 2b and 3).
5. Cisplatin (only to those subjects as determined following surgical results -
per protocol definition - "High Risk") 100mg/m2 intravenously (lV) 1xlwk
weeks 1, 4 and 7 (or Day 1, 22, 43 of start of radiotherapy course) (Table
2 and Appendix 1).
6,2.2 Study Drug Administrat¡on (Group 2)
The following medications and study drug are to be administered as per protocol
to subjects randomized to Multikine + SOC (the non-ClZ) group (Group 2):
1. Multikine 400 lU (as lL-2, total daily dose) (2.0 mL), one half (1 mL)
injected peri-tumorally (200 lU) and the other half (1 mL) injected peri-
lymphatically (200 lU) on Days 1-5, 8-12 and 15-19 for a total of 15 daily
treatments, for all subjects randomized to receive either Multikine
treatment (Appendix 2a and 2b).
2. Cisplatin (only to those subjects as determined following surgical results -
per protocol definition- "High Risk") 100mg/m2 intravenously (lV) 1xlwk
weeks 1, 4 and 7 (or Day 1,22, 43 of start of radiotherapy course) (Table
2 and Appendix 1).
6.2.3 The following medications are g¡ven to subjects
random¡zed to SOC only group (Group 3)
1. Cisplatin (only to those subjects as determined following surgical results -
per protocol definition- "High Risk") 100mg/m'intravenously (lV) 1xlwk
weeks 1 , 4 and 7 (or Day 1 , 22, 43 of start of radiotherapy course) (Table
2 and Appendix 1).
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6.3 Post-Multikine Treatment Evaluations
Except for ltems 9 and 10 below, which are obtained during the time specified,
the following assessments and data are to be obtained between Days 21 and 28
following the first day of Multikine administration (i.e. after Multikine treatment,
but prior to surgery) for subjects in the group not receiving Multikine, this
evaluation will be done at baseline and or between study entry and surgery (and
all evaluations will be completed before the day of surgery).
Note: All evaluations are done for all subjects whether they received Multikine
treatment or not. Since there is no equivalent "experimental" treatment time
period for SOC only subjects, comparable baseline assessments are required for
evaluation of laboratory changes for all subjects not receiving Multikinetreatment
as listed below.
1. lnterim medical status, including review of medical history and physical
examination.
2. Vital signs and body weight.
3. CBC and ESR (Appendix 4).
4. Urinalysis (Appendix 4).
5. Blood chemistry tests (Appendix 4).
6. Appropriate evaluations of intercurrent diseases.
7. Clinical staging of the primary tumor and regional lymph nodes. Note
whether there are additional positive node(s) found during the physical
exam or whether there are clinical changes in the primary tumor or
nodes.
8. Measurement of the primary tumor and clinically positive regional lymph
node(s) documented using CT/MRl and photographs with ruler
measurements. The same imaging modality used in baseline for a lesion
should be consistently used during follow-up assessments.
Measurements done by physical means will record bi-dimensional
measurement of the primary tumor and clinically positive regional lymph
node(s) and be accompanied by color photographs (color electronic
camera photos are acceptable) with adjacent metric scale. RECIST
criteria (Appendix 10) will be used to evaluate the response of the
primary tumor to Multikinetreatment and the response to SOC therapy
during the course of the study.
9. Histological examination of the resected primary tumor and positive
lymph nodes for the presence of squamous cell carcinoma, grading of
tumor cell activity and evaluation of white blood cell infiltrate and other
host responses to the tumor. lt should be noted whether lymph nodes
found on physical examination are confirmed positive, negative or
whether there is evidence of previous tumor, but tumor cells are no
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Protocol No: CS001P3
longer evident or are dead. Total number of lymph nodes removed
during surgery and the number found to be positive by histologic
examination should be recorded. Surgery should occur between Days
29 and 38 for Multikine treated subjects and Group 3 subjects are
targeted for surgery between Days 8-38 (for subjects receiving SOC,
only) from the date of enrollmenVrandomization, unless indicated
medically othenrise.
10. Subject Compliance Assessment - final counts of indomethacin and
multivitamins with zinc to assess overall subject compliance will be
performed one day prior to surgery (or as necessary) and recorded on
the Concomitant Drug Log.
lf any result of items 1 through 5 and 7 is abnormal, appropriate examinations
and tests are conducted to document the extent, duration and appropriate
treatment of the abnormality and relatedness (if any) to study investigational drug
or other concomitant medication.
6.3.1 Tumor measurements (to be performed at baseline and one
day prior to surgery)
1. Measurement of the primary tumor and clinically positive regional lymph
node(s) documented using CT/MRl or photographs with ruler (metric)
measurements. The same imaging modality used at baseline for a
lesion should be consistently used during follow-up assessments.
RECIST criteria (Appendix 10) will be used to evaluate tumor response
to treatment.
2. Color photographs of the primary tumor with adjacent metric scale.
6.4 Standard of Gare
6.4.1 Dental Care
The subjects may be grouped into four Dental Care Categories in accordance
with the dental care problems they present with prior to irradiation.
DentalCateoorv 1
lncludes edentulous patients. They may require surgical removal of any
symptomatic cysts, infected retained root tips, or alveolar abscess/ hyperplasia.
These patients require hygiene instruction and precautionary instruction about
trauma with premature use of a prosthesrs.
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Protocol No: CS001P3
Dental Cateoory 2
lncludes those with poor dental hygiene, including those patients whose teeth
are beyond repair by ordinary dental procedures, those with generalized oral
sepsis, those with generalized periodontal disease, and those with chronic
periapical abscesses or granulomas. Procedures performed on this group
include removal of all remaining teeth prior to irradiation with primary closure and
surgical preparation of the alveolar ridges to laterally support a prosthesis. There
should be antibiotic coverage during the healing stage and adequate time prior to
the start of radiation therapy. These patients need complete hygiene instruction
and precautionary instruction about premature use of a prosthesis.
Dental Cateqorv 3
lncludes those in whom dental condition is fair, including those patients whose
teeth are restored, ordinary dental procedures, periodontal pockets are less than
3 mm deep, carious lesions are not in proximity to the pulp, and no more than 20
restorable carious lesions are present. X-ray examinations show at least 112 of
the bone still present around root surfaces. These patients require removal of
any teeth which are non-salvageable in accordance with the above and
restorations of the remaining teeth as required. The subjects are instructed for
dental prophylaxis and the subjects utilize custom-made fluoride carriers.
Dental Category 4
lncludes those in whom dental hygiene is good. This includes patients who do
not have severe malocclusion in whom few carious lesions are present. Carious
lesions are not in close proximity to the pulp and are correctable by conventional
methods. These patients require periodontal evaluation and dental prophylaxis
training, restorations as needed, no extractions prior to radiation therapy, and
fitting for custom carriers.
Extraction of Teeth Procedure
lf extraction of teeth is necessary prior to radiation therapy, the bone must be
contoured so that closure at the extraction site is possible. All loose spicules and
sharp projections must be removed. The approximation of the gingival tissue
must be such that the closure is neither too loose nor too tight. At least 10 days
are required for adequate healing prior to initiation of therapy.
6.4.2 Surgery
As a result of the RTOG and EORTC trials 8'e the oncology community has
adopted the RTOG/EORTC patient selection criteria and treatment regimens as
the current SOC that is: Patients with locally advanced primary SCCHN would
undergo surgery and be treated (post-operatively) with either radiotherapy or in
the presence of defined post-operative risk factors (lymph node involvement,
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Protocol No: CS001P3
extra capsular spread, etc.) with a prescribed concurrent radiotherapy and
chemotherapy (chemoradiotherapy) regimen.
Study subjects randomized to SOC only group (Group 3), will be scheduled for
surgery as soon as practicable but within I - 38 days of
enrollmenUrandomization. Multikine treated groups (Groups I and 2) will be
scheduled for surgery between Days 29-38 following enrollmenUrandomization
(however, Groups 1 and2 Surgery may also take place sooner, if medically
indicated). Surgery will consist of complete surgical resection of tumor and
involved nodes as indicated, followed by post-operative radiation therapy.
To clarify, in subjects where regression of tumor or lymph nodes is observed at
surgery a more sparing surgery than what was planned at randomization should
NOT be performed. The surgical plan and its execution (wide-margin tumor
resection and neck dissection) as decided on at study entry (randomization) for
each subject must be strictly followed, regardless of any response which may
have occurred in the time between study entry and surgery.
Note: All subjects in this trial that undergo surgery will also receive at least
radiation therapy following the surgical procedure (per protocol).
Histopathological examination of excised tumor margins is necessary to confirm
complete resection and assist in the determination of whether the subject is
"High Risk". Subjects who are considered "High Risk" (i.e., having involvement of
2 or more lymph nodes or extracapsular nodal spread or positive tumor margins)
will receive concomitant chemoradiotherapy (per protocol as described below). A
general description of procedures is as follows:
6.4.2.1 Tl and T2 Disease
Complete resection of localized tumors followed by radiotherapy or
chemoradiotherapy as necessary. For T2 lesions that are invasive, local excision
of primary lesion followed by radiotherapy or chemoradiotherapy (for "High-Risk"
only).
For oral tongue T1 disease, local excision followed by radiotherapy or
chemoradiotherapy (for "High-Risk" only). ForT2 disease, hemiglossectomy and
selective nodal dissection.
6.4.2.2 T3 and T4 Disease
Neck dissection for subjects with cervical lymphadenopathy (or for "High-Risk" of
occult metastases), followed by radiotherapy or chemoradiotherapy for "High-
Risk" only.
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Protocol No: CS001P3
Table 4. 
Summary of Surgery, Radiotherapy and Ghemotherapy (SOC)
*Chemotherapy: cisplatin bolus iv infusion, 100
x 3 weeks (on weeks 1,4 and 7 or Days 1,22,43 oÍ
radiotherapy course given within t3 days for each scheduled day of administration of chemo during the
radiotherapy period) to start on Day one of radiotherapy if indicated (i.e. in "High - Risk" subjects) to start on
Day one of radiotherapy if indicated (i.e. in "High -Risk" subjects).
6.4.3 Radiotherapy
lntensity modulated radiation therapy (IMRT) is the latest method of increasing
the therapeutic ratio of radiation treatment. There have been no reports of
prospective randomized clinical studies using IMRT, therefore IMRT's impact on
clinical outcome is not known, and the technique carries with it a number of
potentially difficult problems that still need to be addressed. With IMRT, it is
much more difficult than with 3D conformaltherapy to verify that treatment has
been delivered correctly to the subject. At present, IMRT is not the standard of
care for the treatment of head and neck cancers; however, selected subjects
may benefit from this new technology if they are treated in centers that have
expertise in IMRT.
This protocol stipulates that adjuvant radiation therapy is delivered using
conventional external beam techniques with standard radiation fractionation. ln
instances where the investigator has reason to believe that deviation from this
prescribed radiation administration schema would materially benefit the subject
with improved outcome, a waiver to change the radiation therapy treatment plan
would be granted by the study's medical monitor, but only on a case by case
basis.
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TNM Classification
Primary Surgical Treatment
Radiotherapy
Concurrent
Chemotherapv*
Resectable, T34, N0
Excision of primary and
reconstruction as indicated and
unilateral or bilateral selective
neck at risk dissection.
External RT
60 - 70 Gy in 30-35
fractions for 6-7 weeks
N1: excision of primary,
ipsilateral com prehensive neck
dissection (levels 1-5) t
contralateral selective neck
dissection. Reconstruction as
indicated.
External RT
60- 70 Gy in 30-35
fractions for 6-7 weeks
Resectable, T 1-4,
N1-2
N2; excision of primary,
ipsilateral or bilateral
comprehensive neck dissection
(levels 1-5). Reconstruction as
indicated.
External RT
60 - 70Gy in 30-35
fractions for 6-7 weeks
High-Risk Subject
Category
1 Positive margins or
2 Nodal involvement (>
2 positive nodes) or
3. Extracapsular nodal
spread
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An independent Radiotherapy Quality Assurance Committee (iRTOA) will be
formed and will conduct radiotherapy QA, to assure radiotherapy (RTx) quality.
The committee will have responsibility for assuring that all participating
institutions have the equipment, personnel and procedures necessary to
administer radiation in doses that are clinically comparable to those of other
participating institutions The monitoring tools to be used may include on-site
dosimetry and ports reviews; remote auditing tools and adequacy of proposed
radiation therapy per site anthropomorphic phantoms and reviews of benchmark
and actual protocol subject treatments at time of treatment and at the end of the
study. The radiation therapy committee as determined by the iRTQA (for this
study) will include at minimum, a radiation oncologist (with H&N experience) and
an H&N surgeon.
The |RTQA willfocus on the following areas:
RTx Treatmenf - assess the RT treatment plan and protocols, as well
as training and instrumentation at each participating institution
RTx Adequacy- assess the adequacy ofthe RT therapy at the end of
the trial
6.4.3.1 Treatment
Dose: Total dose will be >60Gy but not exceeding 70Gy in 30 - 35 fractions:
2 Gy once a day, five days a week for six (to seven) weeks. All "High-Risk" sites
(defined as microscopically involved resection margins, areas with >2 positive
nodes, and extracapsular spread of tumor from neck nodes) shall receive 70 Gy
and all sites may receive 60 Gy. A conedown boost of up to 6 Gy delivered in 3
fractions (2 Gy each) over 3 days will also be administered to the "High-Risk"
site(s) only. A minimum of 54 Gy must be delivered to low risk sites; (e.9. areas
requiring radiation that are distant from the region that rendered subject high-
risk).
The protocol doses will be specified at the center of the target volumes (at
central axis in the midplane for parallel opposed beams or at the intersection of
the central axes of multiple beams). The protocol dose to the hiqh-risk target
volume will be 70 Gy in 6 weeks. To the low-risk target volume, it shall be at least
54 Gy, al2 Gy per day, but may receive 60 - 70 Gy. For a subject who has a T1
tumor of the oral tongue that is resected without any tumor at the margins, and
also has at least two involved nodes in the mid to low anterior cervical region, it
is permissible to treat lateral fields which encompass the oraltongue region to 54
Gy and to treat the dissected hemi-neck to 60 -70 Gy. Alternatively, a subject
who has a T3 floor of mouth lesion that is resected, but has microscopic
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Protocol No: CS00'lP3
involvement of the margins of resection, and who also has only a single
ipsilateral high cervical node containing tumor, needs to have the lateral fields
directed to the primary tumor treated to 60 - 70 Gy, but could have the neck field
treated to only 54 Gy. Dose non-uniformity within the target volume should be
kept to within ! 5 o/o of the protocol dose. lf larger differences are anticipated due
to contour changes of the neck, then this should be reduced by the use of tissue
compensators or appropriate fields reductions. The dose to clinically uninvolved
"electively treated" areas of the undissected lower neck will be 44 Gy at a depth
of 3 cm.
The dose to the structures anterior to the spinal cord (mid-vertebral body) is to be
calculated at the central axis midplane. Posterior to the spinal cord, the dose is
calculated at a point I cm below the skin surface.
The maximum dose to the spinal cord and the length of spinal cord irradiated
must be recorded for each field. The direct beam dose to the spinal cord must
not exceed 45 Gy. The maximum dose to spinal cord is likely to occur at the
junction of upper and lower field. Details of dose calculation at the junction must
be provided.
Localizing films and all images (or the electronic files) of each radiation field will
be taken and made part of the subject's medical record together with a copy of
the treatment prescription and initial calculations. Localization films and machine
portal films will be made on all fields and repeated at the time of any field change
and must be submitted in advance of therapy to the ¡RTQA for approval of the
radiation therapy for a specific type of tumor, tumor stage and tumor location.
lnstitutions that cannot provide electron beams portal films may substitute a
Polaroid picture of the electron beam portal.
Cumulative isodose distributions 1 cm from top of the lateral fields, 1 cm from the
bottom of the lateral fields, and at the center, and a copy of the treatment record
indicating cumulative doses must be submitted at the completion of radiotherapy.
The entire operative bed must be included in the treatment portals. A
combination of lateral opposing fields, anterior and lateral wedged fields, or
several beam-directed fields will be used for the primary tumor site at the
discretion of the investigator. A single anterior A-P field with a mid-line block
approximately 2 cm wide will be used to treat the neck below the fields for the
primary tumor. This lower neck field should abut the primary field at the skin.
Administration: Radiotherapy should begin as soon as adequate healing after
surgery has been established. Normally, this will be within 24 weeks of the
surgical procedure but RT must be started no later than I weeks (56 calendar
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Protocol No: CS001P3
days) followíng surgery. For all groups, radiation and chemotherapy must begin
on the same day post surgery.
A continuous course should be maintained if at all possible. lf the radiation
reaction requires an interruption of therapy, this should be kept to a minimum
and reported on the CRF. Daily dose reduction to 1.8 Gy is allowed only if a
treatment break has become necessary and must be fully documented on the
CRF.
6.4.3.2 Primary Treatment Fields Tumors by Site
Oral Tongue, Cheek (Buccal Mucosa) and Floor of the Mouth
The primary tumor is to be radiated in the postoperative setting to a dose of 60 -
70 Gy based on institutional preference. Radiation fractions should be 2.0 Gy
each. The neck should be treated in the following fashion:
lnvolved nodal stations:
o 60-66 Gy (2.0 Gy/fraction)
Uninvolved nodal stations:
o 44-64 Gy (1.6 - 2.O Gylfraction)
Adequate protection of the spinal cord is to be observed
Soft Palate
The primary tumor is to be radiated in the postoperative setting to a dose of 60 -
70 Gy based on institutional preference. Radiation fractions should be 2.0 Gy
each. The neck should be treated in the following fashion:
lnvolved nodal stations:
o 60-66 Gy (2.0 Gy/fraction)
Uninvolved nodal stations:
o 44-64 Gy (1.6 - 2.0 Gylfraction)
a
a
a
a
Adequate protection of the spinal cord is to be observed.
(As recommended by the National Comprehensive Cancer Network (NCCN)
Head and Neck Cancers v.1.2010) 83'
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Lower Neck Field
An undissected clinically uninvolved neck must receive at least 45 Gy at 3 cm
depth. The lower border of the field will include the supraclavicular nodes and
must be below the clavicles.
6.4.3.3 Rad ioprotective Agents
There is insufficient evidence that radioprotective agents, such as Ethyol@
(amifostine), offer clinically significant protection of parotid glands. Therefore,
administration of such agents is not encouraged, but their use is left up to the
discretion of each investigator.
6.4.3.4 Tech nical Factors
lrradiation will be given with cobalt teletherapy, supervoltage energy equipment
(1-6 MV), or electron beams. The treatment distance will be 80 cm or more to the
isocenter. Allfields are to be treated each day. The beam should be shaped with
blocks to avoid unnecessary irradiation of normal structures.
6.4.3.5 Radiation Treatment lnterruptions for Toxicity
lnterruptions in treatment may be necessitated by skin reaction, mucositis,
ulceration, edema or other acute radiotherapy complications.
ln general, NCI CTC AE Grade 3 toxicity (Appendix 8) may warrant treatment
interruption but this will be left to the discretion of the treating physician. NCI
CTC AE Grade 4 non-hematologic toxicities will require treatment interruption
untilfunctioning has improved as evidenced by clinical examination and
supportive laboratory results (as appropriate). Any hospitalization for
management of an adverse event will require radiation interruption until the
subject is well enough to be discharged.
Regarding hematologic toxicity, radiation therapy will be delayed for
ANC < 1000/mm3 or platelet count of < 50,000/pL. Counts will be obtained twice
weekly while subject is on break and treatment resumed when counts are
ANC > 1000/mm3 and platelets are > 50,000/pL.
The reason for and the length of an interruption must be documented in the
medical records and on the appropriate CRF.
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6.4.3.6 Appropriateness of Radiation Therapy
Protocol No: CS001P3
An independent radiotherapy quality assurance committee (¡RTOA) will be
formed consisting of radiation oncologist(s) and head and neck surgeon(s) to
review treatment plans during the trial and evaluate the adequacy of the therapy
at the end of the study. All radiation treatment information (port films, dosimetry,
simulation films, etc.) will be submitted to the review committee for quality control
review of the technical adequacy of the treatment as delivered. The guidelines
and definitions of the committee's task will be defined prospectively.
6.4.4 Ghemotherapy: Cisplatin (U.S.P. or equ¡valent) lV Bolus
Infusion
Subjects with identified "High-Risk" factors [tumor margins unclear or infiltrative,
local invasion, nodal involvement >2 lymph nodes or extracapsular nodal
spread)l will receive chemotherapy concurrently with radiotherapy.
6.4.4.1 Adm inistrat¡on (Gisplati n)
"High-Risk" subjects will receive three courses of cisplatin (lV bolus). Each
course of chemotherapy will consist of cisplatin (100 mg/m2) given as an lV bolus
infusion over 1-2 hours with pre-hydration and diuretics. Chemotherapy will be
given on weeks 1,4 and 7 (e.9., on days 1,22, and 43 of radiotherapy plus or
minus 3 days) concurrently with radiotherapy. First dose of cisplatin will be given
on the same day as the first dose of radiation therapy; chemoradiotherapy must
commence within 8 weeks of surgical procedure aimed at removing the H&N
tumor and any involved lymph nodes.
6.4.4.2 Formu lation (Cisplatin)
Cisplatin (USP or equivalent) is available in the following formulations:
10 mg lyophilized vial, containing Mannitol 100 mg and
sodium chloride, 90 mg;
50 mg lyophilized vial, containing Mannitol 500 mg and
sodium chloride 450 mg;
I mg/ml solution of cisplatin in normal saline, 50 or
100 mL vials.
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a
a
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Protocol No: CS001P3
6.4.4.3 Storage (Gisplatin)
Room temperature.
6.4.4.4 Preparation (Cisplatin)
Cisplatin powder for injection is reconstituted by adding 10 or 50 mL of sterile
water for injection to a vial labeled as containing 10 or 50 mg of the drug,
respectively, to provide solutions containing I mg/mL.
6.4.4.5 Pharmacology and Pharmokinetics (Cisplatin)
The dominant mode of action appears to be the inhibition of incorporation of DNA
precursors although protein and RNA synthesis are also inhibited. Cross linking
of DNA has also been shown. Plasma levels of cisplatin decay in a biphasic
mode with an initial half-lite oÍ 25 to 49 minutes and a secondary phase ranging
from 58 to 73 hours. This prolonged phase is due to protein binding which
exceeds 90% of the radioactivity in the second phase. Urinary excretion is
incomplete with only 27 to 45% of the radioactivity excreted in the first five days.
Although this drug seems to act as an alkylating agent, there are data to indicate
that its mode and sites of action are different from those of nitrogen mustard and
standard alkylating agents. Also, there appears to be potentiation of other anti-
tumor agents by cisplatin in tissue culture, animal tumor models and in early
human work. Studies have shown that cisplatin has no cell cycle dependency
and that cytotoxicity of this agent is similar in all stages of the cell cycle.
6.4.4.6 Toxicity (G isplatin)
Toxicity includes nausea, vomiting, alopecia, decreased Mg and Ca, elevated
SGOT and SGPT, anorexia, renaltoxicity (with elevation of BUN, creatinine and
impairment of endogenous creatinine clearance), ototoxicity (with hearing loss
which initially is in the high frequency range, as well as tinnitus), and
hyperuricemia. Much more severe and prolonged toxicity has been observed in
subjects with an abnormal or obstructed urinary excretory tract.
Myelosuppression, often with delayed erythrosuppression, is expected. The nadir
white cell and platelet counts occur at about two weeks with recovery generally
at about three weeks after initiation of therapy. Peripheral neuropathy and acute
myeloid leukemia have been reported in a few cases where long-term cisplatin
was used in combination with other forms of therapy.
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6.4.4.7 Supplier
Any commercially available USP or equivalent grade product.
6.4.4.8 Chem otherapy Dose Mod ifications (G isplati n)
Protocol No: CS001P3
Neutropenia may occur. lf on the day of scheduled treatment with cisplatin (Day
22 and 43), the absolute neutrophil count (ANC) is < 1000/mm', hold
chemotherapy (cisplatin) treatment until ANC > 1000/mmt then treat at 1OO%
dose. ANC counts are to be obtained two times per week until neutrophil
recovery is documented.
Thrombocytopenia may occur. lf on the day of scheduled treatment with cisplatin
(Day 22 and 43), the platelet count is < 75,000/pL hold treatment until platelets
are > 75,000/pL then treat at 100% dose. Platelet counts are to be obtained two
times per week until platelet recovery is documented.
Neurotoxicitv: The most typical expected neurologic toxicities attributable to
cisplatin therapy are peripheral sensory (including hearing loss) and motor
neuropathies. Dose adjustments for neurotoxicity are as follows:
. Grade 1 - no change
. Grade 2 - reduce cisplatin by 25o/o
. Grade 3/4 - omit cisplatin therapy. Cisplatin may be re-initiated at a 50%o
dose reduction at the next scheduled administration if neurotoxicity has
resolved to Grade 2 or less.
6.4.4.9 Antiemetic Regimen for Cisplatin Administrat¡on
An antiemetic regimen for high emetic risk chemotherapy should be administered
with each cisplatin dose but should be based on the standard of care within each
institution where the therapy will be administered. Suggested components of this
antiemetic regimen are:
. Dexamethasone lV or po given prior to chemotherapy and at daily doses
for three days following cisplatin administration.
. A serotonin (5-HT3) antagonist on the day of chemotherapy
. A Neurokinin 1 antagonist (if available) on the day of chemotherapy and
daily doses for two days following cisplatin administration.
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Protocol No: CS001P3
Lorazepam as needed on the day of chemotherapy and for up to 3 days
following
H2 blocker or proton pump inhibitor as needed.
6.4.4.10 Renal Toxicity
Cisplatin should be administered on the scheduled day of treatment using the
following guidelines:
a
a
Creatinine
> 1.2*
> 1.2*
Creatinine
Clearance (CrCl)
> 50 ml/min.
'100 mq/m'
40-50 ml/min.
lzlmotm'
< 40 ml/min
Discontinue
*lf creatinine is > I 2, creatinine clearance must be done in order to
make dose adjustment.
Creatinine clearance may be estimated by Cockcroft-Gault formula as long as
the creatinine is not changing rapidly; otherwise determine 24-hour urine
collection. Nomogram to calculate creatinine clearance is:
CrCl Male = (140 - aqe) x (wt. in kq)
(mUmin) (SCr) x (72)
CrCl Female = 0.85 x (CrCl male) where CrCl = Creatinine clearance and
SCR = serum creatinine
Note: Although some subjects receiving Multikine will receive
cyclophosphamide, indomethacin, and vitamins with zinc (+ClZ), subjects
receiving SOC will not receive these drugs (as control) as there is no
known anti-tumor benefit shown as a result of administration of the low
doses of these drugs when administered alone (i.e. without an
immunomodulator) to cancer subjects. SOC subjects will also not receive
"mock" injections because of associated morbidity and lack of benefit.
6.4.5 Safety follow-up
Every subject (in this trial) will attend a safety evaluation follow-up visit
approximately 30 days (28-35 days) following the last radiotherapy (or
chemoradiotherapy) treatment. The following tests will be performed:
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Protocol No: CS001P3
a. CBC and ESR (Appendix 4)
b. Blood chemistry test (Appendix 4)
c. Urinalysis (Appendix 4).
d. Vital signs (Blood pressure, temperature, pulse, respiratory rate,
weight)
e. Physical Exam
f. EKG
g. lnterim medical status including adverse events and inter-current
illness
Appropriate monitoring and treatment of ongoing AEs will continue as standard
of care.
6.5 Long-term Follow-up
Subjects will be followed-up after the completion of study drug and standard of
care related procedures for a period of up to 30 to 36 months (duration of follow-
up is event driven). The purpose of long-term follow-up is to assess the subject's
medical condition and to determine if there is evidence of disease progression
and the effect of treatment on overall survival. The first visit will occur 2 months
after the last radiotherapy/chemoradiotherapy treatment. ln addition, any AE
elucidated by the investigator at scheduled visits during long-term follow-up will
be entered in the CRF.
The following assessments will be performed every 2 months for the first year,
every 3 months for the second year, then every 4 months thereafter for the third
year. Subjects will be assessed for the following outcomes until death:
. Survival
o lnterim Medical status including adverse events and inter-current
illness
. Physical exam including performance status and weight
. Tumor measurements onlv if clinicallv indicated (as specified in
Section 6.3.1)
. Progression (loco-regional, distal)
. Quality of life (Section 3.1.4.3)
. TSH levels checked every 6-12 months beginning 6 months after
completion of radiation treatment.
. Toxicities including serious and unexpected adverse events.
. CT scans only if clinically indicated (as specified in Section 6.3.1)
. CBC with differential, ANC
. ESR
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Protocol No: CS001P3
Unscheduled subject visits, which result in the documentation of disease
progression, shall have this data recorded in the medical record and in the CRF
ln addition, the assessments noted in Section 6.5 (above) will be performed.
6.6 Safety and Efficacy lnteruals of lnterest
The safety observation interval extends to 30 days after completion of the
treatment regimen; i.e., 30 days following the last administration of radiotherapy
or concurrent chemoradiotherapy. ln addition, serious and unexpected adverse
events will be collected through the three year follow-up interval.
Efficacy information will be collected for up to 30 to 36 months (duration of follow-
up is event driven) post-randomization (for each trial subject) as follows:
1. Tumor assessments will be recorded at baseline before administration of
randomized study treatment and prior to surgery. The measurable lesions
will be tumor or positive lymph node(s) defined by RECIST criteria. The
most appropriate imaging modality determined by the investigator will be
used which can include physical examination, digital photography using
rulers, X-ray, CT scan or MRl. The same imaging modality will be used for
subsequent tumor assessments at scheduled follow-up visits after surgery
and radiochemotherapy.
2. The histological characteristics of the resected primary tumor will be
reviewed by a qualified pathologist. Clinically positive lymph node(s) will
also be evaluated by the pathologist to determine whether it (they) is (are)
positive, negative or show(s) evidence that it (they) was (were) previously
positive, but cancer cells are either no longer present or have undergone
necrosis. Tumor cell activity and host immune responses will be compared
for changes in these parameters per se, and for correlations with changes
in the size of the primary tumor before and one day or just prior to surgery.
The Study definitive histological evaluations of tumor specimens (frozen
and/or paraffin block) for the trial population will be conducted by a Central
Pathology Laboratory. lt is intended that sections obtained from all
subjects participating in the trial, along with sections similarly collected
and processed from untreated subjects, will be evaluated for T-cell and
other white blood cell infiltrations into the tumor and in the marginal tissue
around the tumor as well as other tumor cells parameter (Appendix 4).
3. Date of death and cause, if available.
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6.7 Genomic Microarray - A Stand Alone collaborative study
(with the US NIH/NGI) that derives its samples from the subjects
of this Phase lll study
For those subjects who have consented for the genomic microarray study, two
samples of tumor (and any clinically involved lymph nodes) biopsy specimen (as
well as PBMCs) will be collected. One sample will be collected before treatment
(e.9., injection of Multikine) at time of screening (FNA or core/punch biopsy) and
another sample will be collected at the time of surgery from the surgical
specimen. Samples for the genomic microarray study will be obtained from
patients only in those countries where the health authorities have approved of
this testing. Subject participation in the genomic microarray component of the
study, which requires lnstitutional Review Board (lRB) / lndependent Ethics
Committee (lEC) approval, is optional. Refusal to participate will not result in
ineligibility for the main part of the clinical study. Any subject that consents to
participate in the genomic microarray study will not be identified and the samples
obtained from all individuals will be blinded. ln no way will the samples be
traceable back to the specific individual that consented to allow their samples to
be tested for genomic microarray (in the collaborative study with the US
NrH/NCr).
6.7.1 Rationale for DNA Collection
Genetic differences within the population can be an important contributory factor
in inter-individual variability in response to drug and can also serve as a marker
for disease susceptibility and prognosis. An association between gene
expression and clinical outcomes may help to identify a population subgroup that
is likely to better respond to or better tolerate the drug thereby maximizing benefit
and minimizing risks. Therefore; biopsy samples, as well as blood samples, will
be collected in this clinical study in order to help address emerging clinical issues
and to develop a safer and more effective personalized drugs in the future.
There are two parts to the genomic microarray component of this study. Part I
allows using tumor biopsy (FNA or core/punch biopsy at study entry, and tumor
samples obtained from resected tumors at surgery) and blood samples for
analysis of gene expression using genomic microarray. Pa¡t2 allows for the
storage of biopsy samples for future testing. Subjects will be given the option to
participate in Part 1, Part 2, both parts, or neither part of the genomic microarray
study (where local regulations permit).
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6.7.2 DNA Sample Disposition Procedures for Genomic
Microarray Testing
Protocol No: CS001P3
lnstructions on sample handling, labeling, and shipment are given in Appendix 4.
The details of the subject will be blinded using unique code. A subject may
withdraw consent for genomic microarray testing at any time, and still remain in
the study. lf a subject withdraws consent for genomic microarray testing; any
biopsy sample extracted or obtained from the subject's blood will be destroyed,
provided that the sample has not yet undergone conversion to the blinded
format. The investigator must notify the sponsor (or designee) site contact, who
will request sample destruction using the withdrawal of consent for genomic
microarray testing form. The investigator will receive written confirmation from
the sponsor or designee that the biopsy sample for genomic microarray can be
destroyed before converting to non-identifiable blinded codes. lf the sample has
already undergone conversion to the non-identifiable format, then the sponsor or
designee will notify the investigator in writing.
6.8 Blinding of Central Lab Specimens and lmaging Data
This study will have a number of central laboratories, where specimens or results
of imaging, and lab values will be collected and analyzed for the study. These
laboratories are:
(1) A Central Pathology Laboratory - the central pathology laboratory
will receive coded samples (Paraffin embedded and frozen sections of
tumor or lymph node) from all the subjects participating in this study.
The samples will be coded prior to shipment to the Central Pathology
Lab. The pathology lab reader will be unaware of the subject's medical
history, subject's treatment arm, or clinical outcome.
(2) A Central lmaging Genter - the central imaging center will catalogue
and read all imaging (X-rays, CT, MRl, etc.) from allsubjects
participating in this study. All images will be coded by the Central
lmaging Center prior to shipment to the central imaging radiologist(s)
for reading by the central radiologist(s) who will be unaware of the
subject's medical history, subject's treatment arm or clinical outcome.
(3) A Central Laboratory Data Genter - the central laboratory data
center, will house all clinical laboratory data (values) taken / recorded
for each subject participating in this study. All laboratory data (values)
will be coded prior to transfer to the central laboratory data center for
analysis. A central Medical Monitor will evaluate all the laboratory
values for all the subjects participating in this study.
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Protocol No: CS001P3
Note: Blinding of all samples collected for the stand-alone genomic microarray
collaborative study to be conducted at the NIH/NCI (USA) will be done at the sample
collection source or at a regional "central collection" laboratory. All samples collected for
the independent genomic microarray study shall be coded in such a way as to not allow
any subject specific identifying information to accompany the sample to the NIH/NCl.
The only information the samples will be able to be connected with is if the samples
were collected before or after definitive treatment. ln addition, but only at a later point
(after the code has been broken) the samples will only be able to be traceable to the
specific arm in the study the samples came from. Under No Circumstance will any
sample destined for the stand-alone NIH/NCl collaborative genomic microarray study be
traceable back to its specific donor.
6.9 Unblinding of Central Lab Specimens and lmaging Data
The initial data analysis for DNA microarray will occur after samples from the first
40 subjects have undergone microarray testing. The final data analysis will occur
at the end of the study. The blinding code will be broken at the time of initial
analysis and during final data analysis of DNA m¡croarray results. While breaking
the blinding code for DNA microarray, only details of treatment received and
study visits will be revealed but the details of individual subjects will continue to
remain blinded perpetually - and not be revealed at any point of time after
completion of study.
Unblinding of Central lmaging data, Clinical Lab data (not DNA microarray) and
Central Pathology Laboratory Data will occur at the time of statistical analysis (or
at the request of the |DMC). Unblinding of Central lmaging data, Clinical Lab data
and Central Pathology Data will reveal allthe details of each of the subject's
visits, including the treatment received, and study visit dates specific for each
subject in the study, study arm, etc.
7. Statistical Gonsiderat¡ons
7.1 Study Design
This is a Phase lll open-label, multi-center, randomized study to determine the
efficacy and safety of peri-tumoral and peri-lymphatic injection of Multikine
(400 lU as lL-21 daily dose for 3 weeks at 5 times per week) given prior to SOC
The following treatment groups will be enrolled:
(1) Multikine + CIZ + SOC
(2) Multikine + SOC
(3) SOC alone
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Protocol No: CS001P3
7.2 Primary hypothes¡s and analyses
The primary hypothesis will compare overall survival in the Multikine + CIZ +
SOC group to that in the SOC alone group for superiority of the former.
Overall survivalwill be accessed via a Kaplan-Meier life-table and compared
using a log rank test and confirmed further with stage-, location-, and
geographic-stratified log rank tests. The unstratified logrank test constitutes the
primary analysis. Further details on the statistical analyses can be found in
section 7.9.
7.3 Secondary Hypotheses and Analyses
The following secondary comparisons are also planned
(1) Overall survival in Multikine + SOC vs. SOC
(2) Progression Free Survival in Multikine + CIZ + SOC vs. SOC
(3) LRC in Multikine + CIZ + SOC vs. SOC
(4) OOL in Multikine + CIZ + SOC vs. SOC
The Holmsa closed-sequential procedure will be used to control the type I error
probability to at most 0.05. The analysis of the secondary hypotheses is
described in section 7.9.
7 .4 Tertiary Hypotheses and Analyses
The following tertiary comparisons are planned:
(1) Equivalence between overall survival in the Multikine + CIZ +
SOC vs. Multikine + SOC
(2) Tumor response in Multikine + CIZ + SOC vs. SOC
The equivalence between overall survival in the Multikine + CIZ + SOC vs.
Multikine + SOC will be explored by constructing a 95% two-sided confidence
intervalto rule out a 10% 3-year overall asymptotic survival difference for
Multikine+ CIZ + SOC vs. Multikine + SOC. The analysis of the tumor response
is described in section 7.12.4 below.
Tumor response as assessed by dimensional analysis (e.9., physical
measurement, CT scan, etc), is not expected to yield data that will reflect the
efficacy of this (Multikine immunotherapy) treatment. ln fact, it has been shown
in Phase I and ll studies that, tumor measurements were not reflective of the
tumor status in subjects treated with Multikine (or in other studies with immune
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Protocol No: CS001P3
stimulating drugs). The reason for that is that through relatively short period of
time of drug administration prior to definitive surgical removal of the tumor (3
weeks in this study), the treatment with Multikine (an immuno-stimulatory drug)
markedly increases the immune cell infiltrate into the tumor bed, such that the
tumor may appear larger (by dimensional measurement). However, when the
tumor is removed, at surgery, and tumor sections representative of the whole
tumor are analyzed by pathology, the pathology results indicate that the tumor
bulk is largely made of immune cell infiltrate and not tumor cells. Thus, physical -
dimensional measurement does not necessarily reflect on the efficacy of
immune-stimulating drugs, and tumor size change is not expected to be a useful
measurement for assessing the efficacy of this treatment modality.
7.5 Randomization
An lnteractive Voice Response System (IVRS) will be used for randomization
and stratification. Subjects will be randomized in a 3:3:1 allocation with Multikine
+ SOC (without CIZ) being the treatment group to be assigned least often in
contrast to Multikine + CIZ + SOC and SOC alone. Subjects will be stratified by
country, by tumor location (tongue, floor of the mouth, check and soft palate),
and tumor stage (Stage lll: and Stage lVa T4a (N0-2, T1-3N2) [see Table 3 -
TNM Categories and corresponding stage permitted in this triall.
A dynamic randomizationsl'82 will be used to promote balancing across study
sites within a country and globally.
7.6 Sample Size Rationale
Historical basis
Current SOC for SCCHN adopted by the oncology community [includes: post-
operative concurrent chemoradiotherapy (CRTx) or radiotherapy (RTx)l is based
on trials conducted by the Radiation Therapy Oncology Group (RTOG - NEJM
2004; 350(19): 1937), and the European Organization for the Research and
Treatment of Cancer (EORTC - NEJM, 2004; 350(19): 1945). Both trials
demonstrated improvements in the 3-year Overall Survival rates: an absolute
increase of 12 % (48% vs. 60%) for the EORTC study and an absolute increase
of 10o/o (47% vs. 57%) for the RTOG study.
This study will assume a 55o/o 3-year overall survival rate for SOC alone. This
assumes 7O-8Oo/o of the subjects will be lower risk at the time of surgery; sample
sizes will be smaller if a higher percent turn out to be at high risk. As for the
EORTC and the RTOG studies, a 10o/o absolute gain in overall survival is
regarded as being clinically meaningful. The primary study goalto test Multikine
+ CIZ + SOC superiority vs. SOC alone will be to reject the 55% 3-year overall
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ProtocolNo:Cs001P3
survival rate for SOC alone against a 650/o 3-year overall rate for Multikine + CIZ
+ SOC.
7.7 Assumptions and Galculations
The primary comparison will be based on 80% power and a two-sided 5% Type I
error to detect a 10o/o absolute survival advantage at 3 years (55% vs. 65%).
Assuming exponential hazards, this yields a hazard ratio of 0.721. For this
comparison, the log rank test will require a total of 298 deaths. The trial will be
conducted as an event-driven trial, and will conclude once a total 298 deaths
have been observed.
Since death certificates should be available for virtually all subjects, the
calculations assume no losses to follow-up for overall survival. A 24 month (total)
recruitment period and a 30 month follow-up period yields a sample size of 336
subjects in each of the Multikine + CIZ + SOC and SOC alone groups. Under a
3:3:1 randomization, this yields 112 subjects in the Multikine + SOC group for a
total estimafe of 784 subjectsEs.
7.8 Study Populations
The key study populations will be defined as follows
lntent to Treat (lTT) Population:
All subjects who are randomized, regardless of treatment and trial
group (Multikine treatment or SOC), will be included in the ITT
analysis. The rationale for this is motivated by the open-label design.
Thus, investigators should make all efforts to ensure that subjects are
compliant, complete the protocol specified treatment regimen, follow
the subsequent standard of care regimen, and may be followed for up
to 36 months (duration of follow-up is event driven).
a
a
Per Protocol Population:
Phase ll clinical studies 26 have demonstrated that objective tumor
response in H&N cancer subjects requires at least 5 Multikine
injections (administrations) per week for a 2 week period. Another
Phase ll study 28 demonstrated objective tumor responses and marked
anti-tumor immune responses when subjects were given 5 injections
per week for 3 weeks. These results suggest that a "minimum" number
of Multikine injections may be necessary for responses to be
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Protocol No: CS001P3
demonstrable. Other studies have indicated a supportive role for
administration of Clz86' 87' 88' 8e in SCCHN. Factoring in an expected
low rate of "missed" injections (possibly 1-3, over a 3 week period), the
"per-protocol" subject population is defined as those subjects receiving
12 injections (administrations) over the 3 week treatment period.
Therefore, the per-protocol population will be defined as follows:
(a) Multikine + CIZ + SOC Arm (Group l): Eligible subjects receiving
12 Multikine injections (administrations) as randomized, having
completed surgery (as defined in the protocol) and receiving at least;
cyclophosphamide lV (as defined in the protocol), 2 courses of
cisplatin (if as a result of surgical findings the subject is slated for the
concurrent chemoradiotherapy sub-group treatment) and receiving
75%o of indomethacin, TS%o of scheduled radiation, and at least 75% of
all other protocol required treatments.
(b) SOC Arm (Group 3): Eligible subjects having completed surgery
(as defined in the protocol) as randomized and receiving at least two
courses of cisplatin (if as a result of surgical findings the subject will
receive the concurrent chemoradiotherapy as a sub-group treatment)
and receiving at least 75% oÍ all other protocol required treatments
(e.9.,75% of all scheduled radiation).
(c) Multikine Treatment + SOC Arm(Group 2): Eligible subjects
receiving 12 Multikine injections (administrations) as randomized but
without administration of any CIZ components, having completed
surgery (as defined in the protocol) and receiving at least 2 courses of
cisplatin (if as a result of surgical findings the subject will receive the
concurrent chemoradiotherapy as a sub-group treatment) and
receiving at least 75% of all other protocol required treatments (e.9.,
75% of all scheduled radiation).
Safety Population
a
All subjects receiving any study therapy such as one or more injections
of Multikine, any CIZ components, or surgery will be included in the
safety population.
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7.9 Missing Data Conventions
Protocol No: CS001P3
Subjects who are enrolled, but who do not receive Multikine treatment or surgery
(for the SOC group) will be replaced. Subjects who receive Multikine but do not
undergo resection will also be replaced. Data from the subjects that were
replaced will be included in the efficacy analysis for only the ITT population.
Subjects who are removed from the study for reasons related to drug toxicity will
not be replaced.
Tumor measurement, quality of life, and Karnofsky status will be analyzed using
longitudinal GEE models in the ITT analysis and in the analysis of treated per
protocol subjects (see Section 7.8 for definition). Missing measurements will not
be counted for treated subjects for any analyses; the actual sample sizes will be
noted to be different.
lf a subject cannot be contacted after several attempts by telephone and /or letter
and/or due diligence, the subject will be deemed to be lost to follow-up and this
will be noted in the source document and CRF.
7.9.1 Statistical Analysis Strategy
Multiple analysis strategies are to be used in this study. These address study
design, study populations, data analysis, analysis confirmations, multiple
endpoints, data pooling, and interim assessments.
The choice of the study population is the ITT population for the primary and
secondary analyses because an open-label design is to be used. This means
that all randomized subjects are to be followed to the extent that this is feasible,
and included in all efficacy analyses as data permit. A per-protocol population will
be analyzed in selected analysis situations for confirmation; all p-values for the
per-protocol analyses will be regarded as descriptive.
Data analyses and confirmatory analyses are pre-planned to address multiple
complex situations. Life-table methods allow subjects to be used as long as they
have follow-up and investigators will be made aware at the time of study
activation that all subjects need to be followed for at least 3 years. A log rank test
for comparing treatments is the primary analysis, with supporting stratified log
rank and proportional haza¡d models to be analyzed for confirmation; the
stratified log rank and proportional hazard models are needed to address the
impact of correlated baseline factors and the potential for treatment interactions.
Risk factor analyses have a post hoc element since the determination is made
post-surgery and the Multikine regimens may impact the SOC choice if it can
affect tumor margins and positive lymph nodes pre-surgery.
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Study site pooling will also be assessed. Sites with less than 14 subjects will be
pooled together into a combined site in the analyses for the primary and
secondary efficacy endpoints as well as the overall adverse event rate. For these
endpoints, a two-sided p-value >0.05 for the global site effect will be required to
pool data across sites; a site-treatment interaction will also be tested for the
endpoints; in the event of significant site-treatment interactions, baseline site
imbalance will be explored using proportional hazards analysis (for time to event
endpoints), longitudinal model analysis (OOL domains, Karnofsky status,
weight), or logistic regression (overall adverse event rate) including the tumor
stage, tumor location, and geographic strata variables, treatment, site, and
treatment-site interactions.
Prospective study subjects stratification will yield subgroup analyses that are
planned as an exploratory analysis of the primary efficacy endpoint, OS, using
tumor location (tongue, floor of mouth, cheek, and soft palate), and tumor stage
(Stage lll and Stage lVa [see Table 3 - TNM Categories and corresponding
stage permitted in this Triall) and country.
Further prospective subgroup analyses may be identified in the statistical
analysis plan (SAP). Subsequently, subgroups may be identified on a data-driven
basis, and such analyses will be considered exploratory and hypothesis
generating only.
Finally, interlm analyses will be used to confirm Multikine safety expectations:
these safety analyses will be performed after the first 40 subjects in the trial have
been dosed with Multikine and completed surgery and again after all subjects
have completed the safety evaluation follow-up visit approximately 30 days (28-
35 days) following the last radiotherapy (or chemoradiotherapy) treatment.
Additionally, sample size assumptions and futility will also be analyzed as
requested by the study iDMC (lndependent Data Safety and Efficacy Monitoring
Board). Sample size re-estimation will be conducted on blinded data and prior to
any analysis that would require breaking the blind. No penalty is therefore
applicable since the study will not be stopped for superiority, unless so
determined by the |DMC in conjunction with the regulatory authority(ies) and the
sponsor.
7.1 0 Statistical Significance
For the primary and secondary efficacy measures, a two-sided p-value of 0.05 or
less will be considered to be statistically significant in comparing the Multikine
treatments vs. SOC alone for superiority. A Holmsa closed-sequential procedure
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will be used to control the probability of type I error for the secondary
hypotheses.
7.11lnterim Analysis
lnterim analyses will be performed through the study to assess Multikine safety,
sample size assumptions, and futility. The first interim analysis will be performed
when 40 Multikine treated subject's complete surgery, and an additional safety
analysis will be performed when all subjects have completed the 30 day safety
follow-up visit (Day 28-35). Subsequent interim analyses will be performed as
mutually agreed upon with the independent Data Monitoring Committee (iDMC)
and sponsor; the anticipated schedule is to perform interim analyses of safety
and efficacy every 6 months based on the study meeting enrollment objectives.
The iDMC will perform these semi-annual safety and effectiveness analyses
during the study to assess the feasibility of continuing the study and to assess
the sample size according to the primary study endpoint to see if the sample size
is adequate or requires modification (reduction or increase). This sample size re-
estimation will be conducted on blinded data, and prior to any unblinding. The
study will not be stopped for superiority but the study may be stopped for futility
(without penalty). Thus, the overall significance level of the final analysis (0.05)
will be maintained.
7.12 Analys¡s Approach
All analyses will be conducted under a prospectively approved statistical analysis
plan (SAP), which will display all database specifications and conventions in
addition to all planned tables, listings, and flgures. The SAP will be developed
under SOPs for data analyses and the SAP will be approved and implemented
prior to database lock. Any other analyses will be considered ad hoc.
7 .1 2.1 Subject Disposition
All subjects entered in the study will be accounted for in the disposition
summarization report. The subject disposition will include data on randomized
treatment, actual treatment, site enrolment, subject eligibility, subject compliance,
progress through the study, follow-up, discontinuation, data on overall
qualification status of all subjects, and an account of all identified protocol
violations. The number of subjects will be displayed for those who discontinue
before treatment begins, do not qualifo for the per protocol analyses, who
progress during the study, who exhibit loco-regional recurrence, who die during
the study, or who go on to other treatments.
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The progress of subjects through each treatment regimen (Multikine +LC\Z +
SOC) and SOC alone (control group) and through study completion will be
shown in tables and graphs. Reasons for early withdrawal from study will be
displayed. The pattern of being missing completely at random (MCAR) will also
be assessed.
The number of treatment visits at which Multikine is administered and the amount
of each study drug delivered per visit and cumulatively will be summarized and
tabulated. Subjects requiring delay and/or reduction in dose of either, study drug
or radiotherapy and/or concurrent chemoradiotherapy will be displayed with
reasons provided.
7 .12.2 Descriptive Statistics
Descriptive statistics will be provided for items collected for all randomized
subjects for the lTT, per-protocol, and safety populations as appropriate to the
analysis objectives. lmpacted variables will include demographic and pre-
procedure subject characteristics and medical history. Treatment characteristics,
post-therapy outcomes, and safety items will be displayed using descriptive
statistics for each scheduled and follow-up visit.
For continuous variables, descriptive results will include mean, standard
deviation, minimum, median, and maximum. Confidence bounds for the means
and for the mean differences will be computed using two-sided 95% intervals
calculated using a Student's ltest dlstribution.
Ordinal variables will be analyzed using an unpaired t-test or a Wilcoxon rank
sum test to compare treatment groups and using a paired t-test or a signed rank
test to compare changes from baseline within each treatment group.
Discrete outcomes will be presented as category percentages noting the
numerator and denominator used to derive the percentage. Treatment groups
will be compared using two-sided, 95% exact confidence intervals for proportions
while individualtreatment groups will be compared using Fisher's exact test.
7 .12.3 Subject Demographics
A summary of subject characteristics will also be provided, including
demog raphic information, basel ine disease characteristics, pre-existing
conditions, prior therapies, and concomitant medications. Other subject
characteristics will be summarized as deemed appropriate.
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7.12.4 Tumor Response
Tumors will be measured as described in Section 6.3.1 to allow calculation of
response according to RECIST criteria (Appendix 10). Tumors treated with
Multikine will be measured at baseline, (at the onset of treatment just prior to
Multikinetreatment), prior to the last weekly injection of Multikine, just prior to
surgery, to allow evaluation of tumor size changes. Thereafter, subjects will be
evaluated every 2 months after the end of therapy regimen for the first 12
months, every 3 months to 2 years, and every 4 months thereafter to 3 years
(Appendix 1). lf evidence of disease progression or new disease is present, CT
scans and/or MRI of head/neck and chest will be performed.
Each tumor (injected peri-tumorally with Multikine) will be analyzed to include the
primary tumor as well as any clinically involved lymph nodes. These tumor
measurements will be used to determine tumor size changes. For each tumor,
the method of measurement selected at baseline must be the same throughout
the study.
Changes in tumor volume will be assessed using a longitudinal growth model
including all post-baseline measurements. A log normal distribution will be used if
goodness of fit assumptions warrant.
7.12.5 Progression
For subjects who progress (i.e. exhibit loco-regionalfailure), the pattern of
progression will be examined by classifying the first evidence of progression in
local and distal sites for the control group and for the Multikine treated groups.
Progression defined as loco-regionalfailure includes progression of tumo(s) and
nodes or appearance of new disease above the clavicle (but not distant
metastases) following treatment. This definition also includes the reappearance
of tumor in the original tumor bed, development of cervical node metastases after
the treatment regimen and new disease above the clavicle (other than distant
metastases) not present at baseline. All progression of disease will be
documented on each subject's CRF.
Data will be collected on progression at sites not treated with Multikine and
documented in the CRF - including:
. additional nodes
. other local metastatic sites
. distant metastatic sites
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The number and percent of subjects in each category as well as the timing will
be displayed for each treatment group.
7.12.6 Time to Event Outcomes
Time to event outcomes include overall survival, progression-free survival, as
well as loco-regional control. The time to event outcomes will be calculated from
the date of randomization for all subjects and will be estimated for each
treatment group in this study using the Kaplan-Meier method. Treatment groups
will be compared using a stratified log rank test where stratification will be
according to tumor stage, tumor location, and geography. Subjects who receive
confounding anticancer therapies after treatment with Multikine and SOC (i.e.
while on protocol) will be included in the overall survlval analysis and censored in
progression-free and loco-regional control analysis if progression was the reason
for initiating new treatment.
Proportional hazards models will be used to evaluate study treatment as well as
baseline covariates (tumor stage, tumor location, and geography). The
respective models will include interactions between treatments and tumor stage,
tumor site, and geography. Treatment will be modeled with the Multikine + CIZ +
SOC as the reference group to allow simultaneous comparisons to SOC alone
(primary comparison) and to Multikine + SOC (secondary comparison).
Additional analyses will be performed for the risk group assignment and for the
type of therapy administered (radiotherapy, concurrent chemoradiotherapy)
following surgery. The major prognostic factor for the subjects is the assignment
to either the "high risk" or "low risk" group (discussed in Section 1.1) made after
randomization, Multikine treatment and surgery. Thus, stratification at study entry
for this factor cannot be performed. As described above, stratified log rank and
proportional hazards models will be performed; the proportional hazards models
will include tumor stage, tumor location, and geographic location as well as
treatment.
7.12.7 Quality of Life
Assessment of quality of life will be based on the EORTC QLQ-C3O and EORTC
QLQ-H&N3S. The EORTC QLQ-C3O incorporates 30 items and consists of 5
functional scales (physical, role, cognitive, emotional, and socialfunctioning), 3
general symptom scales (fatigue, pain, and nausea/vomiting), a global QOL
scale, and 6 specific symptom scales (dyspnea, insomnia, appetite, constipation,
diarrhea, and financial impact). The EORTC Quality of Life Questionnaire-Head
and Neck35 (QLQ-H&N3S) is a supplement module to the QLQ-C30. Most items
are scored on a four-point response scale: 1 (not at all) to 4 (very much).
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Questions 31 to 48 address symptoms specific for head and neck patients, e.g
pain, swallowing, taste, appearance. Questions 49 to 60 address functional
items, e.g. eating, talking, social contact, sexuality. The last 5 items are
answered as 'yes' or'rìo' concerning analgesia, nutritional supplemental, tube
feeding, and changes in weight.
Quality of Life (OOL) data will be scored according to the algorithm described in
the EORTC QLQ-C3O scoring manual. All scales pertaining to the EORTC QLQ-
C30 and OLQ-H&N3S range from 0 to 100. A high score for a functional or global
QOL scale represents a relatively high/healthy level of functioning or global QOL;
whereas a high score for a symptom scale indicates a higher level of symptoms
or problems. QOL data will be summarized using descriptive statistics for the
multi-item subscales at baseline and at each follow-up visit. Missing data points
for multi-item scales will be imputed using the method described in the scoring
manual where at least half the items from a given scale were answered. ln
addition, changes in QOL scores at each follow-up as compared to baseline and
the percentage of subjects achieving a 10 point improvement at 6 month, 12
months, 18 months and up to 36 months will also be summarized.
Quality of life data will be assessed for the change in QOL from baseline within
and between treatment groups. The comparisons between treatment groups will
be performed using ANOVA (or Wilcoxon rank sum test) while the change in
QOL from baseline within treatment group will be performed using a paired t-test
(or a signed rank test). Two-sided test will be used with no adjustment for the
Type I error. ln addition, a 10 point improvement between treatments will be
performed by an exact binomial test for each treatment group and using a Fisher
Exact test for between group comparisons.
7.12.8 Safety
All adverse events will be reported regardless of causality. Severity of AEs will be
graded by the investigator according to the NCI CTCAE version 4.0 (Appendix
8). The adverse events will be reviewed and coded by sponsor or sponsor's
representative using MedDRA. Using MedDRA, each adverse event will be
referred to by preferred term and system organ class. The total number of events
and total number of subjects with events will also be displayed for overall safety
population and also for each system organ class and preferred term. Displays
will also be provided for the timing of adverse events (post-randomization, pre-
surgery, postsurgery during SOC, postSOC) to provide insight into the Multikine
related adverse events distinct from adverse events related to surgery and SOC.
Serious and unexpected adverse events will be summarized in a listing and
described by narrative. Treatment groups will be compared at the subject level
using a Fisher Exact test and will be compared at the event level using a Poisson
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model for the total counts. The cumulative incidence of adverse events at the
subject level will also be displayed graphically to help depict the impact of each
therapeutic component. Results will also be displayed separately for the post-
surgical treatment g roups (radiotherapy, concurrent chemoradiotherapy)
according to the randomized treatment group.
Laboratory data, including abnormal labs and clinically significant labs, will be
analyzed descriptively and subjected to statistical analyses for the change from
baseline through the end of treatment (pre-surgery, SOC, post-SOC). Laboratory
measurements will be investigated between and within treatment groups for the
pre-surgery treatment as well as for SOC using ANOVA (or a Wilcoxon rank sum
test) to compare treatments and using a paired t-test (or a signed rank test) to
compare changes from baseline. Shift tables will also be assessed using a
Fisher Exact test to compare treatments and using a marginal homogeneity test
within treatment groups. The incidence of clinically significant laboratory values,
as determined by the investigators, will be summarized and compared using a
Fisher Exact test.
8. Safety and Adverse Events
8.1 Definitions
8.1.1 Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that develops
or worsens in severity during the course of the study. lntercurrent illnesses or
injuries should be regarded as adverse events. Abnormal results of diagnostic
procedures are considered to be adverse events if the abnormality:
. results in study withdrawal
. is associated with a serious adverse event
. is associated with clinical signs or symptoms
. leads to additional treatment or to further diagnostic tests
. is considered by the investigator to be of clinical significance
8.1.2 Serious Adverse Event
Adverse events are classified as serious or non-serious. A serious adverse
event is any AE that is:
fatal
life-threatening
requires or prolongs hospital stay
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results in persistent or significant disability or incapacity
a congenital anomaly or birth defect
an important medical event or medically significant event in the opinion of the
investigator
A life{hreatening adverse event is defined as any adverse experience that
places the subject at immediate risk of death from the reaction as it occurred;
i.e., it does not include a reaction that, had it occurred in a more severe form,
might have caused death.
Hospitalization is defined as any in-patient admission (even if less lhan 24 hours)
as a result of a precipitating, treatment-emergent adverse event. For chronic or
long-term subjects, in-patient admission also includes transfer within the hospital
to an acute/intensive care in-patient unit. Hospitalizations for administrative
reasons or a non-worsening preexisting condition should not be considered
adverse events (e.9. admission for workup of a persistent pretreatment lab
abnormality, yearly physical exam, protocol specified admission, elective
surgery, transfusion, or routine central catheter care). Preplanned treatments or
surgical procedures should be noted in the baseline documentation. However, if
a hospitalization due to an unknown event occurs, it should be considered as a
serious adverse event. See also Section 8.7.
Prolongation of hospitalization is defined as any extension of an in-patient
hospitalization beyond the stay anticipated/required for the original reason for
admission, as determined by the investigator or treating physician.
Disability is defined as a substantial disruption of a person's ability to conduct
normal life functions.
lmportant medical events are those that may not be immediately life threatening,
but are clearly of major clinical significance. They may jeopardize the subject,
and may require intervention to prevent one of the other serious outcomes noted
above. For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization or intensive treatment of bronchospasm in an emergency
department would typically be considered serious.
All adverse events that do not meet any of the criteria for a serious adverse
event are regarded as non-serious adverse events.
8.1.3 Unexpected Adverse Event
An unexpected AE is an event not previously reported in or which the
nature or severity is not consistent with the current edition of the clinical
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lnvestigator's Brochure (for investigational product) or the Summary of
Product Characteristics (for authorized products).
8.1.4 Expected Adverse Events Related to Treatments in this
Protocol
8.1.4.1 Medication Related Toxicities
a. Gyclophosphamide (low-dose, 300 mg/m2, lV x 1 dose)
. Alopecia
. Nausea
. Vomiting
. Pulmonary fibrosis
. Hypersensitivity reactions
. Hemorrhagic cystitis
. Myelosuppressron
. Thrombocytopenia
. Anemia
b. Indomethacin (25 mg p.o. t.i.d, during Multikine injection
period)
. Anorexia
. Nausea
. Abdominal pain
. Gastritis
. Upper gastrointestinal tract ulcer
. Renal insufficiency
. Hypersensitivity reactions
. lmpaired platelet function
. Bleeding tendency
ultivitamin with Zinc (zinc dose of l5 - 40 mg, orally during
ultikine injection period)
Abdominal discomfort
Fatigue
Hypersensitivity reactions
8.1.4.2 lnvestigational Agent -- Multikine (Leukocyte
lnterleukin, lnjection) Possible Toxicities
o Hypersensitivityreactions
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. Fever
. Chills
. Malaise
. Fatigue
. Anorexia
. Weight loss
. lnjection site pain / swelling
. lnfection at injection sites
. Bleeding associated with injection
. Localized erythema
8.1.4.3 Surgery Related Toxicities
. Facial nerve paralysis
. Oral incompetence
o Trismus (inability to fully open mouth)
. Nutritional deficiency
. Fatigue
. Dysphagia
o Difflculty speaking
. Difficultyswallowing
. Odynophagia
. Change in voice characteristics
. Dry mouth
. Salivary duct stenosis
. lnjurv to nerve and vascular structures
. lnfection
. Ongoing drainage from surgicalwound
. Ongoing bleeding from surgicalwound
. Pain at incision site(s)
. Neck stiffness (associated with neck dissection)
. Neck weakness (associated with neck dissection)
. Shoulder weakness (associated with neck dissection)
. Depression
. Food regurgitation into nasopharynx (especially with soft palate
resection)
. Anesthesia related complications including hypersensitivity reaction,
myocardial infarction, cerebrovascular accident
. Post-operativevenousthrombosis/pulmonaryembolus
. Death
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8.1.4.4 Radiation Associated Toxicities
. Facial nerve paralysis
. Oral incompetence
. Fatigue
. Dysphagia
. Difficulty speaking
. Difficultyswallowing
. Change in voice characteristics
. Dry mouth
. Salivary duct stenosis
. Injury to nerve and vascular structures
. lnfection
. Neck stiffness (associated with neck radiation)
. Neck weakness (associated with neck radiation)
. Shoulder weakness (associated with neck radiation)
. Depression
. Mouth sores
. Mucositis
. Soft tissue ulceration / necrosis
. Osteonecrosis of jaw
. Dentalcaries
. Tooth / gum decay
. Dry skin
. Moist skin desquamation
. Burning of skin
. Skin erythema
. Trismus (inability to fully open mouth)
. Nutritional deficiency
o Halitosis
. Oral fungal infection
. Odynophagia
8.1.4.5 Cisplatin Related Toxicities
. Anorexia
. Weight loss
. Renal insufficiency
. Nausea / vomiting
. Electrolyte imbalance
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. Peripheralneuropathy
o Auditory impairment
. Tinnitus
. Myelosuppression
. Thrombocytopenia
. Anemia
. Hypersensitivityreaction
. Seizure
. Visual impairment
. Fatigue
8.1.5 Severity of Adverse Events
All events will be graded according to the NCI CTCAE version 4.0 (Appendix 8)
by the lnvestigator. For events not listed in the toxicity table, severity should be
recorded as:
Grade 1
Mild adverse event
Grade2
Moderate adverse event
Grade 3
Severe adverse event
Grade 4
Life-threatening or disablinq adverse event
Grade 5
Death related to AE
8.1.6 Causal Relationship to Study Drug
The following criteria should be used in assessing the apparent causal
relationship of an AE to study drug:
Definitely - The AE:
. follows a reasonable temporal sequence from drug administration
. abates upon discontinuation of the drug (de-challenge)
. is confirmed by reappearance of the reaction on repeat exposure
Probably - The AE:
. follows a reasonable temporal sequence from drug administration
. abates upon discontinuation of the drug (de-challenge)
. cannot be reasonably explained by the known characteristics of the
subject's state
Possibly - The AE:
. follows a reasonable temporal sequence from drug administration
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. could have been produced by either the subject's clinical state or by study
drug administration
Not related - The AE:
. does not have a reasonable temporal association with the administration
of study drug
. has some other obvious explanation for the event
8.2 Adverse Event Reporting Period
The study period during which adverse events must be reported is defined as the
period from signing of informed consent to the end of the study treatment follow-
up in each group. For this study, there will be an end of study follow-up for
adverse events 30 and 60 days following the last study treatment (Multikine
treatment group as well as the SOC group treatment). Particular attention should
be paid to relatedness of AEs to study drug, as these AEs will be compared to
those recorded for subjects receiving SOC only.
8.3 Pre-existing Gonditions
A pre-existing condition is one that is present at the time of enrolment. A pre-
existing condition should be recorded as an adverse event only if the frequency,
intensity, or the character of the condition worsens during the study period.
8.4 Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a pre-
existing condition. Subsequent to screening, and until the end of the study, any
new clinically significant findings/abnormalities that meet the definition of an
adverse event must also be recorded and documented as an adverse event.
8.5 Post-study Adverse Event
All unresolved serious adverse events should be followed by the investigator until
the events are resolved, the subject is lost to follow-up, or the adverse event is
otherwise explained. At the last scheduled visit, the investigator should instruct
each subject to report any subsequent event(s) that the subject, or the subject's
personal physician, believes might reasonably be related to participation in this
study. The investigator should notify the study sponsor and its designee/agent of
any death or adverse event occurring at any time after a subject has
discontinued or terminated study participation that may reasonably be related to
this study. The sponsor or designee should also be notified if the investigator
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should become aware of the development of cancer or of a congenital anomaly
in a subsequently conceived offspring of a subject that has participated in this
study.
8.5.1 Pregnanc¡es
lf the investigator becomes aware following administration of study drug, of a
pregnancy in a female subject, which occurred prior to or subsequent to the
drug's administration, the pregnancy will be reported, and follow-up
assessments/reports of any possible effects of the study drug on the outcome of
the pregnancy will be provided until the subject completes or withdraws from the
study.
lf the outcome of the pregnancy meets the criteria for immediate classification of
an SAE the investigator will report the event by phone and by faxing a completed
SAER form to the sponsor (or designee) within 24 hours of knowledge of the
event. The investigation of the SAE will be conducted and will determine the
relatedness (if any) of the study treatment regimen to pregnancy outcome,
should the pregnancy result in an SAE report and investigation. (Section 8.9.4).
8.6 Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an adverse event if
any one of the following conditions is met:
The laboratory abnormality is not otherwise refuted by a repeat test to confirm
the abnormality
The abnormality suggests a disease and/or organ toxicity
The abnormality is of a degree that requires active management; e.g. change of
dose, discontinuation of the drug, more frequent follow-up assessments, further
diagnostic investigation, etc.
The event is possibly, probably or definitely related to study drug.
The event is of clinical significance as determined by the investigator.
8.7 Hospitalization, Prolonged Hospitalization
Any adverse event that results in hospitalization or prolonged hospitalization
should be documented and reported as a serious adverse event unless
specifically instructed otherwise in this protocol.
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are
reported as an adverse event in the following circumstances:
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Hospitalization or prolonged hospitalization for diagnostic or elective a surgical
procedure for a preexisting condition which does not worsen or increase in
frequency during the study. Surgery should not be reported as an outcome of an
adverse event if the purpose of the surgery was elective or diagnostic and the
outcome was uneventful.
Hospitalization or prolonged hospitalization required to allow efficacy
measurements for the study.
Hospitalization or prolonged hospitalization for therapy of the target disease of
the study, unless it is a worsening or increase in frequency of hospital
admissions as judged by the clinical investigator.
Hospitalization for transfusion or routine central catheter care. Blood products will
be reported as concomitant medications.
8.8 Recording of Adverse Events
At each contact with the subject, the investigator must seek information on
adverse events by specific questioning and, as appropriate, by examination.
lnformation on all adverse events should be recorded immediately in the source
document, and also in the appropriate adverse event module of the case report
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic
procedures results should be recorded in the source document, though should
be grouped under one diagnosis.
All adverse events occurring during the study period must be recorded. The
clinical course of each event should be followed until resolution, stabilization, or
until it has been determined that the study treatment or participation is not the
cause. Serious adverse events that are still ongoing at the end of the study
period must be followed up to determine the final outcome. Any serious adverse
event that occurs after the study period and is considered to be possibly related
to the study treatment or study participation should be recorded and reported
immediately.
8.9 Reporting of Serious Adverse Events
8.9.1 Study Sponsor Notification by lnvestigator
A serious adverse event must be reported to the sponsor or his designee within
24 hours of the event. A Serious Adverse Event (SAE) Form must be completed
by the investigator or responsible site personnel and faxed to the sponsor or his
designee. The investigator will keep a copy of this SAE form on file at the study
site. Report serious adverse events by phone or e-mail or facsimile to:
Aptiv Solutions
Tel:+1 508 597-6158 Fax: +l 508 416-2654 Email:
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Pharmacovigilance
Marlborough, USA
(For United States,
Canada, Taiwan)
Pharmacovig i lance_SBO@aptivsol utions.com
Aptiv Solutions
Pharmacovigilance
Glory Park, UK
(For Europe,and
all other reqions)
Tel: +44 (0) 870 7107157 Fax:+44 (0) 870 710
71 57 Email: safety@aptivsolutions.com
lf further follow-up is required the investigator must provide further information on
the serious adverse event in the form of a written narrative or follow-up SAE
reports. This should include any other diagnostic information that will assist in the
understanding of the event. Significant new information on ongoing serious
adverse events should be provided promptly.
8.9.2 EC/lRB Notification by lnvestigator
Reports of all serious adverse events (including follow-up information) must be
submitted to the EC/lRB within 10 working days or as directed by the IRB
guidelines. Copies of each report and documentation of EC/lRB notification and
receipt will be kept in the clinical investigator's binder, and a copy of the EC/IRB
notification will be sent by the clinical investigator to the study sponsor or
designee.
8.9.3 FDA, Health Ganada and other Regulatory Agenc¡es
Notification by Sponsor
The study sponsor shall notify the FDA and Health Canada by telephone or by
facsimile transmission of any unexpected fatal or life-threatening experience
associated with the use of the drug as soon as possible but no later than 7
calendar days from the sponsor's (or designee) original receipt of the
information.
lf a previous adverse event that was not initially deemed reportable is later found
to fit the criteria for reporting, the study sponsor will submit the adverse event in
a written report to the FDA and Health Canada as soon as possible, but no later
than 15 calendar days from the time the determination is made, and
communicated to the study sponsor by the investigator.
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Other regulatory agencies will be notified of SAE's per the requirements of the
specific regulatory jurisdiction regulations and laws.
8.9.4 Pregnancies
lf the investigator becomes aware following administration of study drug, of a
pregnancy in a female subject, which occurred prior to or subsequent to the
drug's administration, the pregnancy will be reported and follow-up
assessments/reports of any possible effects of the study drug on the outcome of
the pregnancy will be provided until the subject completes or withdraws from the
study. The pregnancy will be reported immediately by phone and by faxing a
completed Pregnancy Report to the sponsor (or designee) within 24 hours of
knowledge of the event. The pregnancy will not be processed as an SAE:
however, the investigator will follow the subject until completion of the pregnancy
and must assess the outcome in the shortest possible time but not more than
30 days within completion of the pregnancy. The investigator should notify the
sponsor (or designee) of the outcome of the pregnancy by submitting a follow-up
Pregnancy Report.
lf the outcome of the pregnancy meets the criteria for immediate classification of
an SAE (e.9., spontaneous or therapeutic abortion, any congenital anomaly
detected in an aborted fetus, stillbirth or neonatal death is to be documented),
the investigator will report the event by phone and by faxing a completed SAER
form to the sponsor (or designee) within 24 hours of knowledge of the event.
The investigation of the SAE will be conducted and will determine the
relatedness (if any) of the study treatment regimen to pregnancy outcome,
should the pregnancy result ln an SAE report and investigation.
8.1 0 Unbinding Procedures
Not Applicable. This is an open label Study.
The blinding and unblinding procedures for central laboratories, DNA microarray
and radiology data are described in Section 6.8 and Section 6.9 respectively.
8.ll Stopping Rules
Because significant toxicity has not been observed with Multikine treatment, it is
not anticipated that safety stopping rules will be implemented. However, patients
in other studies examining the effects of combined radiotherapy and
chemotherapy have demonstrated rates of Grade 3 and 4 toxicities significantly
above those observed in patients who receive radiotherapy alone or similar
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chemotherapy treatment. For this reason, an independent Data Monitoring
Committee will be constituted (Section 8.13).
8.12 Medical Monitoring by lnvestigators
It is the responsibility of the Principal lnvestigator to oversee the safety of the
study at his/her site. This safety monitoring will include careful assessment and
appropriate reporting of adverse events as noted above, as well as the
construction and implementation of a site data and safety-monitoring plan
(Section 10 - Monitoring ,Auditing and lnspecting). Medical monitoring will
include a regular assessment of the number and type of serious adverse events
8.13 lndependent Data Monitoring Gommittee (¡DMC)
An independent data monitoring committee (iDMC) will review interim data
according to the FDA Guidance: "Guidance for Clinical Trial Sponsors on the
Establishment and Operation of Clinical Trial Data Monitoring Committees". The
iDMC will be formed to provide scientiflc and medical direction for the study.
The |DMC will focus on the following areas:
Efficacy - to assess the primary efficacy measure as well as the
conditional power and sample size
Safety - to assess the magnitude of adverse events and monitor for
safety concerns
The iDMC will consist of experts (clinical oncologists, radiologist, H&N surgeon,
pathologist and biostatistician) with experience in the treatment and analysis of
head and neck cancer patients who receive concurrent chemoradiotherapy. They
will be provided with the lnvestigators Drug Brochure, study protocol and relevant
literature. The |DMC will operate under a charter and will provide prospective
data analysis and display specifications to conduct independent data reviews.
The |DMC will make recommendations to the sponsor to continue the study as
planned or to stop the study due to safety or lack of efficacy. The iDMC will meet
at least semi-annually to perform safety and efficacy evaluations and to make
recommendation to the sponsor. The |DMC reserves the right to request more
frequent evaluations. No sample size penalty will be imposed by the ¡DMC
evaluations since only recommendations to continue as is, to modify the sample
size, or to stop for futility will be made. The sponsor retains the right to accept,
modify, or reject the |DMC recommendations. The purpose of the ¡DMC will be to
assess frequency, causality and severity of toxicities of the subjects in the
protocol on a periodic basis. The iDMC will review all signiflcant Grade 3 and 4
toxicities as well as all unexpected adverse events possibly related to the study
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treatment; the |DMC willforward opinions on individual cases to the sponsor and
to sponsor representative. The iDMC will determine if toxicities exceed those
rates and severities normally seen with this subject population and make
recommendations on the continuing progress of the study to the sponsor,
medical monitor and investigators.
The |DMC will be expected to review the protocol and lnvestigator's Brochure in
the context of the iDMCs analyses of the study data and to recommend any
changes judged necessary for investigators and EC's/lRBs to adequately assess
potential risks and benefits to subjects participating in the study. The iDMC will
make recommendations to the sponsor for changes to the protocol or
lnvestigator's Brochure; the sponsorwill again have the final decision to
implement iDMC recommendations.
The |DMC will also periodically assess the required sample size as well as the
conditional power. lf the new sample size is smaller than that calculated prior to
the study or if there are other indicators that the results are more favorable than
expected, the study will continue as planned so as not to incur the statistical
penalties that would normally be associated with a traditional interim analysis
involving superiority stopping; in addition, the impact on the other study
endpoints will be taken into account in making a recommendation. lf the new
sample size is greater than that calculated prior to the study or if there are other
indicators that the overall effectiveness results are not as favorable as expected,
the sponsor may accept the iDMC recommendation that the study be expanded
or may make the decision to terminate the trial. ln the event that a decision is
made to expand the sample size, the impact of the final treatment effect will be
projected subject to the assumptions regarding enrollment, follow-up and
underlying hazard rates.
8.13.1 lnterim Safety Analysis
An interim safety analysis will be performed after the first 40 patients complete
surgery following randomization to the Multikine treatment groups and have
undergone surgery and again when all subjects have completed the 30 day
safety follow-up visit (following all protocol treatments). This assessment will
include a review of adverse events, serious adverse events, and clinically
significant laboratory findings as determined by the investigators. Overall safety
events will be assessed as well as safety events grouped in the time period from
randomization though surgery, in the 30-day post-operative period, and from the
30-day post-operative period through 30 days following completion of
chemo/radiation therapy. Descriptive statistics and tabulations of events will be
presented.
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The interim safety assessment will be conducted by the |DMC (Section 7.11 and
8.13). lf changes in the conduct of the study are warranted as a result of the
evaluation, these will be communicated to the investigators, sponsor and the
regulatory authorities. lf appropriate, the protocol will be amended to incorporate
the recommended changes in study conduct.
9. Data Handling and Record Keeping
9.1 Gonfidentiality
lnformation about study subjects will be kept confidential and managed
according to the requirements of the Health lnsurance Portability and
Accountability Act of 1996 (HIPAA) or other applicable laws in the countries
participating in this study. Those regulations require a signed subject
authorization informing the subject of the following:
What protected health information (PHl) will be collected from subjects in this
study
Who will have access to that information and why
Who will use or disclose that information
The rights of a research subject to revoke their authorization for use of their PHI
ln the event that a subject revokes authorization to collect or use PHl, the
investigator, by regulation, retains the ability to use all information collected prior
to the revocation of subject authorization. For subjects that have revoked
authorization to collect or use PHl, attempts should be made to obtain
permission to collect at least vital status (i.e. that the subject is alive) at the end
of their scheduled study period.
9.2 Source Documents
Source data includes all information, original records of clinical findings,
observations, or other activities in a clinical trial necessary for the reconstruction
and evaluation of the trial, which are clearly marked as belonging to the study
subject. Source data are contained in source documents. Examples of these
originaldocuments, and data records include: hospital records, clinical and office
charts, laboratory notes, memoranda, subject diaries or evaluation checklists,
pharmacy dispensing records, recorded data from automated instruments,
copies or transcriptions certified after verification as being accurate and
complete, microfiches, photographic negatives, microfilm or magnetic media, x-
rays, CT/MRI, pathology slides and tissue, subject files, and records kept at the
pharmacy, at the laboratories, and at medicotechnical departments involved in
the clinical trial.
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9.3 Case Report Forms
The study case report form (CRF) is the primary data collection instrument for
the study and will be supplied by the sponsor or his designee. lt is intended that
all sites will utilize Electronic Case Report Forms (eCRFs), but in some cases it
may not be possible and it may be necessary to use Paper Case Report Forms.
All data requested on the CRFs must be recorded. All missing data must be
explained.
9.3.1 Electronic Case Report Form (eCRFs)
Data will be entered into the eCRF at the sites and accessed remotely by Data
Management (DM). Electronic review of the data may result in queries being
generated that will be accessed by the appropriate investigator or designee for
prompt resolution. Resolutions will be reviewed by data monitor [which includes
data analyst and clinical research associate (CRA)]. The data analyst reviews the
queries once they are resolved by the site in 5 working days and CRA will review
queries in their monitoring visits to the site. All data modifications resulting from
review or querying of the data will be electronically tracked via electronic Data
Clarification Forms (eDCFs). Any errors detected by either the clinical study
monitor or the investigator after query resolution should be communicated via
eDCFs. An electronic signature will be required by the Pl or designee (so
designated in writing by the Pl).
9.3.2 Paper CRFs (GRFs)
lf a space on the CRF is left blank because the procedure was not done or the
question was not asked, write "N/D" initial and date. lf the item is not applicable
to the individual case, write "N/4" initial and date. All entries should be printed
legibly in black ink. lf any entry error has been made, to correct such an error,
draw a single straight line through the incorrect entry and enter the correct data
above it. All such changes must be initialed and dated. DO NOT ERASE OR
WHITE OUT ERRORS. For clarification of illegible or uncertain entries, print the
clarification above the item, then initial and date it.
9.4 Records Retention
ln compliance with ICH GCPs and applicable regulatory requirements, copies of
all records (e.9., informed consent documents, laboratory data slips, source
documents, IND safety reports, test article dispensing records, etc.) which
support CRFs of this study, must be retained in the files of the responsible
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investigator for a minimum of two years following notification by the sponsor that
all investigations at all sites are completed, terminated, or discontinued, or that
the Food and Drug Administration has approved the New Drug Application or
Biologic License Application. lf the investigator retires, relocates, or for other
reasons withdraws from the responsibility of keeping the study records, custody
must be transferred to a qualified person (within the same institution) who will
accept the responsibility for keeping and maintaining these records from the
"departing" Pl. Such assignment of responsibility will be communicated in writing
naming the new custodian and its affiliation and contact information by the Pl
(and the lnstitution) to the sponsor and sponsor representative. Please note that
the accepting custodian may need to file documents with the local IRB/lECs, as
well as state and federal regulatory authorities.
9.5 lnspection of Records
ln compliance with local regulations, US Federal regulations and ICH GCP
guidelines, it is required that the investigator and institution permit the sponsor,
authorized representatives of the sponsor, and representatives of the regulatory
agency(ies), and the IEC direct access to review the subject's original medical
records for verification of study-related procedures and data. Direct access
includes examining, analyzing, verifying, and reproducing any records and
reports that are important to the evaluation of the study. The investigator is
obliged to inform the study subject(s) and obtain their consent to permit the
sponsor and agency representatives to have full access to his/her study-related
records without violating the confidentiali$ of the subject.
10. Study Monitoring, Auditing, and lnspecting
l0.l Study Monitoring Plan
This study will be monitored by the sponsor or its designee according to a
monitoring plan to be provided separately. The investigator will allocate adequate
time for such monitoring activities. The investigator will also ensure that the
monitor or other compliance or quality assurance reviewer is given access to all
the above noted study-related documents and study related facilities (e.9.
pharmacy, diagnostic laboratory), and has adequate space to conduct the
monitoring visit.
10.2 Auditing and lnspecting
The investigator (and the investigational clinical sites) will permit study-related
audits and inspections by the EC/lRB, the sponsor, sponsor authorized
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representatives, government regulatory bodies, and university compliance and
quality assurance groups of all study related documents (e.9. source documents,
regulatory documents, data collection instruments, study data). The investigator
will ensure the capability for inspections of applicable study-related facilities (e.9.
pharmacy, diagnostic laboratory). Participation as an investigator in this study
implies acceptance of potential inspection by the sponsor, sponsor authorized
representatives, government regulatory authorities and applicable university or
institutional compliance and quality assurance offices.
11. Ethical Considerat¡ons
This study is to be conducted according to US and international standards of
Good Clinical Practice (FDA Title 21 part312 and lnternational Conference on
Harmonization guidelines), applicable government regulations and institutional
research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted
independent Ethics Committee (EC) or lnstitutional Review Board (lRB), in
agreement with local legal prescriptions, for formal approval of the study conduct.
The decision of the EC/IRB concerning the conduct of the study will be made in
writing to the investigator and a copy of this decision will be provided to the
sponsor before commencement of this study. The investigator should provide a
list of EC/lRB members and their affiliate to the sponsor.
All subjects for this study will be provided a separate consent form describing this
study and providing sufficient information for subjects to make an informed
decision about their participation in this study. This consent form will be
submitted with the protocol for review and approval by the EC/lRB for the study.
The formal consent of a subject, using the EC/lRB-approved consent form, must
be obtained before that subject is submitted to any study procedure. This
consent form must be signed and dated by the subject or legally acceptable
surrogate, and the investigator-designated research professional obtaining the
consent.
Where applicable the subject will also give consent to the use of their medical
information as described by the US Health lnsurance Protection Administration
Act (HIPAA). As per institutional policy, a separate document may be provided or
the HIPAA compliant statement may reside in the body of the consent form.
11.1 Written lnformed Gonsent
The informed consent must contain all elements required by the FDA under 21
CFR Part 50 and ICH GCP (E6) (Section 4.8), as well as any other elements
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required by state, local and institutional policies. All subjects (or legally
authorized representative) must provide consent in writing after having had
adequate time to ask questions and consider their participation in the study.
Consent must be obtained before any protocol related procedures that are not
part of the subject's normal care are applied to any subject in the trial. Written
documentation of consent must be provided by signing an IRB/lEC approved
informed consent document. The date and time the consent was finalized should
be recorded in the subject's medical chart. The subject or their legal
representative must receive a copy of a timed, dated, and signed consent form
according to ICH GCP guidelines. The exact definition of legal representative
should be determined for a hospital by its IRB/IEC in compliance with local and
state statutes. Subjects will be informed of any significant new finding developed
during the course of the research that may affect their decision to continue
participation.
11.2 Genomic Microarray Study
A separate independent and stand alone genomic microarray study will be
performed in conjunction with the NIH/NCl utilizing tumor specimens and
peripheral blood mononuclear cells (PBMCs) obtained from a number of subjects
participating ln this study. The specimens will be collected at study entry and at
time of surgery from s.ubjects in this trial. To ensure subject privacy is protected
NO subject specific identifying information will be attached to or be allowed to
accompany any of the sample(s) shipped to the NIH/NCI. Neither will subject
specific data from which the genomic microarray study results will be derived be
able to be traceable back to any subject. The purpose of the genomic microarray
study is to determine if subjects whose tumor display a specific genomic array
will have a greater chance of being responsive to Multikine treatment than
subjects whose tumor lack the same genomic array pattern. lt is anticipated that
the data from this study will only become available at the end of the study after
all subjects have been dosed and treated and may in fact only become available
during or near the end of the follow-up period of this study.
11.3 Ethics Review
The protocols and local lnformed Consent (lC) forms must be reviewed and
approved in writing by each of the participating institutions' IRB/lEC prior to the
initiation of subject recruitment. Each of the IRB/IEC must be notified of all
subsequent protocol amendments. ln addition, progress reports will be submitted
to the IRB/lEC by the investigator as indicated by each IRB/lEC's guidelines. A
copy of each of these IRB/IEC progress reports submitted bythe investigatorto
its local IRB/lEC will be sent to the sponsor and sponsor's representative. Each
IRB/lEC must meet the FDA, and/or European Medicines Agency (EMEA), lCH,
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and any additional state and/or national requirements for composition,
documentation, and operational procedures.
The investigator shall provide the sponsor with the IRB/lEC's written notification
of approval along with the IRB/lEC membership list and/or statement that the
IRB/lEC operates in accordance with GCP.
ll.4 Ethical Conduct of the Study
The study will be conducted in accordance with this protocol, the principles that
have their origins in the Declaration of Helsinki, as well as ICH GCP and
applicable federal, state, and local regulatory requirements. All essential
documents will be archived at each participating institution.
12. Study Finances
12.1 Funding Source
This study is financed by the sponsor of the study, CEL-SCI Corporation, Vienna,
VA, USA.
12.2 Financ¡al Disclosure/Conflict of lnterest
Any investigator, who participates in this study, must disclose whether they do or
do not have any financial interest (patent ownership, royalties, or financial gain
greater than the minimum allowable by their institution, etc.) in the study or its
outcome. lf an investigator has a financial interest, Form FDA 3455 must be
completed and filed disclosing the financial arrangements. lf there is no financial
interest or arrangement, form FDA 3454 will be completed and filed.
12.3 Subject Stipends or Payments
Subjects will not receive payment for their participation in this clinical study. ln
accordance with country-specific rules and regulations and customs, subjects
may be compensated for travel and other expenses related to participation in this
trial, which otheruvise may lead to financial burden (hardship) for subjects
participating in the trial.
13. Publication Plan
Should any investigator desire to publish the results (including meeting abstracts)
of this study, a copy of the DRAFT manuscript will be provided to CEL-SCI
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Corporation for review and approval at least 60 days prior to the expected
initial date of submission to the intended publisher. Subject names and other
identifiers, such as photographs, audio or videotapes, may not be disclosed in
any publication without prior written authorization from the subject. ln no case
can study results be presented or published by an investigator without prior
written consent of the sponsor, nor can study results be published by an
investigator prior to the conclusion of the study and not until sufficient follow-up
of subjects is obtained, and publication is authorized in writing by CEL-SCI
Corporation (the study's sponsor).
Neither the complete nor any part of the results of the study carried out under
this protocol, nor any of the information provided by the sponsor for the purposes
of performing the study, will be published or passed on to any third party without
the prior written consent of the study sponsor. Any investigator involved with this
study is obligated to provide the sponsor with complete test results and all data
derived from the study.
14. Required Concom¡tant Medications
14.1 Cyclophospham¡de (USP or equ¡valent)
The chemical name of cyclophosphamide is:
2-[bis(2-chloroethyl)-amino]tetrahydro-2ï-1,3.2- 
oxazophosphorine 2-oxide
monohydrate.
lndications for cyclophosphamide include treatment of various solid
malignancies, acute and chronic leukemias, and various autoimmune diseases,
including nephrotic syndrome, Lupus erythematosis, Wegener's granulomatosis
and rheumatoid arthritis. The role of cyclophosphamide in this protocol is as an
immunomodulator to reduce T-suppressor cell activity.
ln animal tumor immunotherapy models and at least two human studies involving
tumor cell vaccines the immune response to antigenic immunization is markedly
augmented by pretreatment with cyclophosphamide. The presumed mechanism
of action is the abrogation of T-cell suppressor (and T-reg) activity, permitting a
more effective anti-tumor immune response, as a result of Multikine
administration.
A dose of 300 mg/m2 intravenously, as proposed in this protocol, is the dose
which has been shown to be active in the above described immunotherapy
models.a2' 44' 4s' 46' 47 This is a dose well below that which is used in cancer
chemotherapy. Doses of 500-600 mg/m2 are given in combination with other
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cytotoxic agents, while as a single agent doses in the range of 1000 mg/m2 are
used. To date, there have been no reports of myelosuppression in the more than
120 subjects who have received cyclophosphamide at the 300 mg/m2 dose being
evaluated in various CEL-SCl sponsored trials.
Cyclophosphamide, lnj. USP or equivalent is commercially available and is
supplied as a sterile powder containing 45 mg sodium chloride, 75 mg mannitol
or approximately 82 mg sodium bicarbonate per 100 mg cyclophosphamide for
reconstitution prior to intravenous injection or infusion.
14.2 lndomethac¡n (USP or equ¡valent)
The chemical name of indomethacin is:
1 -(4-chlorobenzoyl)-5-methoxy-2-methyl- 
1 H-indole-3-acetic acid.
lndomethacin is a non-steroidal anti-inflammatory (NSAID) and antipyretic agent.
lndications for indomethacin include anti-inflammatory activity in rheumatoid
arthritis and as an antipyretic in Hodgkin's disease. lt is further indicated in the
treatment of ankylosing spondylitis and osteoarthritis. lndomethacin is a potent
inhibitor of prostaglandin synthesis. lt has been demonstrated that monocyte and
macrophage-mediated suppression of the immune response is via the synthesis
and release of prostaglandins (e.9., PGE-2). The role of indomethacin in this
protocol is as an inhibitor of macrophage-mediated suppressor cell activity.
lndomethacin USP or equivalent is commercially available and is supplied in
capsules of 25 mg and 50 mg for oral administration. lndomethacin, 25 mg PO
three times daily (with food), is utilized in this study.
14.3 Nutritional Supplementation - Multivitam¡ns with zinc
Subjects with previously untreated, potentially curable head and neck cancers
exhibit high incidences of nutritional deficiencies and impaired immune
responses. Both nutritional status and immune competence have been
correlated with patient survival after definitive treatment of the tumors.
lmmune responses are reduced by deficiencies of certain vitamins and minerals,
particularly vitamins A, B, C, D, E and zinc. These findings support the addition of
nutritional supplementation with vitamins to minimize deficiencies in cancer
patients that may impair immune responses and reduce survival rates after tumor
treatment.
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To ensure good nutritional status, a commercially available multivitamin
supplement with zinc is used for self-administration by subjects receiving
Multikine once daily orally.
14.4 Gisplatin lV Bolus lnfusion (USP or equ¡valent) (Section
6.4.41
Subjects with identified "High-Risk" factors [tumor margins unclear or infiltrative,
local invasion, nodal involvement (>2 lymph nodes or extracapsular nodal
spread)lwill receive chemotherapy (cisplatin, lV, bolus infusion) concurrently
with radiotherapy. Concurrent chemoradiotherapy is currently adopted as the
standard of care for these high risk subjects and has been shown to result in
statistically significant increases in rate of local regional control, and in some
cases, increases in overall survival.
lf indicated, subjects will receive three courses of cisplatin lV bolus. Each course
of chemotherapy will consist of cisplatin (100 mg/m2) given as an lV bolus
infusion over 1-2 hours with pre-hydration and diuretics. Chemotherapy will be
given on weeks 1 , 4 and 7 of radiotherapy (or Days 1,22 and 43 of the
radiotherapy course) and concurrently with radiotherapy.
88
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Amendment #3 Protocol; 27 June 2014, Version 4.0


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ASSESSMENT
(All study groups)
enrollmenlrandomization)"
Radiotherapy (within 8 weeks
(56 days) post surgery, 60 Gy -
70 Gy, 30 - 35 fractions, 6 '- 7
weeks)
isk"
,4,7 post
RT for
CONFIDENTIAL
1. ANC is Absolute Neutrophil Count (WBC x (% neutrophils + % bands))
2. ESR ¡s Erythrocyte Sedimentation Rate
3. Ïh¡s v¡sit occurs at Day 30 after completion of radiation +/- chemotherapy
4. F¡rst v¡sit occurs at Day 60 after completion of radiation +/- chemotherapy
5. Surgery for SOG Group 3 only, may be scheduled on Days 8-38 (from enrollmenvrandomization), unless otheM¡se indicated med¡cally - by the investigator
6. Group 1 only.
7. Groups 2 and 3 only.
8. Surgery for Groups 1 and 2 only may be scheduled on Days 29-38 (from EnrollmenV Random¡zat¡on), unless otherwise indicated medically - by the ¡nvest¡gator
92
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Protocol No: CS001P3


CONFIDENTIAL
Protocol No: CS001P3
APPENDIX 2A. Technique for Peri-tumoral, Subepidermal lnjection of Multikine
Figure 1. SURFACE VIEW
Figure 2. SAGITTAL VIEW
F
F
E
C
E
Epidermis
Location of Peri-tumoral,
Sub-Epidermal Injection
The extent of the primary tumor at its longest dimension (Fig.1, A-B) and the extent at right angles to and at the midpoint of the longest
dimension (Fig.1, C-D) are determined by digital palpation. When the anatomical location of the tumor permits, one-fourth of the total dose of
Multikine is injected in the region of each of the four tumor extents. For example, for the peri-tumoral Multikine dose of 200 lU (1.0 mL), 50 lU
(0.25 mL) is injected in each of the four regions. Multikine is injected into the subepidermal tissue adjacent to the tumor (Fig. 2) using a 25, or
smaller, gauge needle. Before injecting, aspiration is attempted to ensure against injection of Multikine into peri-tumoral blood vessels. The
needle is inserted sufficiently into the subepidermal tissue to prevent leakage of Multikine out of the puncture site after the needle is withdrawn.
lf necessary to prevent leakage, additional peri-tumoral injection sites may be utilized (Fig. 1, E) and a second series of injection sites (Fig.1, F)
adjacent to and peripheral to injection sites A-E may be required to avoid leakage from injection sites.
After completing the three-week regimen of Multikine injections, label the sketch of the primary tumor on the Case Report Form, Post Protocol
Regimen, PRIMARY TUMOR, with the locations (A-F) of the injection sites.
93
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F
A
F
F
B
F
E
E
F
D
F
Tumor


CONFIDENTIAL
Protocol No: CS001P3
APPENDIX 28. Technique for Peri-tumoral, Subepidermal
Injection of Multikine
Figure 3. ANATOMICAL LOCATION OF THE TUMOR PREVENTS
CIRCUMFERENCIAL INJECTION OF Multikine
E
D
Note: Product is to be injected in approximately equal volumes at
minimum of four sites around the injectable portion of the tumor margin.
The anatomical location of the primary tumor may prevent peri-tumoral injections
of Multikine at the entire circumference of the tumor. For example, in Figure 3,
proximity and adherence to bone may prevent injections of Multikine at points A-C
of the circumference of the tumor. ln such instances, the Multikine is injected
outwardly at equidistant points in the peri{umoral subepidermal tissues at the
circumference of the tumor where the injections can be accomplished without
leakage of the Multikinefrom the injection sites (Fig.3, D-E).
After completing the three-week regimen of Multikine injections, labelthe sketch
of the primary tumor on the Case Report Form, Post Protocol Regimen,
PRIMARY TUMOR, with the locations (A-E) of the injection sites.
94
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E
E
D
D
D
Tumor


CONFIDENTIAL
Protocol No: CS001P3
APPENDIX 3. Jugular Region Perilymphatic Administration of
Multikine
PROCEDURE
The subject is positioned in an otorhinolaryngeal examination chair with the head held
upright by the occipital support. The skin in the area of the mastoid process is cleansed
for percutaneous puncture. At the discretion of the investigator, a local anesthetic may
be administered to the proposed injection site. A 25 gauge, or smaller, needle is
introduced at a point 1.5 cm inferior to the tip of the mastoid process at the area of the
insertion of the sternomastoid muscle. The needle is inserted 1.5 cm and aspiration
attempted to determine if a blood vessel has been punctured. lf there is no evidence of
blood vessel puncture, the specified dose of Multikine is injected without additlonal
manipulation of the needle. After each injection, the side of the neck to which the
injection was administered, the dose of Multikine injected and ANY DEVIATION(S)
thereof are recorded on the Daily Medical Treatment Case Report Form.
Selection of Injection Site
ln subjects who do not display clinical evidence of tumor metastatic to a regional lymph
node, the neck on the side of tumor is injected. With a clinically positive lymph node, the
neck on the side of the positive lymph node is injected, regardless of the location of the
primary tumor. With midline tumors and neck lymph nodes that do not display clinical
evidence of tumor metastases, one side of the neck is selected by the Principal
lnvestigator and all injections are made on that side.
Contraindications to lnjection
lnjection is contraindicated if the skin of the proposed injection site shows acute or
chronic infection or inflammation, dermatological disease, pre-cancerous lesion or
cancer. lnjection is contraindicated if the neck on the side of the proposed injection has
had incisional (open) biopsy of a lymph node within the previous four weeks.
Procedure after Evidence of Blood Vessel Puncture
Multikine is not injected if there is evidence of blood vessel puncture. The needle is
withdrawn and re-introduced at 1.0 cm inferior to the tip of the mastoid process; i.e., 0.5
cm superior to the previous puncture site, and inserted to a depth of 1.0 cm, compared
with a 1.5 cm depth of insertion that led to puncture of a blood vessel. The performance
of this procedure and any deviations are recorded on the Daily Medical Treatment Case
Report Form.
95
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CONFIDENTIAL
Protocol No: CS001P3
APPENDIX 4. Glinical Laboratory Tests Obtained in the Protocol
Regimen
BLOOD CHEMISTRY BLOOD HEMATOLOGY URINALYSIS
TESTS 
TESTS
TSH
Sodium
Potassium
Chloride
Bicarbonate
Glucose
Urea
Creatinine
Urate
Calcium
Phosphate
Total Protein
Albumin
Total Bilirubin
Alanine Transaminase
Aspartate Transaminase
Alkaline Phosphatase
Lactate Dehydrogenase
Cholesterol
Triglycerides
Glutamyl Transferase
White Blood Cell Count
Red Blood Cell Count
Hemoglobin
Hematocrit
Platelet Count
(A) Neutrophils
(A) Bands
(A) Lymphocytes
(A) Monocytes
(A) Eosinophils
(A) Basophils
ESR
Color
pH
Specific Gravity
Protein - Urine
Glucose - Urine
Ketone - Urine
Blood - Urine
RBC - Urine
WBC - Urine
Epithelial Cells
Bacteria - Urine
Mucus
Amorphous Material
Crystals
Casts
SERUM PREGNANCY
HIV TEST
"IMMUNOH ISTOCHEMISTRY/PATHOLOGY
cD3, CD4, CD8
CD3/CD25, CD4|CD25, CD8/CD25, FOXP3
CD56/CD16, CD13
cDl lb, cD45, CD4sRA, CD4sRO
CDR2, CDlA
HLA Class ll (DP, DQ, DR)
*These determinations to be performed at a Central Pathology laboratory
96
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CONFIDENTIAL
Protocol No: CS001P3
Multikine Phase-lll Study: Tumor Sample Gollection and
Preparation Guideline and Histopatho¡ogy Protocol
(overview)
1. Prc-treafirent phase - Biopsy Guideline
A. Primarv tumor
(1) take one punch-biopsy for each 1cm of tumor size
(2) prepare freshly about 113 of sampled material taken for genomic studies, immerse
into an Eppendorf tube containing 0.5 ml RNA-later and send ice-cold to NIH Lab (Dr.
Marincola)
(3) fix the remaining 213 of sampled material in buffered neutral formalin and embed
into paraffin. ln case of more than one punched piece, embed each piece into separate
paraffin blocks
(4) prepare H&E section from each paraffin block and store in local path archive one,
while send the paraffin block(s) to central path lab. (Blocks will be returned after
analysis).
English version of the original local path report excluding personal identification data
(PlD) must be sent electronically to the central pathology laboratory with paper copy of
the original path report excluding PlD.
B. Reoional lvmph node
ln case of clinical N positivity it is recommended to confirm it by using fine needle
aspiration biopsy (FNAB) technique. Cytological smears are fixed immediately by
alcohol-containing fixative. Fixed smears are further processed in local pathology
laboratory using HE, Giemsa or Papanicolau staining.
ln case of multiple cytological smears, one representative is to be sent to the central
pathology laboratory. ln case of single smear it is possible to send a virtual smear after
scanning via lnternet to central pathology.
English version of the original local path report excluding PID must be sent
electronically to the central pathology laboratory with paper copy of the original path
report excluding PlD.
2. Postopentive (Surgical) sample Prcpantion - Guideline
A. Primary tumor
Surgical sample kept at 4oC, has to be sent to local pathology laboratory immediately
without fixation.
(1) after gross photography and marking of the resection surfaces representative
sample has to be taken from fresh unfixed tumor for frozen section. After fixation and
staining microscopic analysis must indicate the presence of tumor and stroma. This
frozen section and the native gross photo (electronic form) must be sent to the central
pathology laborarory. A parallel serial sample must be placed into Eppendorf tube
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Amendment #3 Protocol: 27 June 2014
Version 4.0


CONFIDENTIAL
Protocol No: CS00'lP3
contain¡ng 0.5 ml of RNA-later and to be sent for genomic studies at NIH (prof.
Marincola).
(2) after fixation of the rest of the tumor sample (buffered neutral formalin) gross
photography must be prepared demonstrating the maximal diameter of the tumor
(ustified by ruler). One
(3) tumor blocUcm and peritumoraltissue at 1 cm distance must be sampled beside
resection margins. From each paraffin block an extra HE section must be prepared and
sent to the central pathology laboratory for sampling review. Central pathology will
select paraffin block for further analysis, which has to be sent to there. After the central
pathology laboratory studies the paraffin block, these blocks will be returned to local
pathology for archiving.
English version of the original local path report excluding PID must be sent
electronically to the central pathology laboratory with paper copy of the original path
report excluding PlD.
B. Neck dissection (Reqional lvmph nodes)
Labelled and oriented neck dissection sample(s) (by surgeon) is to be fixed in buffered
neutral formaline. After fixation all available lymph nodes must be analysed to define pN
stage. Lymph node(s) from treated area must be labelled. Excess HE sections must be
prepared from each available lymph node(s) which have to be sent to the central
pathology laboratory for reviewing. Central pathology will select paraffln block for further
analysis, which has to be sent to there. After the central pathology laboratory studies
the paraffin block, these blocks will be returned to local pathology for archiving.
English version of the original local path report excluding PID must be sent
electronically to the central pathology laboratory with paper copy of the original path
report excluding PlD.
Case-specific materials to be provided for Central Pathology Analysis - Required
Samples and Information
Samples from Trtil Subjecß - tultlklne Treated and Non-T¡eatcd (No flultikine):
. 
1 fresh sample of the non-treated primary tumor in RNA-later (NlH)
. 1 paraffin block of the non-treated primary tumor (Central Path)
¡ 1 stained cytology smear of FNAB of clinically N+ case (Central Path)
. 
1 frozen section of resected primary tumor (fixed and stained) (Central Path)
o 1 fresh sample of the resected primary tumor in RNA-later (NlH)
. All HE slides of the fixed and sampled resected primary tumor (Central Path)
. Upon request selected paraffin block(s) is to be provided (Central Path)
. All HE slides of the fixed and sampled lymph nodes (Central Path)
. Upon request selected paraffin block(s) rs fo be provided (Central Path)
. Electronic version of the gross photography of the native and fixed resected
primary tumor (Central Path)
98
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CONFIDENTIAL
Protocol No: CS001P3
English version of all the original local path reports excluding PID must be sent
electronically to the central pathology laboratory with paper copies of the original
path reports excluding PlD.
It ß hlghly advlsable to uselconslder the modmed CAP Report fotms to prcpare
Iocal path rcpotß.
99
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CONFIDENTIAL
Protocol No: CS001P3
Genomic Microarray Study
This Study will involve the collection and transport of tumor samples and PBMCs from a
predetermined number of subjects in this study. No subject specific lD or information will
be attached to any of the samples delivered to the NIH/NCI for genomic microarray
testing.
a
Dr. Francesco M, Marincola (Pl); Dr. Timar and Dr. Talor (Co-Pls)
Chief lnfectious Disease and lmmunogenetics Section (lDlS)
Department of Transfusion Medicine, Clinical Center,
Associate Director, Trans-NlH Center for Human lmmunology, National lnstitutes
of Health
Director, CC/CHl FOCIS Center of Excellence
Bldg 10 - Room 1N226
Bethesda - Maryland 20892
Genomic Microarray Study
Tissue biopsies collection and storage Biopsies should be processed at the bed side
For gene profiling analysis, punch biopsies or excisional biopsies should be collected
and processed according to the following protocol:
Direct deposit punch (or FNA) biopsy immediately in 1.8m1 cryo tube with the addition
of 50-100u1 of RNAlater (5 time of the sample volume) and keep sample at 4oC for 4hr
before snap freeze and store at -80oC till RNA isolation or shipment.
For excisional biopsies, depending on the size of the biopsies, increased amount of
RNAlater should be used to cover the whole tissue (5 times of the sample volume) and
sample should be sliced into no more than Smm in thickness. Store sample in RNAlater
at 4oC over night before freeze at -80oC. Frozen samples should never be thawed till
RNA isolation.
Ship complete frozen sample collection to:
Dr. Ena Wang (c/o Dr. F. Marincola)
9000 Rockville Pike, Building l0 room 1C711
Bethesda, MD 20892
USA
Tel:301451-8501
Fax: 301 -420-1 360
NIH will process RNA isolation; amplification and array hyb upon receiving the samples.
100
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APPENDIX 5. Karnofsky Performance Status
Protocol No: CS001P3
Subject Ability
Percent
Status
Able to carry on normal
activity; no special care is
needed
r00
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or
symptoms of disease
80
Normal activity with effort; some signs or
symptoms of disease
Unable to work; able to
live at home; cares for
most personal needs; a
varying amount of
assistance is needed
70
Cares for self; unable to carry on normal activity
or do active work
60
Requires occasional assistance, but is able to
care for most personal needs
50
Requires considerable assistance and frequent
medical care
Unable to care for self;
requires equivalent of
institutional or hospital
care; disease may be
progressing rapidly
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated
though death not imminent
20
Very sick; hospitalization is necessary, active
supportive treatment necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
101
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Protocol No: CS001P3
APPENDIX 6. Amer¡can Joint Gommittee on Cancer (AJCC) Staging,
7th Edition 2010
AJCC STAGING
Oral Cavity
Buccal mucosa"
Floor of mouth*
Ton gue (anterior two{hirds)*
*allowed in protocol
Primarv Tumor lT) - Oral Gavitv
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor < 2 cm in greatest dimension
T2 Tumor > 2 < 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension
T4a Moderatelyadvanced local disease
Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of
face, that is, chin or nose. Tumor invades adjacent structures.
T4b Very advanced local disease
Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal
carotid artery
Oropharynx
Soft palate*
"allowed in protocol
Primarv Tumor lT) - Oropharvnx
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor < 2 cm in greatest dimension
T2 Tumor > 2 < 4 cm in greatest dimension or extension to lingual surface of epiglottis
T3 Tumor more than 4 cm in greatest dimension
T4a Moderatelyadvanced local disease
Tumor invades the larynx, estrinsic muscle of tongue, medial pterygoid, hard palate, or
mandible
T4b Very advanced local disease
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull
base or encases carotid artery
102
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Protocol No: CS001P3
tumors)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension
N2 Metastasis in a single ipsilateral node, more than 3 cm, but not more than 6 cm in
greatest dimension or multiple ipsilateral or bilateral or contralateral nodes, none more
than 6 cm in greatest dimension
N2a Metastasls in a single ipsilateral node more than 3 cm, but not more than 6 cm in
greatest dimension.
N2b Metastasis in a multiple ipsilateral nodes, none more than 6 cm in greatest
dimension
N2c Bilateral or contralateral lymph node not more than 6 cm in greatest dimension
N3 Metastases in a lymph node more than 6 cm in greatest dimension.
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis present
Staqe Groupinqs
Stage I
NO MO
Stage ll
NO MO
Stage lll
NO MO
-3 Nt M0
Stage IVA
4a N0-l M0
-4a N2 M0
Stage IVB
yTN3M0
4b N2 M0
Stage IVC
yTAnyNMl
103
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1.7
2.r
3.7
CONFIDENTIAL
Protocol No: CS001P3
APPENDIX 7. Management of Dental Problems in lrradiated Patients
(Adapted from RTOG protocol 95-01)
Dental Care for lrradiated Patients
Goals for a dental care program include
o reduce incidence of bone necrosrs.
o reduce incidence of irradiation caries.
o allow proper fitting of dentures following treatment
Pre-irradiation Gare and Procedures
The patients may be grouped into four groups in accordance with the problems they
present prior to irradiation.
Dental Caterøorul
lncludes edentulous patients. They may require surgical removal of any symptomatic
cysts, infected retained root tips, or alveolar abscess and hyperplasia. These patients
require hygiene instruction and precautionary instruction about trauma with premature
use of a prosthesis.
Dental Catesorv 2
lncludes those with poor dental hygiene, including those patients whose teeth are
beyond repair by ordinary dental procedure, those with generalized oral sepsis, those
with generalized periodontal disease, and those with chronic periapical abscesses or
granulomas.
Procedures performed on this group include removal of all remaining teeth prior to
irradiation with primary closure and surgical preparation of the alveolar ridges to laterally
support a prosthesis. There should be antibiotic coverage during the healing stage and
adequate time prior to the start of radiation therapy. These patients need complete
hygiene instruction and precautionary instruction about premature use of a prosthesis.
Dental Cateaorv 3
lncludes those in whom dental condition is fair, including those patients whose teeth are
restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep,
carious lesions are not in proximity to the pulp, and no more than 20 restorable carious
lesions are present. X-ray examinations show at least 112 of the bone still present
around root surfaces. These patients require removal of any teeth, which are non-
salvageable in accordance with the above and restorations of the remaining teeth as
required. The patients are instructed for dental prophylaxis and the patients utilize
custom-made fluoride carriers.
Dental Cateooru I
104
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Protocol No: CS001P3
lncludes those in whom dental hygiene is good. This includes patients who do not have
severe malocclusion in whom few carious lesions are present. Carious lesions are not in
close proximity to the pulp and are correctable by conventional methods. These patients
require periodontal evaluation and dental prophylaxis training, restorations as needed,
no extractions prior to radiation therapy, and fitting for custom carriers.
Extraction of Teeth
lf extraction of teeth is necessary prior to radiation therapy, the bone must be contoured
so that closure at the extraction site is possible. All loose spicules and sharp projections
must be removed. The approximation of the gingival tissue must be such that the
closure is neither too loose nor too tight. At least 10 days are required for adequate
healing prior to initiation of therapy.
Causative Factors
The major causative factors appear to be the reduction of the amount of saliva and
secondarily, reduced pH in the mouth. This occurs following high dose radiation to the
major salivary glands using parallel opposed flelds. The decay process usually occurs in
the first year following radiation therapy. lt tends to occur more quickly in teeth which
have a large amount of root cementum exposed to those teeth with large amounts of
plaque formation present. Doses of radiation in excess of 20 Gy to salivary tissue place
the teeth at risk.
Preventive Proqram
The rationale behind the use of fluoride treatments is to make the tooth surfaces less
susceptible to the decay process. This is accomplished by a combination of increasing
fluoride concentration on the tooth surface and by the effect of fluoride on the plaque
and flora that are present in the oral cavity. Adequate results are obtained by: 1)
cleansing the teeth thoroughly, followed by a good home care dental prophylaxis
program, 2) construction of fluoride carriers, custom-made mouth guards which provide
local application of fluoride solution to the gingiva and tooth surfaces. Fluoride carriers
are made individually with the use of casts. Material used for making a mouth guard is
"Sta-Guard" plastic used in conjunction with vacutrole unit produced by Jelrus Technical
Products, Corp., both of which are available through local dental supply. This material is
moulded to the cast impression and allowed to harden. A fluoride solution prepared at
the M.D. Anderson Hospital is now available from the Emerson Laboratories, lnc.,
Dallas, Texas 75221. lt has been used to coat the plastic carrier for use in the mouth.
The patients are instructed to cleanse their teeth prior to placement of the carrier. lt is
then worn in place for 5 minutes each day. The patients are instructed to rinse their
mouths thoroughly following the use of the carrier. This will be continued for an
indefinite period of time. Close follow-up is necessary.
Results
105
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Protocol No: CS001P3
ln the 5-112 year program at the M.D. Anderson Hospital beginning in 1966, a study of
304 patients shows that the incidence of necrosis of the jaw was reduced to
approximately 21% compared to 37% prior to initiation of the study. Groups 3 and 4
patients randomized with and without fluoride treatment showed reduction in radiation
caries Írom 670/o to 34% among Group 3 patients, and from 65% to 22o/o amon! Group
4 patients.
Failure to Control Decav
Management of failure to control radiation decay includes silver fillings with continued
use of fluoride treatments. lf the decay process is sufficiently advanced that a filling will
no longer stay in place, these teeth are merely smoothed so that there will be no sharp,
irritating edges. The mere existence of such a decayed tooth is not necessarily reason
for extraction, for it must be remembered that extraction could lead to complications
such as bone necrosis.
Pulp exposure resulting from the decay process can usually be handled by use of
antibiotics and/or root-canal therapy.
Hvpersens itivitv of Teeth
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to
diminished amounts of saliva, and has been shown to be reduced in incidence with the
fluoride treatments.
Should this problem become manifest, increasing the fluoride treatment to 10 to 15
minutes 3 times a day is recommended.
lnfections
lnfections occurring in patients under or after radiation therapy are best managed
conservatively with good oral hygiene, irrigation and flushing procedures, and systemic
antibiotics.
Bone Necrosis
The patients receiving radiation therapy to a high dose to the head and neck region
have increased susceptibility to bone necrosis for several reasons including: impairment
of normal metabolism, increased susceptibility to infection and severely limited repair
process. Bone necrosis occurs most often after post-irradiation surgery or other
traumas. Conservative management should be tried first, though in more aggressive
lesions a more radical approach may ultimately be necessary.
106
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Protocol No: CS001P3
APPENDIX 8. NCI Common Toxicity Griteria Ver.4.0, May 28, 2009
A Booklet containing the NCI Common Toxicity Criteria Ver 4.0, May 28, 2009 will be provided to sites as
part of submission package
Common Terminolqy Criteria for Adversc Events v4.0 (CfCAEl
Publirh Drtc: Moy 26, 2@9
¡¡r¡*.É¡¡¡
lhr ttfl Gonçren lqñinole¡y Crîtr¡i¡ l*
Adverse Events ts a desrrlptl¡æ terminolocr whlch
c¡n bc uüli!.d for Advør¿ EvÊnl (At) rêponiña"
A grading (rev€rltyl sc¡le is prwided lor e¡ch At
lctil t.
bEnrû¡ÅeËu¡¡rü!
so(
tTrlcrn OrB¡rì Cbrf lfu highrr hml of thr
MedDRA hleorchy, is ldentitled \ an¿tomkd or
pfudolo¡lcal rlrtõn, ct¡ology, or purpoæ 1c4.,
SflC Invcsligetinnr fr lehretory teçt rñlkl-
ÊlÊÀÊ t¿rm¡ rrc gmupcd b9 MdDRA Primrry
lOG, W'rthh ¿¡dr !OÇ AEs ¡¡e llíed ¿rd
xcompenial hy dcryiptbn. ùf 5êyÊrlty [Gradcl.
CICIE lcnnr
Á¡ Mvers¿ Évent (AÊf ls any unfavøeble and
unnmdcd
Drñnlrl¡r
A brirl dcfinit¡cn ir prc*/cd te cl¡r'fy tlx
mee nl¡g of each AE term,
€rdn
6r¿dè re4ers rc üê saJerfry ol ü€ AC, Tte CT'çAE
dkp{ryr ôredcr t thrwgh 5 vrfth ml6rc cllnlcrl
descriptionE of ¡erærity for e¡ch AE based on thÍ¡
ûcr¡rnl Suiddino:
Gr¡dr 1 ¡lild; ¡Ë\/lîelÕñ¡tic or nìld
tynetomlj cllnk¡l or dlegnosdc
o'b¡crullm trfyt lntftôtion mt
¡rrliøtÞri-
Gr¿úe 2 Mcder¡Îe; m{¡lmal, lor¿l or
nd¡ínrrivô ¡ñtûr¡int¡on indiai}dl
lirnifnS 
ag*approprla*
l¡ul¡urnq¡r¡l AOt'"
Gr¡d¡ ! l¡q¡s o¡ mrl'í<elly d¡nlkrnt but
not iírrÍ.dir¡aly lffê'lhro¡t.â¡ngi
hospit¡lhâtbn ø grolon¡ation ol
ho6p1(åll¡È¡þn lr¡dkår.<l; dlsåblrn$
limitin¡ rclf earcr\D|.",
Çrcdr¡ U!-thr!.frñ¡n3 cstrrgvt^,crri
úrtãìt lnterYÊRt¡ôn indc¡ted-
Gr¡dc5 oÊ.rhrÈlåtêdtóÅÈ
A 3enrl-,ur¡}¡rr hxllcEtËà 'ur' w[hl¡t thÊ dénrlÉioil
ofthe grxG,
A ¡lnfle d¡eh l-l rndrc.tff r gradr |¡ not .varlab¿e,
|{u oll Gr¿dc: rrc ùppropr¡orç for oll ÂEa
Thcrefore. some Afs ¡re l¡sted mth faver th¡n
fnr oprionr for Gndo solec¡¡on.
Ond¡ 5
fîndr ( (fleethl i( mt ¡nlrôndlt^ fnr mm¡ Àft
erd ú¡erefore ls nqt ¡n optlo¡,
,l{suitu el o!¡t ltN¡ñg l,\Dll
al¡¡trvncrrtrl AOt ru{rr to prrprrin¡ moh,
¡hopdng lor grc(eries or rlothes, uslry the
teleptrcne, managlq r¡oney, etc
"sell r¡re ADI rplpr to hlthl4: irerting rnd
undresslng feedlng selt, udng dre tollet, uklng
mdic¡lioø, ¡nd not bdriddm,
loborotory
tempo¡¿llv
rryr frn ludrn¡ tn ¡knrrul
flnJlq), rympton¡ o¡ dl¡c¡æ
¿ssoci¿ted wi$ lhp usp of e nedic¿l
Eeåtmeot or procedure lhat may or rnôy !g! be
cor¡iidcrtd ral¡tôd ro tha mad¡cl t.r¿lmtrlt 9r
præedurc, A¡ At l: ¿ tcrm ìhôt b o uolq,re
rêÉréá¿Õtltbn ol ¡ soeejlx ËÙcnt u:¿d for
medk¡l docrnnentatloo ¡nd scienttfic ¿n¿lï:e:,
E*h CTCAE s4.0 t¿¡m ls ¡ Med0ft,{ LtT ltúyr€ál
trvel Terml,
107
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Protocol No: CS001P3
APPENDIX 9.
Quality of Life lnstrument - EORTC QLQ-G3O and EORTC QLQ-H&N 35
(Please see the following four pages for assessments)
108
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Protocol No: CS001P3
ENGLLSH
@
EORTC QLQ-C30 (version 3)
We are interested in soure tlúngs about you and yoru lreallh, Please a¡rsws all of the qræstioræ yoruself by circling fhe
utunber thnl best applies to you. There are uo "right" o¡ "wrolìg" iür¡wers, The irformafion that you provide will
rannin strictly confidemial.
Please fill inyoru initials:
Yotu birlhdate @a¡ Month, Year):
Toda/s date (Day, Monll¡ Year);
rlrlr
JI
1, Do you hnve any honble doing stenuous activities,
like canyhg a healy shopping bâg or â suitcâße?
2, Do you trave auy houble taking a !9¡¡g walk?
3, Do you lnve any houble takiug a glq!!walk outside of the horse?
4. Do you need 1o stay in lred or a chair dttrilq the daf
5. Do you ueed lteþ with eatiug, úessilg wasl'in8
¡'oruself or usìng the toilet?
During the past week:
6, Were you limited in doiug either your wor* or otlrer daily activities?
7. Were you linríted in pLusuing you¡ hobl¡ies or other
leisure tirne activities?
8, Werc you short ofbrcath?
9, Haveyouhadpaût?
10. Didyou r¡eedto rest?
ll. Have youhad rouble sleepinpf
12. llareyoufeltweak?
13. Ffave you lacked ap¡ætite?
14, l-hve you felt nauseated?
15, Hnve yor¡ vomited? 
1Og
Not nt
AII
I
I
I
I
A
Little
2
2
7
)
Quite
a Bit
3
3
3
3
Very
Much
4
4
4
4
À
Llttle
3
4
Not ît
Ail
Qulfe
å Blt
\tcty
Mucl
4
2
3
2
2
2
2
2
2
2
a
4
4
4
4
4
4
4
4
4
4
3
3
J
3
J
I
3
3
rh s mater a r ,ît prfåî[ry"úS1!-,i3¿,ß?ff.,."& not d sc ose or use except as author zed n wr t ns bI the studå sponsor 
3
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Ple¡se qoor tro thenextpase


CONFIDENTIAL
Protocol No: CS001P3
ENGLISH
During the past week:
17. Have you had dianhea?
lE. Were you tired?
19. Did pain interferc with your daily activities?
2O. Have you had difficulty in concenhating on things.
like reading a newqraper tr warching television?
2l Didyou feel torse?
22. Didyouwoq?
23. Ddyoufeelimtable?
24. Did you feel dçressed?
25. llave you had ditrcnlty rmenúering things?
26. llas yoru physical condition or medical tse¿[Ent
interfercd withyour family life?
27. Hasyov physic¿l condition or rnedical beahneut
interfered with yow social activities?
2E. Has your plrlaical condition or medical h'%hneot
caused you filalcial dificulties?
Not at
All
i
t
I
A
Littte
)
a
2
Qúte
å Bit
3
3
1
!'er.v
Much
4
4
4
4
4
4
4
4
4
I
3
J
3
3
3
a
2
2
2
2
2
J
')
2
3
4
4
5
4
For the following questions please circle the number between 1 and 7 tha;t
best npplies to you
29. How would you rate you' overall health ûrring the past \ileek?
1234367
!-erypoor 
Excellent
30. How wonld you tate yoru overall oualitv of life ùring the past weelfl
t2345óJ
Verypom 
Excellent
110
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6 C¡p]îighl 1995 EORrc Qr:litt of Lifr CroìS, All riglts wræd. Vmim 3 0
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Protocol No: CS001P3
ENGL1SH
a
EORTC OLO - II&N35
Patients sometiûres report thât they have the following sFnptorns or problems. Please indicate the
extent to which you have experienced these synptor¡¡s or problems du¡inq the oast week. Please
answer by circling the nur¡rber that best applies to yotr.
During the past week:
31,
32.
33.
34.
35.
36.
31.
3E.
39.
40.
41.
42.
43.
11.
45.
46"
47.
48,
Have you lud pain in yow nrouth?
Have you had pain in your jaw?
Hove you had soreness in your mouth?
Hare you lmd a pnfuful throaP
Have you had probleos sw¡llo¡¡¡ingt liqrdds?
Have you had problerm swalloningpureed food?
Have 1ou had probleus swallowing solid food?
Have you chokedwhen swallowilg?
Have you had problems with your teeth?
Have you had probler¡s opeling yorn mouth wide?
flave you bacl a dry mouth?
Have you had sticky saliva?
Hale you had problems with your sense of srnell?
Have you bad problems with yoru sense of taste?
Hare you cou¡üed?
Ha\€ yoù been hoarse?
I'Iale ¡rou felt i.ll?
Hns your appearnrrce bothered you?
Not
ùt ¡ll
I
I
t
I
I
I
I
I
I
I
I
I
I
L
I
l
I
I
.4,
llttle
7
)
,
.,
t
,
I
2
)
7
)
I
7
)
2
)
)
,
Quite
f, l¡lt
3
l
3
3
3
J
1
3
3
3
3
3
3
3
3
1
3
3
Very
much
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Please eo on to tlÌe next !¡Êe
111
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CONFIDENTIAL
Protocol No: CS001P3
ENGLISH
49.
50.
51.
52.
53.
54.
55-
56.
57.
58-
During the past week:
Have you harl trouble eating?
Have you had trouble eating iu ûont ofyou family?
Have you had houble eating in ûont of other people?
Have you had ftouble eqioying yotuureals?
Have you had houble talking to other people?
IIave you had trouble talking on the telephone?
Hare you had trouble having social coltact with yoru famiþ4
Have you had trouble having social contactwith frieods?
Have you had trouble going out in public?
Ilave you had trouble having physical
contact with family or friends?
Have you felt less interest ir sex?
Have you felt less sexual enjoyrrelt?
Not
ât trll
I
1
I
I
I
I
L
1
I
A 
Quite
little âbit
23
?'l
z3
)t
23
23
23
23
23
!'er]'
much
4
4
4
4
4
4
4
4
4
59
60
4
4
4
J
_t
2
)
)
1
During the past week:
61. Har,e you used pain-killers?
62- Have you taken any nutritional supplements (excluding vitamins)?
ó3. Haveyouuseda feedingtube?
64. Haveyoulostweigbt?
65. Have you gained weiglrtz
112
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Yes
No
2
2
2
2
2
I
I
0$:llt#-fî{,#fueotq!nefil; ?/oolt6ñ?BJ*t "'íre 
crow ,,ffiim , Ar rish,E *ftd


CONFIDENTIAL
Protocol No: CS001P3
APPENDIX 10. RECIST Response Griteria Version 1.0
At baseline, tumor lesions will be categorized as:
Measurable: Lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as > 20 mm with
conventionaltechniques or as 110 mm with spiral CT scan.
OR
Non- 
All other lesions, including small lesions (longest diameter
measurable: < 10 mm with spiral CT scan) and truly non-measurable lesions.
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.
Lesions that are considered as truly non-measurable include the following:
. bone lesions,
. leptomeningealdisease,
. ascites,
o pleural/pericardial effusion,
. inflammatory breast disease,
. lymphangitiscutis/pulmonis,
. abdominal masses that are not confirmed and followed by imaging
techniques,
. cystic lesions.
Methods of Measurements
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.
lmaging-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
Clinically detected lesions will only be considered measurable when they are superficial
(e.9., skin nodules, palpable lymph nodes). For 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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Chest X-ray
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly
defined and surrounded by aerated lung. However, CT is preferable. lt is assumed that
chest radiographs are performed erect, in the postero-anterior (PA) projection, in full
inspiration. However patients in trials with advanced disease may not be well enough to
fulfill these criteria and such situations should be reported together with the
measurements.
Note: Lesions bordering the thoracic wall are not suitable for measurements by chest
X-ray, since a slight change in position of the patients can cause considerable
differences in the plane in which the lesion is projected and may appear to cause a
change that is actually an artifact. These lesions should be followed by CT or MRl.
Similarly, lesions bordering or involving the mediastinum should be documented on CT
or MRl.
CT, MRI
CT and MRI are the best currently available and reproducible methods to measure
target lesions selected for response assessment. When possible, oral or lV contrast
should be used to increase the differences in density between the structures. The same
imaging protocol should be used for successive evaluations of the same patients [same
machine (MRl), same timing for contrasts enhancement (CT), same slice thicknessl.
The same radiologist at an investigative site (named on FDA Form 1572) shall read all
slides (as far as possible) to ensure consistency.
CT and MRI should be performed with contiguous cuts of 10 mm or less in slice
thickness contiguously (this applies to the chest, abdomen and pelvis). Lesions should
be measured on "soft tissue" settings.
Note: Lung lesions should be imaged on both "soft tissue" and "lung" windows to ensure
that small, miliary metastases are not being inadvertently overlooked.
Ultrasound
Ultrasound should not be used to measure tumor lesions for objective response
evaluation. lt is however a possible alternative to clinical measurements of superficial
palpable nodes. Ultrasound might also be useful to detect new lesions that must be
considered for the overall response assessment.
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation has not yet been fully
and widely validated. Their uses in this specific context require sophisticated equipment
and a high level of expertise that may only be available in some centers. Therefore, the
utilization of such techniques for objective tumor response should be restricted to
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Protocol No: CS001P3
validation purposes in specialized centers. However, such techniques can be usefulto
confirm complete pathological response.
Tumor Markers
Tumor markers alone cannot be used to assess response. However, if initially above
upper normal limit, they must return to normal for a patient to be considered in complete
clinical response when all tumor lesions have disappeared.
Cytology, Histology
These techniques can be used to differentiate between PR and CR in rare cases (eg
after treatment to differentiate between residual benign lesions and residual malignant
lesions in tumor types such as germ cell tumors).
Cytological confirmation of the neoplastic nature of any effusion that appears or
worsens during treatment is required when the measurable tumor has met criteria for
response or stable disease. Under such circumstances, the cytological examination of
the fluid collected will permit differentiation between response or stable disease.
New Techniques
New techniques to better investigate the objective tumor response (eg, PET scanning,
Spiral scanning) are currently being validated. However, standard procedures and
definitions to be used in the context of tumor response evaluation are not yet available.
Therefore, the utilization of such techniques for objective tumor response do not form a
part of this protocol.
Assessment of Overall Tumor Bulk and Measurable Disease
To assess objective response, it is necessary to estimate the overall tumor burden at
baseline and use this as a comparator for subsequent measurements. Measurable
disease is defined by the presence of at least one measurable lesion with a diameter
(single dimension) > 20 mm. lf the measurable disease is a solitary lesion, its neoplastic
nature should be confirmed by cytology/histology.
Baseline Documentation and Non-Tarqet Lesions
Tarqet Lesions
All measurable lesions up to a maximum of 5 leslons per organ, 10 lesions total
representative of all involved organs should be identified as target lesions and will be
recorded and measured at baseline. Target lesions should be selected on the basis of
their size (lesions with the longest diameter [LD]) and their suitability for accurate
repeated measurements (either by imaging techniques or clinically). A sum of the LD for
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Protocol No: CS001P3
alltarget lesions will be calculated and reported as the baseline sum LD. The baseline
sum LD will be used as reference to further characterize the objective tumor response.
Non-tarqet Lesions
All other lesions (or sites of disease) should be identified as non-target lesions and
should also be recorded at baseline. Measurements of these lesions are not required,
but the presence or absence of each should be noted throughout follow-up.
Response Criteria Definitions- Evaluation of Target Lesions
Complete Response (CR) 
Disappearance of all target lesions.
Partial Response (PR)
At least a 30Yo decrease in the sum of LD of target lesions
taking as reference the baseline sum LD.
Progressive Disease (PD)
At least a 20o/o 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 reference the smallest sum
LD since the treatment started.
Evaluation of Non Taroet Lesions
Complete Response (CR) 
Disappearance of all non-target lesions and normalization
of tumor marker level.
lncomplete Response/Stable Persistence of one or more non-target lesion(s) and/or the
Disease (non-CR) 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD) 
Appearance of one or more new lesions, and/or
unequivocal progression of existing non-target lesions.
Although a clear progression of "non target" lesions only is exceptional, in such
circumstances, the opinion of the treating physician should prevail and the progression
status should be confirmed later on by the review panel or study chairperson.
Evaluation of Best Overall Response
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arget
resPonse
lesions
Non-
CR
CR
PR
SD
PD
Any
Anv
CR
lncomplete
response/SD
Non-PD
Non-PD
Any
No
No
No
No
Yes
Yes
Yes
CR
PR
PR
SD
PD
PD
AnV
PD
PD
or No
or No
CONFIDENTIAL 
ProtocolNo:Cs001P3
Table 8.2.2.3: Criteria Used for Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of
treatment until disease progression/recurrence (taking as reference for
progressive disease the smallest measurements recorded since the treatment
started).
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". ln such cases, every effort
should be made to document any subsequent objective progression.
Conditions that may define "early progression, early death and inevaluability
are study specific and should be clearly defined in each protocol (depending
on treatment duration, treatment periodicity).
ln some circumstances it may be difficult to distinguish residual disease
from normaltissue. When the evaluation of complete response depends
on this particular situation it is recommended to investigate the residual
lesion (fine needle aspiration/biopsy) before confirming the complete
response status.
Confirmatorv Measurement and Duration of Response
The main goal of confirmation of objective response is to minimize the risk of over-
estimation of the response rate. This aspect of response evaluation is particularly
important in non-randomized trials where response is the primary endpoint. ln order to
be assigned a status of PR or CR, changes in tumor measurements must be confirmed
by repeat assessments that should be performed no less than 4 weeks after the criteria
for response are first met. ln the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval (in general not less than 6
to I weeks).
Duration of Overall Response
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a
a


CONFIDENTIAL
Protocol No: CS001P3
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 flrst 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.
Best Overall Response
The best overall response is the best response recorded from the start of the treatment
until disease progression/recurrence. ln generalthe patient's best response assignment
will depend on the achievement of both measurement and confirmation criteria.
APPENDIX ll. lnvestigational Drug Thaw Procedure
The drug (Multikine, Leukocyte lnterleukin, lnjection) is stored frozen in the
pharmacy at -20oC until needed. The vial contents should be thawed at ambient
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Protocol No: CS001P3
temperature just before use, and the drug allowed to reach ambient temperature
before injection. lt must be injected within 4 hours of thawing. Multikine may also be
thawed at refrigerator temperature (2-8oC) one day before use, and allowed to come
to ambient temperature just prior to injection - either procedure for thawing the Drug
vial may be followed. However, the overnight thaw at 2-8oC temperature is
preferable as the drug may be kept for up to 24 additional hours at 2-8oC
temperature if need be. Once the drug is brought to ambient temperature, it must be
used within 4 hours or be disposed of. Please follow the Drug Accountability
Procedure for all drug vials in this Study.
Multikine Vial Thaw Procedure
This procedure provides for the thawing of Leukocyte lnterleukin, lnjection. The
following steps should be followed in order to minimize the loss of biological
activity during thawing.
NOTICES AND PRECAUTIONS
This material is derived from human blood. Use Universal Precautions when
handling.
. DO NOT shake vial or thaw in water bath.
. DO NOT use the Leukocyte lnterleukin, lnjection vial after more than
four (4) hours at ambient temperature (21-22oC) or twenty-fow l24l
hours at 2-8oG.
. DO NOT administer this drug if cold.
. DO NOT refreeze vial.
Return unthawed, unused Leukocyte lnterleukin, lnjection vial to the pharmacy
for storage and accountability by the Clinical Monitor.
PROCEDURE
1. Thawing at Approximately 4oC (See attached Figure I )
Remove Leukocyte lnterleukin, lnjection vial from freezer (-20oC).
lmmediately place in 4oC (2-8oC) refrigerator for 2-24 hours.
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Protocol No: CS001P3
Note: Thawing of a2.2 mL vialwilltake approximately 2 hours at
2-goc.
Keep Leukocyte lnterleukin, lnjection refrigerated (2-8oC) until needed for
injection.
Approximately fifteen (15) minutes prior to injection, remove Leukocyte
lnterleukin, lnjection vial from the refrigerator and place on bench top.
Note: This time (fifteen (15) minutes) of removal of vials from 2-
8oC ¡s based on approximately 21-22oC ambienttemperature.
Gently swirl and use for injection when the vial temperature approximates
ambient temperature.
2. Thawing at Ambient Temperature, approximately 21-22oC (See
attached Figure 2)
Remove Leukocyte lnterleukin, lnjection vialfrom freezer (-20oC).
Place vial on bench top and allow to thaw for a period of 30 minutes to 4
hours.
Note: Thawing of a2.2 mL vial directly removed from -20oC
storage will take approximately 30 minutes at approximately 21-
220C.
Gently swirl and use for injection when the vial temperature approximates
ambient temperature.
(See Figures I and 2 below)
Figure l: Leukocyte Interleukin, lnjection (Multikine) Vial Thaw (4oC)
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Protocol No: CS001P3
-20oC Freezer
Ll,
lnj.
1. Store at -20oC
2. Thaw overnight at2-8oC. Do not use after a
maximum period of twenty-four (24) hours at
2-goc.
----------->
4. Gently swirl and use for injection
when the vial temperature
approximates ambient temperature
3. Approximately fifteen (15) minutes prior to
injection, place vial on bench top.
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2-goc
Refrigerator
Lt,
lnj.
Lt,
lnj.


CONFIDENTIAL
Protocol No: CS001P3
Figure 2: Leukocyte lnterleukin, Injection (Multikine) Vial Thaw (amblent
tem peratu re, a pproxim ately 21 -22' Cl
-20oC Freezer
LI,
lnj
1. Store at -20oC
2. Remove the vial from the freezer and place on
bench top. Do not use for a minimum period of
thirty (30) minutes or after a maximum of four (4)
hours at ambient temperature.
3. Gently swirl and use for injection when the vial
temperature approximates ambient temperature
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lnj.


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Protocol No: CS001P3
15. References
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Protocol No: CS001P3
1e Yasumoto, K., Miyazaki, K., Nagashima, 4., et al. lnduction of Lymphokine activated Killer Cells by
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Zsuzsa; Elo, Janos; Balatoni, Zsuzsa; Pocza, Karoly; Zempleni, Bela; Chretien, Paul; and Talor, Eyal;
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Patients with Head & Neck Tumors, Cancer Res. '199'l; 50:5551-5557.
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Protocol No: CS001P3
37 Taylor, C.W , and Hersh, E. M., Use of Recombinant Cytokines in Cancer Therapy, ln Kunkel, S. L.,
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6 Livingston, P.O., et al., lnhibition óf suppressor cell activity by cyclophosphamide in patients with
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o' Berd, D. et. al., lnduction of cell mediated immunity to autologous melanoma cells and regression of
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ot Chirigos, M.A, Talor E., Sidwell, R.W., Burger, R.4., Warren, R P., Leukocyte lnterleukin, lnj. (Ll)
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I mmunotoxicology 1 995; 17 (2), 247 -264.
o' Feinmesser, R., Hardy, 8., Sadov, R., et al , Report of a Clinical Trial in 12 Patients with Head and
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129:874-881.
50 Rathmell AJ, Ash DV, Howes M, Nicholls J. Assessing quality of life in patients treated for advanced
þead and neck cancer. Clin Oncol (R Coll Radiol) 1991; 3:10-6.
51 Gamba A, Romano M, Grosso lM, et al. Psychosocial adjustment of patients surgically treated for head
?nd neck cancer. Head Neck 1992;14:218-23.
u' Logemann JA, Pauloski BR, Rademaker AW, et al Speech and swallow function after tonsil/base of
tongue resection with primary closure. J Speech Hear Res 1993; 36:9'18-26.
'" List MA, Ritter-Sterr CA, Baker TM, et al. Longitudinal assessment of quality of life in laryngeal cancer
patients. Head Neck 1996; 18:1-'10.
* Teichgraeber J, Bowman J, Goepfert H. Functional analysis of treatment of oral cavity cancer. Arch
9tolaryngol Head Neck Surg 1986; 112:959-65.
"" Rapoport Y, Kreitler S, Chaitchik S, Algor R, Weissler K. Psychosocial problems in head-and-neck
cancer patients and their change with time since diagnosis. Ann Oncol 1993; 4'.69-73.
- Bjordal K, Kaasa S, Mastekaasa A. Quality of life in patients treated for head and neck cancer: a follow-
up study 7 to ll years after radiotherapy. lnt J Radiat Oncol Biol Phys '1994; 28.847-56.
"' Bjordal K, Kaasa S. Psychological distress in head and neck cancer patients 7-11 years after curative
treatment. Br J Cancer 1995;71'.592-7.
u8 De Boer MF, Pruyn JFA, Van den Borne HW, Knegt PP, Rijckman RM, C D.A. V. Rehabilitation
-o^utcomes of long-term survivors treated for head and neck cancer. Head Neck 1995; 17:503-515.
"" Dropkin MJ. Coping with disfigurement and dysfunction after head and neck cancer surgery: a
conceptual framework. Semin Oncol Nurs 1989; 5:213-219.
60 Deshmane VH, Parikh HK, Pinni S, Parikh DM, Rao RS. Laryngectomy: a quality of life assessment.
lndian J Cancer 1995;32'.121-130.
125
This material is the property of CEL-SCI Corp Do not disclose or use except as authorized in writing by the study sponsor.
Amendment #3 Protocol: 27 June 2014
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CONFIDENTIAL
Protocol No: CS001P3
61 Gamba A, Romano M, Grosso lM, et al. Psychosocial adjustment of patients surgically treated for head
and neck cancer. Head Neck 1992; 14'.218-223.
62 Langius A, Bjorvell H, Lind MG. Functional status and coping in patients with oral and pharyngeal
cancer before and after surgery. Head Neck 1994; 16:559-668.
ut Rogers SN, Lowe D, Fishãr SE, Brown JS, Vaughan ED. Health-related quality of life and clinical
function after primary surgery for oral cancer. Br J Oral Maxillofac Surg 2002; 40: 1 1-1 8.
o" Deleyiannis FW, Weymuller EA, Jr., Coltrera MD. Quality of life of disease-free survivors of advanced
(stage ll
o" Morto 
Head and Neck 1997; 19'.243-250.
6 Denitt 
eal carcinoma treated with surgery
and radiotherapy: oncologic outcome and functional assessment. Am J Otolaryngol 200'1 ; 22.329-35.
"' Klozar J, Lischkeova B, Betka J. Subjective functional results '1 year after surgery and postoperative
radiation for oropharyngeal carcinoma. Eur Arch Otorhinolaryngol 200'1 ; 258'.546-51 .
oo Campbell BH, Marbella A, Layde PM. Quality of life and recurrence concern in survivors of head and
neck cancer. Laryngoscope 2OOO; 11 0:895-906.
o'Weinstein GS, El-Sawy MM, Ruiz C, et al. Laryngeal preservation with supracricoid partial
laryngectomy results in improved quality of life when compared with total laryngectomy. Laryngoscope
2001;111:191-199.
70 Ward EC, Bishop B, Frisby J, Stevens M. Swallowing outcomes following laryngectomy and
plraryngolaryngectomy. Arch Otolaryn gol Head Neck Surg 2002; 128: 181 -1 86.
" Kuntz AL, Weymuller EA, Jr. lmpact of neck dissection on quality of life. Laryngoscope 1999; 109:'1334-
'1338.
t' Shah S, Har-El G, Rosenfeld RM. Short-term and long-term quality of life after neck dissection. Head
Neck 2001; 23:954-961
73 Terrell JE, Welsh DE, Bradford CR, et al. Pain, quality of life, and spinal accessory nerve status after
neck d issection. La ryngoscope 2000; 1 10'.620-626.
'o Epstein JB, Emerton S, Kolbinson DA, et al. Quality of life and oral function following radiotherapy for
head and neck cancer. Head Neck 1999, 21'.1-11.
75 Harrison LB, Zelefsky MJ, Pfister DG, et al. Detailed quality of life assessment in patients treated with
p^rimary radiotherapy for squamous cell cancer of the base of the tongue. Head Neck 1997; 19:169-175.
'o Huguenin PU, Taussky D, Moe K, et al. Quality of life in patients cured from a carcinoma of the head
and neck by radiotherapy: the importance of the target volume. lnt J Radiat Oncol Biol Phys 1999; 45:47-
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tt Staar S, Rudat V, Stuetzer H, et al lntensified hyperfractionated accelerated radiotherapy limits the
additional benefit of simultaneous chemotherapy-results of a multicentric randomized German trial in
qdvanced head-and-neck cancer. lnt J Radiat Oncol Biol Phys 2001; 50:1161-1171
tt List MA, Mumby P, Haraf D, et al Performance and quality of life outcome in patients completing
concomitant chemoradiotherapy protocols for head and neck cancer. Qual Life Res 1997; 6'.274-84.
tn L¡st MA, Stracks J. Evaluatioñ of quality of life in patients definitively treated for squamous carcinoma of
the head and neck. Curr Opin Oncol 2000; 12.215-20.
to List MA, Siston A, Haraf D, et al. Quality of life and performance in advanced head and neck cancer
patients on concomitant chemoradiotherapy: a prospective examination. J Clin Oncol 1999; 17:1020-8.
o' Pocock SJ, Simon R. (1975) Sequential treatment assignment with balancing for prognostic factors in
the controlled clinical trial, Biometrics 31 : 102-1 15,1975
t' Taves, D. R. (1974). "Minimization: a new method of assigning patients to treatment and control
glroups." Clinical Pharmacology and Therapeutics 15(5): 443-53.
* NCCN Head and Neck Cancers v.1 .2010
e Holm S (1979) "A simple sequential rejective procedure", Scandinavian Journal of Statistics, 6, 65-70.1
85 Lachin JM, Foulkes MA. Evaluation of sample size and power for analyses of survival with allowance
for nonuniform subject entry, losses to follow-up, noncompliance, and stratification. Biometrics.
'1986;42:507-5191.
86 Berlinger NT, Hilal EY, Oettgen HF, Good RA. DeficienT-cell-mediated immunity in head and neck
cancer patients secondary to autologous suppressive immune cells. Laryngoscope '1978; 88l.470-482.
126
This material is the property of CEL-SCl Corp Do not disclose or use except as authorized in writing by the study sponsor.
Amendment #3 Protocol: 27 June 2014
Version 4 0


CONFIDENTIAL
Protocol No: CS001P3
87 Maca RD, Panje W. lndomethacine sensitive suppressor cell activity in head and neck cancer patients
p^re and post irradiation therapy. Cancer. 1982;50:484-489.
oo Coto JA, Hadden EM, Sauro M, Zorn N, Hadden JW. lnterleukin-1 regulates secretion of zinc-thymulin
by human thymic epithelial cells and its action on T lymphocyte proliferation and nuclear protein kinese C.
Procedinq of National Academy of Science USA. 1992; 89:7752-7756
8e Good ñA, Fernandez G, West A. Nutrition, immunity and cancer - a review. Clinical Bulletin. 1979; 9:
3-12.
127
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Amendment #3 Protocol: 27 June 2014
Version 4.0

SAP_005.pdf: 



SAP_001.pdf: 
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Statistical Analysis Plan (SAP) 
Final Analysis - 
Effective Date: 27Nov 2020 
 
 
 
 
 
Sponsor: 
CEL-SCI Corporation 
Study title: 
A Phase III, Open-label, Randomised, Multi-center Study 
of the Effects of Leucocyte Interleukin, Injection 
[Multikine] Plus Standard of Care (Surgery + 
Radiotherapy or Surgery + Concurrent 
Chemoradiotherapy) in Subjects with Advanced Primary 
Squamous Cell Carcinoma of the Oral Cavity / Soft Palate 
Versus Standard of Care Only 
Study number: 
CS001P3 
ICON Study Number 
3140/0001 
SAP version: 
Final: 14Feb2014 
Amendment 1: 27Nov2020 
Yaping Cai 
27 Nov 2020 14:31:032+0000 
Blinded 
Biostatistician: 
REASON: I approve this document 
5847fe6f-1cee-4c47-ac55-feff592129f2 
 
 
Signature 
Date 
Yaping Cai 
Principal Biostatistician 
ICON Clinical Research 
Sponsor's 
Representatives: 
Eyal Talor 
27 Nov 2020 15:09:022+0000 
REASON: I approve this document 
5a7c1b19-989b-4b38-8dd9-45225e5fa404 
 
 
Signature 
Date 
Eyal Talor, PhD 
Chief Scientific Officer 
CEL-SCI Corporation 


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Confidentiality statement: 
▪ 
The information provided in this document is strictly confidential. 
▪ 
The Recipients of the SAP must not disclose the confidential document and any 
related information to other persons. 
▪ 
In addition, they must keep this confidential document in a controlled 
environment which prevents unauthorized access to the document. 
▪ 
This document and information herein is the confidential property of CEL-SCI 
Corporation, and may not be duplicated, reproduced, transmitted or disclosed to 
any third party except as authorized by CEL-SCI Corporation 
 
John Cipriano 
27 Nov 2020 15:29:050+0000 
REASON: I approve this document 
1ab20719-df7a-48a9-9eff-f62f73358e01 
 
Signature 
Date 
John Cipriano 
Senior Vice President - Regulatory Affairs 
CEL-SCI Corporation 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Abbreviations ....................................................................................... 6 
1.0 
Version Control and GCP/ICH Governance ............................. 9 
2.0 
Objectives ................................................................................ 9 
2.1 
Primary Efficacy Objective ......................................................................... 9 
2.2 
Secondary Efficacy Objectives .................................................................. 9 
2.3 
Tertiary Efficacy Objectives ....................................................................... 9 
2.4 
Other Efficacy Objectives .......................................................................... 9 
2.5 
Safety Objective ...................................................................................... 10 
3.0 
Study Design .......................................................................... 10 
3.1 
Randomization ........................................................................................ 10 
3.2 
Sample Size Rationale ............................................................................ 11 
3.2.1 
Historical Basis .......................................................................... 11 
3.2.2 
Assumptions and Calculations .................................................. 11 
4.0 
Endpoint Timing Considerations............................................. 12 
5.0 
Study Hypotheses .................................................................. 12 
5.1 
Primary Hypothesis ................................................................................. 12 
5.2 
Secondary Hypotheses ........................................................................... 13 
5.3 
Tertiary Hypotheses ................................................................................ 14 
5.4 
Other Hypotheses ................................................................................... 15 
5.5 
Safety Hypothesis.................................................................................... 16 
6.0 
Multiplicity .............................................................................. 16 
7.0 
Endpoints ............................................................................... 17 
7.1 
Primary Efficacy Endpoint ....................................................................... 17 
7.2 
Secondary Efficacy Endpoints ................................................................. 17 
7.3 
Tertiary Efficacy Endpoints ...................................................................... 19 
7.4 
Safety 21 
8.0 
Analysis Populations .............................................................. 21 


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8.1 
All Patients Population ............................................................................. 21 
8.2 
Intent to Treat (ITT) Population ................................................................ 22 
8.3 
ITT Evaluable (eITT) Population .............................................................. 22 
8.4 
Per Protocol Evaluable (ePP) Population ................................................ 22 
8.5 
Safety Population .................................................................................... 23 
9.0 
Analysis Timing ...................................................................... 23 
10.0 
Patient Disposition and Baseline Information ......................... 24 
10.1 Patient Disposition ................................................................................... 24 
10.2 Baseline and Demographic Characteristics ............................................. 24 
11.0 
Efficacy Analysis .................................................................... 25 
11.1 Primary Efficacy Analysis ........................................................................ 25 
11.2 Secondary Efficacy Analysis.................................................................... 27 
11.3 Other Secondary Efficacy Analyses ........................................................ 28 
11.4 Tertiary Efficacy Analysis ........................................................................ 30 
11.5 Other Analyses ........................................................................................ 30 
11.5.1 Disease-directed Surgery .......................................................... 30 
11.5.2 Karnofsky Performance Status .................................................. 31 
11.5.3 Other Histopathology Analyses ................................................. 31 
11.5.4 Other Disease-directed Therapies ............................................. 31 
11.5.5 Meta-analyses ........................................................................... 31 
11.5.6 SEER analyses ......................................................................... 32 
12.0 
Safety Analysis ...................................................................... 33 
12.1 Study Drug Exposure and Follow-up ....................................................... 34 
12.2 Adverse Events ....................................................................................... 34 
12.3 Clinical Laboratory Test Results .............................................................. 36 
12.4 Vital Signs ............................................................................................... 37 
12.5 Concomitant Medication .......................................................................... 37 
13.0 
Geographic Region Analysis .................................................. 38 
14.0 
Missing Data Conventions...................................................... 38 
15.0 
Interim Analyses .................................................................... 39 


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16.0 
COVID-19 Study Risk Analysis and Mitigation Strategy ......... 41 
16.1 Background ............................................................................................. 41 
16.2 Overall Study Analysis Strategy .............................................................. 41 
17.0 
Changes to Planned Methodology ......................................... 48 
18.0 
Data Reporting Conventions .................................................. 48 
18.1 Mock-up Template ................................................................................... 48 
19.0 
References............................................................................. 49 


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Abbreviations 
 
AE 
adverse event 
BDRM 
Biostatistics Data Review Meeting 
BSA 
Body surface area 
CIZ 
Cyclophosphamide, Indomethacin, Zinc 
CR 
complete response 
CRTx 
Chemoradiotherapy 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DCFs 
data clarification forms 
DDT 
disease-directed therapy 
DM 
data management 
DMC 
Data Monitoring Committee 
DSUR 
Data Safety Update Report 
eCRF 
electronic Case Report Form 
EGFR 
eITT 
Epidermal growth factor receptor 
Evaluable ITT 
EMA 
European Medicines Agency 
EORTC 30 
European Organization for Research and Treatment of 
Cancer QLQ (Questionnaire) 
EORTC H&N 35 
EOS 
European Organization for Research and Treatment of 
Cancer Head and Neck QLQ (Questionnaire) 
End Of Study 
ERC 
Evaluability Review Committee 
FDA 
Food and Drug Administration 
FFLP-LRC 
Freedom from Local Progression 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
H&N 
Head and Neck 
HIPAA 
Health Insurance Portability and Accountability Act of 
1996 
HNC 
head and neck cancer 
IC 
informed consent 
ICH 
International Conference on Harmonization 
IEC 
Independent Evaluation Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 


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IU 
International unit 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
KPS 
Karnofsky performance status 
LAFU 
Last Alive Follow Up 
LCLLC 
Lavin Consulting LLC 
LD 
Longest Diameter 
LRC 
Loco-regional control 
MCAR 
missing completely at random 
MK 
Multikine 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
OS 
overall survival 
OTR 
Overall tumor response 
pCR 
Pathology complete response 
PD 
progressive disease 
PFS 
progression-free survival 
PHI 
Protected Health Information 
PR 
partial response 
QOL 
Quality of life 
QRL 
Query Resolution Log 
RANTES 
An 8kD Protein belonging to the PF4 (Platelet 
Activating Factor 4) Super Family of chemo-attractants, 
attracting CD4+, CD45RO+ T-cells and Monocytes at 
the inflammatory site 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RTx 
Radiotherapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCC 
squamous cell carcinoma 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SDV 
source data verification 
SEER 
Surveillance, Epidemiology, and End Results 
SOC 
standard of care 
SOPs 
standard operating procedures 
SSP 
Study Specific Procedure 
TEAE 
Treatment emergent adverse event 
TCI 
time-critical interval 


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TLF 
table, listing, and figure 
TNM 
Tumor, nodes, metastases 
TTP 
Time To Progression 
US 
United States 


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1.0 Version Control and GCP/ICH Governance 
This Statistical Analysis Plan (SAP) is based on the protocol amendment 3, version 
4.0, dated 27 Jun 2014. 
The statistical analysis will be conducted under the following ICON SOPs: 
• BST002-SOP Evaluability of Subjects for Analysis 
• BST004-SOP Statistical Analysis Plan 
• BST005-SOP Statistical Review of Statistical Analysis packages. 
and in compliance with the EU GDPR Law for all study subjects in the EU. 
 
2.0 Objectives 
2.1 Primary Efficacy Objective 
The primary objective is to compare overall survival in the Multikine + CIZ + SOC 
group to that in the SOC alone group for superiority of the former. 
 
2.2 Secondary Efficacy Objectives 
The following secondary comparisons are also planned: 
(1) Overall survival (OS) in Multikine + SOC vs. SOC 
(2) Loco-regional Control (LRC) in Multikine + CIZ + SOC vs. SOC 
(3) Progression Free Survival (PFS) in Multikine + CIZ + SOC vs. SOC 
(4) QOL in Multikine + CIZ + SOC vs. SOC 
(5) Examination of the histopathological nature of cellular tumor infiltration 
stimulated by Multikine injection vs. SOC (at the time of planned surgery 
completion) 
 
2.3 Tertiary Efficacy Objectives 
The tertiary objectives of the study include: 
(1) Compare overall survival for Multikine + CIZ + SOC vs. Multikine + SOC 
(2) Compare tumor response for Multikine + CIZ + SOC vs. SOC (at the time 
of planned surgery completion) 
 
 
2.4 
Other Efficacy Objectives 


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Other efficacy objectives of the study include: 
(1) Compare OS controlling for pre-defined histopathology thresholds, 
stage, location, and treatment interactions 
(2) Compare LRC controlling for pre-defined histopathology thresholds, 
stage, location, and treatment interactions 
(3) Compare PFS controlling for pre-defined histopathology thresholds, 
stage, location, and treatment interactions. 
 
 
2.5 
Safety Objective 
 
The safety objectives include: 
 
(1) Compare the incidence of related treatment-emergent adverse events 
(TEAEs) incidence excess for each of the Mulitikine treated arms vs. 
SOC, alone and in combination 
(2) Compare the incidence of related serious adverse events (SAEs) 
incidence excess for the Multikine treated arms vs. SOC, alone and in 
combination. 
 
3.0 Study Design 
This is a Phase III open-label, multi-center, randomized study to determine the 
efficacy and safety of peri-tumoral and peri-lymphatic injection of Multikine (400 IU 
as IL-2 equivalent / daily dose for 3 weeks 5 times per week) given prior to SOC. The 
following treatment groups were enrolled: 
(1) Multikine + CIZ + SOC 
(2) Multikine + SOC 
(3) SOC alone. 
 
3.1 
Randomization 
 
An Interactive Web Response System (IWRS) was used for randomization and 
stratification. Subjects were randomized in a 3:3:1 allocation with Multikine + SOC 
(without CIZ) being the treatment group to be assigned least often in contrast to 
Multikine + CIZ + SOC and SOC alone. Subjects were stratified by country, by 
tumor location (tongue (oral portion only – base of the tongue excluded), floor of 
the mouth, cheek and soft palate), and tumor stage (Stage III and Stage IVa (T4N0- 
2, T1-3N2)) 


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Primary Tumor 
Nodal 
Involvement 
T1 
T2 
T3 
T4 
N0 
NE 
NE 
Stage III 
Stage Iva 
N1 
Stage III 
Stage III 
Stage III 
Stage Iva 
N2 
Stage Iva 
Stage Iva 
Stage Iva 
Stage Iva 
NOTE: Patients with distal metastasis were not allowed into the study. 
A dynamic randomization was used to promote balancing across study sites within 
a country and globally. 
 
3.2 
Sample Size Rationale 
 
3.2.1 Historical Basis 
 
Primary Endpoint 
 
Current SOC for SCCHN adopted by the oncology community [includes: post- 
operative concurrent chemoradiotherapy (CRTx) or radiotherapy (RTx)] was based 
on trials conducted by the Radiation Therapy Oncology Group (RTOG - NEJM 2004; 
350(19): 1937), and the European Organization for the Research and Treatment of 
Cancer (EORTC – NEJM, 2004; 350(19): 1945). Both trials demonstrated 
improvements in the 3-year Overall Survival rates: an absolute increase of 12 % 
(48% vs. 60%) for the EORTC study and an absolute increase of 10% (47% vs. 57%) 
for the RTOG study. 
This study assumed a 55% 3-year overall survival rate for SOC alone. This assumes 
70-80% of the subjects were at lower risk at the time of surgery. As for the EORTC 
and the RTOG studies, a 10% absolute gain in overall survival (OS) is regarded as 
being clinically meaningful. The primary study goal to test Multikine + CIZ + SOC 
superiority vs. SOC alone was to reject the 55% 3-year overall survival rate for SOC 
alone against a 65% 3-year overall rate for Multikine + CIZ + SOC. The Phase 3 
study is being conducted as an event-driven study where death is the event. 
 
3.2.2 Assumptions and Calculations 
 
The primary comparison was based on 80% power and a two-sided 5% Type I error 
to detect a 10% absolute survival advantage at 3 years (55% vs. 65%). Assuming 
exponential hazards, this yields a hazard ratio of 0.721. For this comparison, the log 
rank test requires a total of 298 deaths. The trial will be conducted as an event-driven 


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trial and will conclude once a total 298 deaths in Multikine + CIZ + SOC group and 
SOC alone group have been documented. The deaths in the Multikine + SOC arm 
are not included in the 298 deaths count. 
Since death certificates or death registry information should be available for virtually 
all subjects, the calculations assume no losses to follow-up for overall survival. A 24- 
month (total) recruitment period and a 30-month follow-up period yields a sample 
size of 336 subjects in each of the Multikine + CIZ + SOC and SOC alone groups. 
Under a 3:3:1 randomization, this yields 112 subjects in the Multikine + SOC group 
for a total estimate of 784 evaluable subjects. 
A total of 928 subjects were enrolled in the Phase 3 Study, globally. 
 
 
4.0 Endpoint Timing Considerations 
This study has the following time-critical intervals (TCIs) of interest: 
A. Study entry to completion of study-planned surgery 
B. Immediately after study-planned surgery including the completion of stage- 
specific protocol-directed therapy (RTx or CRTx) to and including Month 36 
C. Immediately after study-planned surgery including the completion of stage- 
specific protocol-directed therapy (RTx or CRTx) to Study Exit 
D. Immediately after Month 36 to Study Exit 
E. Study Entry (date randomized) to Study Exit (date of last follow-up). 
 
There will be efficacy and safety endpoint specific analyses reflecting these time- 
critical intervals. 
 
5.0 Study Hypotheses 
For the primary and secondary efficacy measures, a two-sided p-value of 0.05 or 
less will be considered to be statistically significant in comparing the Multikine 
treatments vs. SOC alone for superiority; for each pre-planned model involving OS, 
LRC, and PFS, contrast tests will be used make pairwise comparisons for all three 
treatment groups will be simultaneously compared without penalty. A Holm closed- 
sequential procedure (as described by Ye1) will be used to control the probability of 
Type I error for the secondary hypotheses. The primary efficacy hypothesis is tested 
first to be followed by the secondary efficacy hypotheses presented below. 
 
5.1 
Primary Hypothesis 
 
OS for Multikine + CIZ+SOC vs. SOC controlling for pre-planned covariates 


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The primary null (H0) and alternative hypotheses (Ha) are: 
H0: h Multikine + CIZ + SOC / h SOC = 1 vs. 
Ha: h Multikine + CIZ + SOC / h SOC < 1, 
where h Multikine + CIZ + SOC is the active (Multikine + CIZ + SOC) hazard rate and 
h SOC is the control (SOC) hazard rate for overall survival time. 
TCI E (see Section 4.0) is the main interval of interest. 
 
5.2 
Secondary Hypotheses 
 
The following secondary comparisons are also planned: 
 
(1) OS for Multikine + SOC vs. SOC controlling for pre-planned covariates 
 
H0: h Multikine + SOC / h SOC = 1 vs. 
Ha: h Multikine + SOC / h SOC < 1, 
where h Multikine + SOC is the active (Multikine + SOC) hazard rate and 
h SOC is the control (SOC) hazard rate for overall survival time. 
TCI E (see Section 4.0) is the main interval of interest. 
 
 
(2) LRC for Multikine + CIZ + SOC vs. SOC controlling for pre-planned covariates 
 
H0: h Multikine + CIZ+ SOC / h SOC = 1 vs. 
Ha: h Multikine + SOC / h SOC < 1, 
where h Multikine + CIZ+ SOC is the active (Multikine + CIZ + SOC) hazard rate and 
h SOC is the control (SOC) hazard rate for progression free survival time. 
TCI E (see Section 4.0) is the main interval of interest. 
 
 
(3) PFS for Multikine + CIZ + SOC vs. SOC controlling for pre-planned covariates 
H0: h Multikine + CIZ+ SOC / h SOC = 1 vs. 
Ha: h Multikine + SOC / h SOC < 1, 
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h SOC is the control (SOC) hazard rate for LRC (Loco-regional control) failure time. 
TCI E (see Section 4.0) is the main interval of interest. 
 
(4) QOL for Multikine + CIZ + SOC vs. SOC 
 
H0: u Multikine + CIZ + SOC = u SOC vs. 
Ha: u Multikine + CIZ + SOC > u SOC 
where u Multikine + CIZ + SOC is the active (Multikine + CIZ + SOC) mean and 
u SOC is the control (SOC) mean for QOL change from baseline for function 
scales and global score. 
H0: u Multikine + CIZ + SOC = u SOC vs. 
Ha: u Multikine + CIZ + SOC < u SOC 
where u Multikine + CIZ + SOC is the active (Multikine + CIZ + SOC) mean and 
u SOC is the control (SOC) mean for QOL change from baseline for symptom 
scales. Note a high score for a symptom scale/item represents a worse outcome. 
TCIs A and B (see Section 4.0) will be of interest with TCI A being of primary 
interest. 
(5) Histopathology differences following Multikine + CIZ + SOC vs. SOC 
Separate hypotheses of distribution (D) shift will be tested for each histopathology 
measure. 
H0: D Multikine + CIZ + SOC = D SOC vs. 
Ha: D Multikine + CIZ + SOC ≠ D SOC 
where D Multikine + CIZ + SOC is the active (Multikine + CIZ + SOC) distribution and 
D SOC is the control (SOC) distribution for each histopathology marker. 
The distribution shift is the noteworthy outcome. 
TCI A (see Section 4.0) is the main interval of interest. 
 
5.3 
Tertiary Hypotheses 
 
The following tertiary comparisons are planned: 


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(1) OS for Multikine + CIZ + SOC vs. Multikine + SOC controlling for pre-planned 
covariates 
 
H0: h Multikine + CIZ + SOC / h Multikine + SOC = 1 vs. 
Ha: h Multikine + CIZ + SOC / h Multikine + SOC < 1, 
where h Multikine + CIZ + SOC is the Multikine + CIZ + SOC hazard rate and 
h Multikine + soc is the Multikine + SOC hazard rate for overall survival time. 
TCI E (see Section 4.0) is the main interval of interest. 
 
(2) Tumor response controlling for pre-planned covariates 
 
Overall tumor response (OTR) is defined as the percent CR or PR per population; 
as determined by RECIST Criteria 1.0; overall response will be evaluated at study- 
directed surgery (following randomized therapy) and then after completion of 
subsequent RTx, or CRTx. 
H0: OTR Multikine + CIZ + SOC = OTR SOC vs. 
Ha: OTR Multikine + CIZ + SOC > OTR SOC 
where OTR Multikine + CIZ + SOC is the active (Multikine + CIZ + SOC) response rate 
and OTR SOC is the control (SOC) response rate. 
As per protocol Section 7.4, the determination of OTR per subject will reflect a 
blinded assessment of histopathology samples to determine patient-specific OTR 
given that the tumor may appear larger resulting from immune cell infiltration into 
the tumor at the interval prior to study planned surgery. 
TCI A is of interest for study therapy and TCI B is of interest for disease-directed 
therapy (DDT). 
 
5.4 
Other Hypotheses 
 
(1) OS for Multikine + SOC vs. SOC controlling for pre-planned covariates including 
histopathology markers 
 
H0: h Multikine + SOC / h SOC = 1 vs. 
Ha: h Multikine + SOC / h SOC < 1, 
where h Multikine + SOC is the active (Multikine + SOC) hazard rate and 


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h SOC is the control (SOC) hazard rate for OS. 
TCI E (see Section 4.0) is the main interval of interest. 
 
 
(2) LRC for Multikine + CIZ + SOC vs. SOC controlling for pre-planned covariates 
including histopathology markers 
 
H0: h Multikine + CIZ+ SOC / h SOC = 1 vs. 
Ha: h Multikine + SOC / h SOC < 1, 
where h Multikine + CIZ+ SOC is the active (Multikine + CIZ + SOC) hazard rate and 
h SOC is the control (SOC) hazard rate for PFS. 
TCI E (see Section 4.0) is the main interval of interest. 
 
 
(3) PFS for Multikine + CIZ + SOC vs. SOC controlling for pre-planned covariates 
including histopathology markers 
 
H0: h Multikine + CIZ+ SOC / h SOC = 1 vs. 
Ha: h Multikine + SOC / h SOC < 1, 
where h Multikine + CIZ+ SOC is the active (Multikine + CIZ + SOC) hazard rate and 
h SOC is the control (SOC) hazard rate for LRC. 
TCI E (see Section 4.0) is the main interval of interest. 
 
5.5 Safety Hypothesis 
 
No formal hypotheses are proposed, but the goal is to rule out a 10% higher 
related TEAE incidence for both Multikine arms vs. SOC, alone and in combination, 
and to rule out a 10% higher related SAE incidence for both Multikine arms vs. 
SOC, alone and in combination. 
See Section 12.2 for the intervals of interest. 
 
 
6.0 Multiplicity 
All p-values will be generated for primary, secondary, and tertiary endpoints. However, a 
Holm closed-sequential procedure will be used to control the probability of Type I error for 
the secondary hypotheses to be tested after the primary hypothesis with the exception of 


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the individual OS, LRC, and PFS hypotheses which will simultaneously compare all three 
treatment groups simultaneously using contrast statements. To support registration 
claims, the Holm closed-sequential procedure will be used for the secondary efficacy 
endpoints only after the primary endpoint OS is tested statistically significant at 0.05 level. 
Thus, these secondary hypothesis tests will not require further Holm testing adjustment. 
With Holm-Bonferroni method, we will order the p-values from smallest to largest for the 
four comparisons of the remaining secondary endpoints, and compare the ordered p- 
values with 0.05/(2-k+1), where 2 is the number of secondary endpoints of interest (LRC, 
PFS) and k is the kth comparison in the sorted sequence, and k ranges from 1 to 2. 
 
The secondary endpoints of interest will be tested with p-values considered as meaningful 
if the primary endpoint is statistically significant (two-sided p<0.05). 
 
 
The Holm procedure will not apply to the histopathology markers or to the QOL measures. 
Thus, for the hypothesis tests on QOL and tertiary endpoints, no Type I error is spent, so 
the tests will only be considered as descriptive. 
 
7.0 Endpoints 
7.1 
Primary Efficacy Endpoint 
Overall Survival Time 
OS is defined as the number of months from randomization to the date of 
documented death or date of last follow-up. TCI E (see Section 4.0) is the main 
interval of interest, but TCIs C and D are also of interest. 
7.2 
Secondary Efficacy Endpoints 
Secondary variables are as follows: 
Progression-Free Survival 
PFS is defined as the number of months from randomization to the date of first 
documented, progressive disease (any tumor recurrence, any new disease above 
clavicle or distant metastases) or the date of last follow-up or death. TCI E (see 
Section 4.0) is the main interval of interest, but TCIs C and D are also of interest. 
Loco-Regional Control 
LRC is defined as the number of months from randomization to the date of 
documented local or regional failure (recurrence or progression) or date of last 
follow-up or death. LRC failure includes the reappearance (recurrence) of disease 
(at the original tumor sites), progressive disease (but not distant metastases), or 
any new disease (including new disease in lymph nodes), above the clavicle, not 


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present at baseline. This is the “traditional” RTOG measure of local-regional 
control, also referred to as Freedom from Local Progression (FFLP-LRC). TCI E 
(see Section 4.0) is the main interval of interest, but TCIs C and D are also of 
interest. 
For each of the time to event endpoints, the censoring rules for patients are 
described in the following table. 
 
Condition 
Date of Censoring 
Randomized and not treated 
Date randomized 
Randomized and treated with no 
follow-up tumor assessments 
Earlier of Date of last treatment or 
surgery 
No tumor assessments at baseline 
or day before surgery 
Earlier of Date of last treatment or 
surgery 
No LRC or progression 
Latest of EOS, LAFU, and 
Last Contact Date 
New anti-cancer treatment started 
before LRC or progression 
Date of last tumor assessment before 
new anti-cancer treatment 
LRC, progression, or death after 
>2 missed follow-up visits 
Date of last non-PD assessment 
 
Quality of Life 
Quality of life is measured by the EORTC QLQ-C30 scales/items and EORTC 
QLQ-H&N35 scales/items. 
The EORTC QLQ-C30 incorporates 30 items and consists of 5 functional scales 
(physical, role, cognitive, emotional, and social functioning), 3 general symptom 
scales (fatigue, pain, and nausea/vomiting), a global QOL scale, and 6 specific 
symptom scales (dyspnea, insomnia, appetite, constipation, diarrhea, and financial 
impact). See the protocol for further QOL specifics. The disease-specific EORTC 
QLQ H&N35 is a supplement module to the QLQ-C30 and consists of 35 questions 
covering aspects of head and neck cancer. Quality of Life (QOL) data will be 
scored according to the algorithm described in the EORTC QLQ-C30 scoring 
manual. Missing data points for multi-item scales will be imputed using the method 
described in the scoring manual where at least half the items from a given scale 
were answered. TCIs A (study therapy) and B (during RTx or CRTx) are of primary 
interest. 
Histologically Confirmed Complete Response Immediately Following Surgery 


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Narratives will be written for all documented complete responders (CRs) achieved 
following the protocol-specified surgery to indicate and describe their tumor 
pathology response (pCR as available from surgical specimens) and the 
subsequent impact on disease-free status following surgery through Month 36 and 
through the end of the study. Complete responders will be documented by 
pathology and imaging as available. The disease-free margins will be noted where 
available. The narrative will also include tabulated information on the cellular 
infiltrate tests for Multikine injected subjects (by group) as well as those treated by 
SOC alone. A table will be generated for pathology findings for each study 
treatment group. TCI A (see Section 4.0) is the main interval of interest. 
Subsequent Complete or Partial Response Following RTx or CRTx 
Narratives will also be written for all documented complete (CR) or partial (PR) 
responses achieved following completion of RTx or CRTx to indicate and describe 
their clinical response (documented by imaging [as available] in the absence of 
biopsies or surgical specimens) and the subsequent impact on disease-free status 
through Month 36 and through the end of the study. Complete and partial 
responders will be documented by imaging as available. The narratives will also 
include reference to the study tumor response including previous histology findings. 
A table will be generated for response outcomes for CRTx and RTx stratified by 
each study treatment group. TCI B (see Section 4.0) is the main interval of 
interest. 
7.3 
Tertiary Efficacy Endpoints 
Tumor response will be derived based on RECIST criteria V1.0. There were no 
non-target lesions assessed at screening on the CRF page, so we will assume all 
lesions (i.e. the primary tumor and any clinically involved lymph node(s)) measured 
at screening were target lesions. The longest diameters (LD) of lesions from 
primary tumor and any clinically involved lymph node(s) are summed. 
Below is the response criteria for target lesions (per RECIST criteria V1.0): 


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Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of LD of target 
lesions, taking as reference the baseline sum LD 
Progressive Disease (PD) 
At least a 20% increase in the sum of LD of target 
lesions, taking as reference the smallest sum LD 
recorded (this includes the baseline sum if that is 
the smallest on study) 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 
reference the smallest sum LD since the treatment 
started 
 
The criteria used for evaluation of overall response at each visit are in the following 
table. 
 
 
Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
SD 
No 
SD 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
 
We will use screening tumor measurement to assess TCI A (see Section 4.0) (i.e., 
change between baseline and day before/on surgery). Following surgery, all 
subjects would have their tumor baseline reset (new baseline) provided the clinical 
and pathology reports indicate a complete removal (or having residual disease 
present post-surgery) of the tumor and any clinically involved lymph nodes. i.e. if a 
subject has their tumor(s) completely removed at surgery, the sum of LD will be 
assumed to be 0 (zero). For Long-Term Follow-up, the focus will be on sustaining 
the complete response as well as avoiding progression of any existing residual 
tumor (i.e., not completely removed at surgery) or the appearance of new tumor[s] 
(and any clinically involved lymph nodes) recorded on the New Lesions CRF page. 
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follow-up, only a small portion of subjects may have data at long-term follow-up 
visits. TCI A (see Section 4.0) is the main interval of interest. 
For TCI B, the following percents will be displayed by CRTx and RTx and stratified 
by study treatment group: (1) having no progression (primary, distal, local), (2) 
having primary progression, (3) having distal progression, (4) having primary 
recurrence above the clavicle (LRC failure), and (5) having primary or distal 
progression (PFS failure). 
 
7.4 Safety 
 
Safety will focus on the number and percentage of subjects with at least one 
TEAE, related TEAE, SAE, related SAE, serious TEAE, serious related TEAE, 
TEAE leading to discontinuation of study treatment and TEAE leading to death will 
be presented by treatment group (each treatment group and the combined 
Multikine treated groups). Events related to study treatment will be summarized 
overall (i.e. related to any study treatment) and for each individual study treatment. 
 
The above tables will be rerun after removing deaths, recurrences, and 
progressions. The rationale is that deaths, recurrence, and progression are each 
components of the major study efficacy endpoints (overall survival, progression- 
free survival, and loco-regional control) in this study. Thus, these are expected 
outcomes on this trial. Therefore, collecting these events as either AEs or SAEs 
would be considered as “double counting”, and thus inappropriate for safety 
reporting purposes. FDA has published this position in the New England Journal of 
Medicine2. 
 
Thus, separate tables will be provided to show all reported AEs/SAEs that include 
deaths/recurrences/progressions as well as filtered tables that do not include these 
events. 
 
See Section 12.2 for intervals of interest. 
 
8.0 Analysis Populations 
8.1 
All Patients Population 
All patients who have attended a screening visit and signed written informed 
consent, including replaced subjects if any, will be included in the All Patients 
population. This population will be used for patient accountability summaries and 
data listings. 


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8.2 
Intent to Treat (ITT) Population 
 
All study subjects who are randomized, regardless of treatment and trial group 
(Multikine treatment or SOC), including any replaced subjects, if any, will be 
included in the ITT analysis. 
The ITT population will be used for a supportive efficacy analysis. 
 
8.3 
ITT Evaluable (eITT) Population 
 
All ITT study subjects who are declared to be evaluable by the blinded Independent 
Evaluation Committee (IEC); see the Evaluability Protocol. The six exclusion criteria 
to remove cases from the ITT population are as follows: 
• Informed consent violations (informed consent not signed) 
• Critical eligibility violations (ineligible stage) 
• Randomization violation (incorrect treatment administration) 
• Multikine treatment violations (failure to administer sufficient dosages) 
• Surgery violations (surgery not performed) 
• Critical radiotherapy or chemotherapy violations (inconsistent with the risk 
group). 
The eITT population will serve as the primary efficacy population. 
 
8.4 
Per Protocol Evaluable (ePP) Population 
 
The following criteria will be used to define the ePP population by excluding cases 
from the eITT population: 
 
(a) Multikine + CIZ + SOC Arm (Group 1): Eligible subjects receiving 12 Multikine 
injections (administrations) as randomized, having completed surgery (as defined 
in the protocol) and receiving at least; cyclophosphamide IV (as defined in the 
protocol), 2 courses of cisplatin (if as a result of surgical findings the subject is 
slated for the concurrent chemoradiotherapy sub-group treatment) and receiving 
75% of indomethacin, 75% of scheduled radiation, and at least 75% of all other 
protocol required treatments. 
(b) SOC Arm (Group 3): Eligible subjects having completed surgery (as defined in 
the protocol) as randomized and receiving at least two courses of cisplatin (if 
as a result of surgical findings the subject will receive the concurrent 
chemoradiotherapy as a sub-group treatment) and receiving at least 75% of all 
other protocol required treatments (e.g., 75% of all scheduled radiation). 


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(c)  Multikine Treatment + SOC Arm (Group 2): Eligible subjects receiving 12 
Multikine injections (administrations) as randomized but without administration 
of any CIZ components, having completed surgery (as defined in the protocol) 
and receiving at least 2 courses of cisplatin (if as a result of surgical findings the 
subject will receive the concurrent chemoradiotherapy as a sub-group treatment) 
and receiving at least 75% of all other protocol required treatments (e.g., 75% of 
all scheduled radiation). 
The ePP population will be used for a supportive efficacy analysis. The analysis will 
have limited value if there are fewer than 298 deaths in the ePP population. 
8.5 
Safety Population 
 
All subjects signing informed consent and having undergone study procedures (e.g., 
tumor biopsy to assess meeting study entry criteria) and/or receiving any study 
therapy/treatment following randomization - such as one or more injections of 
Multikine, any CIZ components, surgery, or any components of the standard of care 
(i.e., surgery or any radiotherapy and/or chemotherapy) will be included in the safety 
population. 
 
9.0 Analysis Timing 
Given that the ITT Evaluable population is a subset of the ITT population, the primary 
analyses will be conducted once the ITT Evaluable population contains at least 298 
documented deaths in the database (eCRF/EDC) in the combined Multikine + CIZ + 
SOC arm and SOC alone arm have been attained; the deaths in the Multikine + SOC 
arm are not included in the required 298 deaths count which has already been 
reached in the ITT population. The ITT Evaluable (primary) and the ITT (supportive) 
populations will be used for registration purposes so the plan is to conduct this final 
analysis once the ITT Evaluable population accumulates at least 298 deaths in the 
combined Multikine + CIZ + SOC arm and SOC alone arm. To provide follow-up 
closure and a cushion against losing cases during the final blinded IEC review, the 
primary analyses will be based on all available follow-up data inclusive of June 30, 
2020 when the last follow-up request was issued. 
In addition, the analysis will be performed concurrently for the ePP population to 
avoid potential analysis influence from the ITT and eITT population analyses. 


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10.0 Patient Disposition and Baseline Information 
10.1 Patient Disposition 
All subjects entered in the study will be accounted for in the disposition 
summarization report. The subject disposition per randomized treatment group will 
include data on randomized treatment, actual treatment, site enrolment, subject 
eligibility, subject compliance, progress through the study, follow-up, 
discontinuation, data on overall qualification status of all subjects, and an account 
of all identified protocol violations. The number of subjects will be displayed for 
those who discontinue before treatment begins, do not qualify for the per protocol 
analyses, who progress during the study, who exhibit loco-regional recurrence, 
who die during the study, or who go on to other treatments. 
The progress of subjects through each treatment regimen (Multikine +/-CIZ + SOC) 
and SOC alone (control group) and through study completion will be shown in 
lifetable output and time to event graphs; the number of subjects will also be 
displayed per randomized treatment group for each of the study populations. 
Reasons for early withdrawal from study will be displayed. The timing of withdrawals 
will also be displayed using a Kaplan-Meier lifetable and compared using an 
unstratified log-rank test. If a subject has reason of “death” or “disease progression” 
for withdrawal, then the subject will be censored at the time of withdrawal, not being 
considered as an event. The pattern of being missing completely at random (MCAR) 
will also be assessed. A logistic regression with early withdrawal as the response, 
treatment group indicator, tumor location (tongue, floor of mouth, cheek, and soft 
palate), tumor stage (Stage III and Stage IVa), and region as the covariates, will be 
performed to examine the pattern for missing data. Baseline characteristics of the 
subjects who withdrew early will be compared to those that did not withdrew early. 
10.2 Baseline and Demographic Characteristics 
Demographic and baseline disease characteristic data will be listed and 
summarized using descriptive statistics for continuous variables and tabulated for 
categorical variables. All summaries will be presented by treatment arm as well as 
overall for the ITT, eITT, ePP, and Safety populations. 
Demographic characteristics for evaluation will include age, gender, race, ethnicity, 
weight, height and BSA. For baseline disease characteristic: details and status of the 
primary tumor at baseline will be summarized by frequency counts of each 
component. This will include physical aspects, biopsy information, location and 
staging. 
Categorical data will be compared between treatment arms using a two-sided 
Fisher exact test, ordinal data will be compared using a Wilcoxon rank sum test, 
and continuous data (e.g., age and BSA) will be compared using an unpaired t-test. 


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11.0 Efficacy Analysis 
All efficacy data will be analyzed in the ITT, eITT, and ePP populations. The ITT 
Evaluable population is the primary population of interest. 
11.1 Primary Efficacy Analysis 
The time to event analysis will be the primary focus for OS; deaths beyond 3 years 
will be included in the analyses. In the analyses for the ITT and eITT populations, 
deaths due to COVID-19 will be censored. The primary efficacy analysis will be 
performed using the unstratified log rank test (as specified in the protocol) with 
stratified log rank and proportional hazard models being supportive given FDA 
preference for predefined multivariate models. The proportional hazard model will 
compare both Multikine arms vs SOC as the referent. TCIs C-E (see Section 4.0) 
are the intervals of interest, with TCI E being primary. 
The stratification is categorized by tumor location (tongue, floor of mouth [referent], 
cheek, and soft palate), tumor stage (Stage III and Stage IVa [referent]) and 
geographical region, respectively. 
Countries will be grouped by the following geographical regions and to best reflect 
medical practices: 
• North America/Europe (EU): US, Canada, UK, Spain, France, Italy, Poland, 
Croatia, Hungary, Romania 
• Europe (Non-EU): Serbia, Bosnia, Turkey 
• Europe/Eurasia: Ukraine, Belarus, Russia 
• Asia/West-Asia [referent]: Sri Lanka, India, Israel 
• Asia-Pacific/Far-East: Malaysia, Philippines, Thailand, Taiwan 
Four series of proportional hazards models will be used to evaluate study 
treatment; the first series will evaluate study treatment as well as baseline covariates 
(tumor stage, tumor location, and geography) while the second series will add 
on-study treatment interactions to the previously cited covariates. The respective 
model will include interactions between treatments and tumor stage, tumor site, and 
geography. Treatment will be modeled with SOC as the reference group to allow 
simultaneous comparisons to Multikine + CIZ + SOC (primary comparison) and to 
Multikine + SOC (secondary comparison). The third series adds negative surgical 
margin after surgery to the first series while the fourth series adds negative surgical 
margin after surgery to the second series; the four series will be performed for TCIs 
C-E with TCI E primary. 
Four additional series of proportional hazards models will be used to evaluate 
study treatment and subsequent DDT (CRTx; RTx); the first series will evaluate study 


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treatment as well as baseline covariates (tumor stage, tumor location, DDT, and 
geography) while the second series will add on-study treatment interactions to the 
previously cited covariates. The respective model will include interactions between 
treatments and tumor stage, tumor site, DDT, and geography. Treatment will be 
modeled with SOC as the reference group to allow simultaneous comparisons to 
Multikine + CIZ + SOC (primary comparison) and to Multikine + SOC (secondary 
comparison). The third series adds negative surgical margin after surgery to the first 
series while the fourth series adds negative surgical margin after surgery to the 
second series; the four series will also be performed for TCIs C-E with TCI E primary. 
 
Subgroup Analysis 
Additional time to event analyses will be performed for the risk group assignment 
reflecting concurrent disease-directed therapy (DDT; radiotherapy or concurrent 
chemoradiotherapy) following surgery - as noted in the protocol; this analysis will 
exclude subjects without surgery or subjects receiving subsequent disease-directed 
therapy other than that prescribed by the protocol following (or instead of) surgery. 
A major prognostic factor for these subjects (in addition to tumor stage at study entry) 
is the respective “high risk” or “low risk” assigned protocol treatment made after 
surgery. Thus, stratification at study entry for this factor cannot be performed. As 
described above, both unstratified and stratified log rank tests and proportional 
hazards models will be performed by risk group; the proportional hazards models will 
include tumor stage, tumor location, geographic location, and treatment. 
In addition, a display of the baseline stage (Stage III, Stage IVa) against subsequent 
DDT (radiotherapy, concurrent chemoradiotherapy) will be generated for each 
treatment group. The choice of adjuvant therapy will depend upon tumor 
characteristics post-surgery as assessed by NCCN Guidelines to determine high/low 
risk administration of radio/chemotherapy. Per NCCN Guidelines3, “High Risk” are 
patients with certain disease characteristics following surgery who are deemed by 
the investigator to be at a “Higher Risk” for recurrence and thus will receive 
concurrent chemoradiotherapy [CRTx] (instead of radiotherapy [RTx] only 
recommended (by the NCCN Guidelines and in the protocol) for the “lower risk” for 
recurrence patients - following surgery). The percents able to “switch” from the 
recommended treatment for Stage IVa or Stage III (at “higher risk”, i.e., CRTx) to 
receiving only radiotherapy (RTx) recommendation based on the pathology and 
clinical assessment following surgery (but not due to the general medical status 
which would not allow the administration of Chemoradiotherapy due to expectation 
of excessive toxicity or patients inability to tolerate CRTx) will be of primary interest 
for this tabulation. The baseline tumor location against subsequent DDT, e.g. 
radiotherapy, concurrent chemoradiotherapy, will also be generated for each 
treatment group by stage (Stage III, Stage IVa). In addition, the percent per treatment 


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group that only received RTx after surgery will be compared to those that received 
CRTx after surgery for each study treatment group. 
To assess the benefit of study-directed therapy and subsequent DDT, additional time 
to event analyses (Kaplan-Meier lifetables and unstratified log rank tests) will be 
performed for the following subgroups: (1) negative surgical margin after surgery, 
and (2) complete or partial response following subsequent DDT. TCIs C-E will be 
the main intervals of interest with TCI E primary. 
Last, prospective stratification will yield subgroup analyses that are planned as an 
exploratory analysis of the primary efficacy endpoint, OS, using tumor location 
(tongue, floor of mouth, cheek, and soft palate), and tumor stage (Stage III, Stage 
IVa) and geographic region. TCIs C-E will be the intervals of interest with TCI E 
primary. 
 
11.2 Secondary Efficacy Analysis 
As for OS, the primary efficacy analysis will be performed using the unstratified log 
rank test (as specified in the protocol) with stratified log rank and proportional hazard 
models being supportive given FDA preference for predefined multivariate models. 
Four series of proportional hazards models will be used to evaluate study treatment 
for PFS and LRC; the first series will evaluate study treatment as well as baseline 
covariates (tumor stage, tumor location, and geography) while the second series will 
add on-study treatment interactions to the previously cited covariates. The 
respective model will include interactions between treatments and tumor stage, 
tumor site, and geography. Treatment will be modeled with SOC as the reference 
group to allow simultaneous comparisons to Multikine + CIZ + SOC (primary 
comparison) and to Multikine + SOC (secondary comparison). The third and fourth 
series adds negative surgical margin after surgery to the first two series; the four 
series will be performed for TCIs C-E with TCI E primary. 
Four additional series of proportional hazards models will be used to evaluate 
study treatment and subsequent DDT (CRTx; RTx); the first series will evaluate study 
treatment as well as baseline covariates (tumor stage, tumor location, DDT, and 
geography) while the second series will add on-study treatment interactions to the 
previously cited covariates. The respective model will include interactions between 
treatments and tumor stage, tumor site, DDT, and geography. Treatment will be 
modeled with SOC as the reference group to allow simultaneous comparisons to 
Multikine + CIZ + SOC (primary comparison) and to Multikine + SOC (secondary 
comparison). The third and fourth series add negative surgical margin after surgery 
to the first two series; the four series will also be performed for TCIs C-E with TCI E 
primary. 


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Last, to assess the benefit of study-directed therapy and subsequent DDT on PFS 
and LRC in subgroups, additional time to event analyses (Kaplan-Meier lifetable and 
stratified and unstratified log rank test) will be performed for the following subgroups: 
(1) negative surgical margin after surgery, and (2) complete or partial response 
following subsequent DDT. TCIs C-E will be the intervals of interest with TCI E 
primary. 
 
11.3 Other Secondary Efficacy Analyses 
The following secondary comparisons are also planned: 
(1) OS in Multikine + CIZ + SOC vs. SOC 
 
(2) LRC in Multikine + CIZ + SOC vs. SOC 
 
(3) PFS in Multikine + SOC vs. SOC 
 
(4) QOL in Multikine + CIZ + SOC vs. SOC 
 
(5) Histopathology differences regarding cellular tumor infiltration following 
Multikine injection vs. SOC. 
 
OS, LRC, PFS 
The Holm closed-sequential procedure will be used to control the overall 5% Type I 
error for the secondary efficacy endpoints (items 1-3 above) corresponding to the 
primary TCI designations with TCI E primary for OS, LRC, and PFS. If the primary 
endpoint OS reaches two-sided statistical significance, we will look at secondary 
endpoints with Holm closed-testing procedure (see Section 6). In addition, the two 
Multikine treatment groups will be compared for these three endpoints as part of the 
previous comparisons of each Multikine group vs SOC. 
LRC and PFS will be analyzed in the same way as OS as designated in Section 11.2. 
Quality of Life 
QOL will be assessed for all subjects prior to randomization (to establish Baseline), 
and then prior to and following (completion of) Multikine administration up to 1 day 
prior to surgery, after RTx and CRTx are completed, and at nominal 6, 12, 18, and 
36 month visits. The change in QOL from baseline within and between treatment 
groups will be assessed. In addition, the change in QOL from prior to surgery at 
each visit during long term follow up period will also be analyzed. Of interest, is 
improvement of swallowing and oral function relative to baseline. The comparisons 
between treatment groups will be performed using ANOVA while the change in QOL 
from baseline within treatment group will be performed using a paired t-test. Two- 
sided mixed model repeated measures will be used to test for treatment differences 
with no adjustment for the Type I error. In addition, a 10-point improvement between 


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treatments at each long-term follow-up visit will be performed by an exact binomial 
test for each treatment group and using a two-sided Fisher Exact test for between 
group comparisons. TCIs A-B will be run. 
Changes in QOL will be assessed using a longitudinal growth model including all 
post-baseline measurements. Study treatment, time point, treatment and time point 
interaction, as well as baseline covariates (baseline score, tumor stage, tumor 
location, and geography) and subject random effect will be included in the model. 
Compound symmetry will be assumed as the covariance structure of the longitudinal 
data. If the model does not converge with subject as random effect, the random 
statement will be dropped from the model. TCIs A-B will be run. 
Histopathology 
Immunohistopathology and histopathology marker parameters (see below with low 
and high thresholds noted for PH regression analyses [see Section 11.5.1]) will be 
assessed for all available and evaluable pathology specimens (tumor-specific 
averages per case to be determined by the Central Pathology at the end of the study) 
will be displayed per study treatment group using a cumulative distribution to be 
compared using a Kolmogorov-Smirnoff test for each of the following markers, 
ratios, and differences: 
1. CD1a DC (10, 50) 
2. CD3 pan-Tcell (100, 1000) 
3. CD4 T helper (100, 1000) 
4. CD8 cytotoxic T (50, 500) 
5. CD4/CD8 (1, 2.5) 
6. CD20 B cell (100, 1000) 
7. CD25 IL2R (100, 1000) 
8. CD68 MPH (100, 1000) 
9. CD163 M2-MPH (50, 100) 
10. CD208 mature DC (50, 100) 
11. FOXP3 Treg (100, 500) 
12. CD8/FOXP3 Treg (1, 2) 
13. p46 NK (10%, 50%) 
14. p16-HPV+ (10%, 50%) 
15. MPOX neutrophil (50, 100) 
16. pan-HLA-I (20, 50) 
17. B2M (20, 50) 
18. PD1 (10, 20) 
19. PDL1 (10, 20) 
20. CTLA4 (10, 20) 
21. MR1 (20, 50) 
22. SCC (squamous cell carcinoma: Yes/No). 


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Any missing cutoffs will be provided prior to database lock. All central pathology 
assessments will be performed on blinded samples by pathologists. TCI A will be 
of primary interest. A third-party statistical vendor (LCLLC - Dr. Lavin) will 
perform the pathology analysis after the study blind is broken. 
• Narratives will be written for all histologically confirmed complete responses 
determined at surgery following study-directed therapy to indicate and describe 
their tumor pathology response (pCR as available from surgical specimens and 
imaging) and disease-free status following surgery through Month 36 and to the 
end of the study; surgical disease-free margins will be noted where available. The 
narrative will also include tabulated information on the type of cellular infiltrates 
present in tumors collected from Multikine injected subjects (by group) as well as 
those treated by SOC alone. 
• Narratives will be written for all subsequent complete or partial response following 
RTx or CRTx to indicate and describe their clinical response (in the absence of 
biopsies or surgical specimens and imaging) and the subsequent impact on 
disease-free status through Month 36 and through the end of the study. The 
narrative will also include reference to the previous histology findings (as available). 
 
11.4 Tertiary Efficacy Analysis 
• 
Tumor Response 
The number of subjects and percentage for each category (CR, PR, SD, PD) of 
overall tumor response (as determined by RECIST Criteria 1.0) will be presented 
by baseline tumor stage, tumor location, treatment group and visit, will be compared 
between the Multikine + CIZ + SOC vs. SOC groups. Results will also be presented 
for the following baseline covariates: tumor stage; tumor location, and geographic 
region. TCIs A (MK effect) and B (DDT effect) will be run. 
• 
OS for Multikine + CIZ + SOC vs. Multikine + SOC 
The hazard rate for overall survival time will be compared between Multikine + CIZ 
+ SOC and Multikine + SOC using proportional hazards model. TCIs C-E are the 
intervals of interest. 
 
11.5 Other Analyses 
 
11.5.1 Disease-directed Surgery 
 
The ability of Multikine to enable disease-directed surgery to be performed. The 
percentage of patients undergoing disease-directed surgeries per treatment group 
will be compared. The surgery rates will be compared using a two-sided Fisher 
Exact test.  TCI A (MK effect) will be of primary interest. 


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11.5.2 Karnofsky Performance Status 
 
The number and percentage of subjects under each Karnofsky Performance Status 
(KPS) score will be summarized per treatment group. The change in KPS from 
baseline within and between treatment groups will be assessed over time. The 
comparisons between treatment groups will be performed using repeated 
measures while the change from baseline within treatment group will be performed 
using a paired t-test. The repeated measures model will include study treatment, 
time point, treatment and time point interaction, baseline KPS, baseline covariates 
(tumor stage, tumor location, and geography). Two-sided test will be used with no 
adjustment for the Type I error. TCIs A (MK effect) and B (DDT effect) will be run. 
 
 
11.5.3 Other Histopathology Analyses 
 
For each biomarker (including the pre-defined ratio and differences), proportional 
hazard models for OS, LRC, and PFS will be run first for just stage, location, lower 
biomarker cutoff, higher biomarker cutoff, and treatment as covariates; the models 
will be repeated by adding treatment interactions with stage, location, and the 
biomarker cutoffs. The goals will be to assess: (1) if any biomarkers have favorable 
prognosis and (2) if any biomarkers downgrade or upgrade the stage. The 
analyses will also be repeated for separate tumor locations (within the oral cavity). 
A third-party statistical vendor (LCLLC - Dr. Lavin) will perform the pathology 
analysis after the study blind is broken. 
 
 
11.5.4 Other Disease-directed Therapies 
 
The impact of other oncology therapies on study participants (not specifically 
prescribed by the protocol) such as: Keytruda, Opdivo, anti-EGFR, and other/or 
approved treatments for H&N or those used “off-label” and which are administered 
post-surgery (and/or given post-randomization) on OS will be examined in the ITT 
and eITT populations. The use of CheckPoint inhibitors, chemotherapies, 
monoclonal antibodies, anti-epidermal growth factor receptor (EGFR) and targeted 
small molecules before as well as after progression will be analyzed using time- 
dependent proportional hazard models to address subjects initiating additional 
disease-directed therapy prior to reaching the respective study endpoint. 
 
11.5.5 Meta-analyses 
Additional analyses are planned to compare the CS001P3 study treatments to pre- 
defined historical controls from the literature for both safety and efficacy. Safety will 


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be compared for TEAEs while efficacy will be compared for 2-year, 3-year, and 5- 
year OS and 2-year LRC rates. 
A completed meta-analysis [reference available upon request] has identified 5 
published surgical control studies with therapies qualifying as SOC. These studies 
provide 2-year, 3-year, and 5-year OS and 2-year LRC estimates as well as safety 
outcomes to compare to the three CS001P3 Study treatment groups. The analysis 
methodology will check if the 2-year, 3-year, and 5-year OS and 2-year LRC lie within 
or below the corresponding Kaplan-Meier lifetable two-sided 95% confidence 
intervals. 
This is relevant since a favorable outcome for Multikine treatment safety may justify 
a lower efficacy standard given the absence of any new breakthrough therapies 
having an OS impact for the advanced primary SCCHN patient population over the 
past 30+ years. This will become a BLA review matter depending on study outcomes 
not yet known. 
Furthermore, the meta-analysis will allow comparison of the 2-year LRC, 3-year OS, 
5-year OS, and overall related TEAE SAE for the three CS001P3 study treatment 
groups to the five surgical controls studies (in the literature) representing SOC. For 
each outcome, results are to be expressed as percent to permit a chi square test to 
be performed to compare the observed vs the expected percent in support of the 
benefit for each (and both) of the two Multikine treatment groups relative to the 
historical control. 
A third-party statistical vendor (LCLLC - Dr. Lavin) performed the meta-analysis for 
the five literature controls without needing to break the study blind. 
 
11.5.6 SEER analyses 
To further assist in such considerations, projected OS outcomes have been 
performed for the SEER database [reference available upon request] to correspond 
to the specific CS001P3 population. This allows a comparison of the overall survival 
curves to assess the performance of both Multikine treatments and the SOC 
treatment relative to the literature control should Multikine treatment safety be more 
favorable than the literature control. The analysis methodology will check if the 2- 
year, 3-year, and 5-year OS and 2-year LRC lie within or below the corresponding 
Kaplan-Meier lifetable two-sided 95% confidence intervals. 
This is relevant since a favorable outcome for Multikine treatment safety may justify 
a lower efficacy standard given the absence of any new breakthrough therapies 
having an OS impact for the advanced primary SCCHN patient population over the 
past 30+ years. This will become a BLA review matter depending on study outcomes 
not yet known. 
The review of the SEER database 18 for 2000-2016 (n=6,641), excluding SEER data 
from 2000 to 2010 (n=3,291), in order to be able to “match” the timing of 


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accrual/treatment of subjects in the CS001P3 Study (using SEER Stat Section 
8.3.5), has informed us that, in the USA (SEER data) in the ‘Oral Cavity and Soft- 
Palate’ matching CS001P3 patients’ tumor location (excluding the base of the tongue 
as in the CS001P3 Study) the survival outcome for the combined Stage III and IVa 
patients (n=3,350). This SEER-database set, designed to approximate the CS001P3 
study patient population, yields 36.75% (‘Observed’) 5-year OS and 46.59% 
(‘Observed’) 3-year OS for SOC only. Of note is that the CS001P3 Study protocol 
estimated (circa 2007 - 2010) that the 3-Year OS for SOC, alone, was 55% and was 
designed to show a 10% absolute increase in OS using the investigational (Multikine) 
treatment regimen + SOC, over that which can be attained with SOC alone (in an 
event-driven study design). 
Table 6: SEER Annual Survival Data: Oral Cavity (including: Tongue [but not base 
of Tongue], Floor of the Mouth + Cheek) + Soft Palate (as in study CS001P3). 
 
Product-Limit Survival Estimates 
Time 
(Months) 
Survival 
Failure 
Survival 
Standard Error 
Number 
Failed 
Number 
Left 
12 
0.7142 
0.2858 
0.00785 
948 
2330 
24 
0.5386 
0.4614 
0.00894 
1474 
1372 
36 
0.4659 
0.5341 
0.00939 
1638 
839 
48 
0.4198 
0.5802 
0.01000 
1707 
498 
60 
0.3675 
0.6325 
0.0116 
1751 
0 
 
The above SEER analyses were already conducted independently by a third-party 
statistical vendor (LCLLC - Dr. Lavin) without needing to break the study blind. 
 
12.0 Safety Analysis 
Safety will be assessed by means of adverse events, laboratory data, and vital signs 
data. All safety data will be summarized by each treatment group for the safety 
population; separately, the two Multikine treatment arms will also be pooled in all 
safety displays. Safety analysis will also be analyzed by timing of the adverse event 
onset from randomization to surgery, from surgery to end of SOC and post SOC 
(also see Sections 2.5, 7.4 and 8.5). See Section 12.2 for the intervals of interest. 
The major safety endpoints are the incidence of related TEAEs and related SAEs for 
each treatment group and for the combined Multikine treated groups. 
Disease progression and death will not be considered to be adverse events as both 
are expected in this population and are endpoints in the study. Disease progression 


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and death adverse events will be separately tabulated, displayed, and compared 
between the three study treatment groups. Separate listings will be generated for all 
SAEs (including progression) as well as for another listing that removes progressions 
from the list of all SAEs. 
 
12.1 Study Drug Exposure and Follow-up 
The number of treatment visits at which Multikine is administered and the amount of 
each study drug delivered per visit and cumulatively will be summarized and 
tabulated. Subjects requiring delay and/or reduction in dose of either, study drug or 
radiotherapy and/or concurrent chemoradiotherapy will be displayed with reasons 
provided for dose reduction. 
The mean follow-up time from randomization to study exit will also be presented for 
each treatment group. 
12.2 Adverse Events 
Results will be presented separately for each treatment group and for combined 
Multikine treated groups. All adverse events except disease progression will be 
reported regardless of causality. Severity of AE will be graded by the investigator 
according to the NCI CTCAE version 4.0. The adverse events will be reviewed and 
coded by sponsor or sponsor’s representative using the latest MedDRA dictionary, 
Version 20.1, or higher. Coding will include system organ class (SOC) and preferred 
term (PT). AEs will be recorded in the electronic Case Report Form (eCRF) starting 
from the time that a subject signs the Informed Consent Form, through the three- 
year follow-up period, and to the end of the study. 
Each AE will be classified as either a pre-treatment AE or a treatment-emergent AE 
(TEAE). Any AE which occurred before the date of randomization in the study will 
be considered as a pre-treatment AE. Any AE which started on or after the date of 
randomization in the study will be considered as a TEAE. AEs with partial or missing 
start dates will be imputed with the rules outlined in Section 14.0. TEAE classification 
will based on the imputed start dates. 
TEAEs with relationship to study treatment recorded in the electronic CRF as 
“possibly related”, “probably related”, “related” or “definitely related” will be defined 
as related TEAEs. 
Pre-treatment AEs will not be included in the summary tables but will be flagged in 
the data listings. 
An overall summary of the number and percentage of subjects with at least one 
TEAE, related TEAE, serious TEAE, serious related TEAE, TEAE leading to 
discontinuation of study treatment and TEAE leading to death will be presented by 
treatment group (each treatment group and the combined Multikine treated groups). 


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Events related to study treatment will be summarized overall (i.e. related to any study 
treatment) and for each individual study treatment. 
Summaries of the number and percentage of subjects with TEAEs by study 
treatment group will also be presented by system organ class and preferred term for: 
o All TEAEs; 
o Related TEAEs; 
o Serious TEAEs; 
o Serious related TEAEs; 
o TEAEs leading to discontinuation of study treatment; 
o TEAEs leading to death. 
In addition, summary of the number and percentage of subjects with TEAEs as well 
as the number of events under each system organ class, and preferred term will be 
presented by maximum CTC grade and relationship to study treatment (“not related”, 
“possibly related”, “probably related”, “related” or “definitely related”) respectively. 
Displays will also be provided for the timing of adverse events to provide insight into 
the Multikine-related adverse events distinct from adverse events related to surgery 
and SOC. The classification of timing will based on the imputed AE start dates (see 
Section 14.0 of this document for imputation rules). The four intervals of interest for 
the timing of the AEs will be: 
(1) post-randomization AEs (start date of AE is on or after the date of 
randomization; these are the TEAEs in this study) 
 
(2) post-randomization/pre-surgery AEs (start date of AE is on or after the date of 
randomization and before the date of surgery), 
 
(3) post-surgery during SOC AEs (start date of AE is on or after the date of surgery 
and start date of AE is on or before 60 days post the last date of 
radiotherapy/chemoradiotherapy) and 
 
(4) Post-SOC AEs (start date of AE is after 60 days post the last date of 
radiotherapy/ chemoradiotherapy). 
 
The overall summary of the number and percentage of subjects with at least one 
TEAE, related TEAE, serious TEAE, serious related TEAE, TEAE leading to 
discontinuation of study treatment and TEAE leading to death will be presented by 
treatment group according to the timing of adverse events as detailed above. Events 
related to study treatment will be summarized overall (i.e. related to any study 
treatment) and for each individual study treatment. 
Summaries of the number and percentage of subjects with TEAEs will be presented 
by system organ class and preferred term for each time-period as determined above. 


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In the summaries of AEs, if severity or relationship to study treatment is missing, the 
AE will be regarded as ‘severe’ or ‘related’ to the study treatment, respectively. 
All verbatim descriptions and coded terms will be listed for all AEs. One listing will 
be produced for all AEs (pre-treatment and TEAEs) and a separate listing will also 
be produced for all serious AEs (SAEs). 
A bar chart showing the percentage of patients with at least one TEAE for each 
treatment group (each treatment group and the combined Multikine treated groups) 
and for each time-period will be presented. Additional figures may be requested as 
appropriate. 
 
12.3 Clinical Laboratory Test Results 
Laboratory tests will be performed by local laboratories operating under full GLP 
standards. The laboratory test battery will include routine laboratory tests 
(hematology, chemistry, and urinalysis) and immunohistochemistry/pathology. 
The laboratory evaluations performed for the safety analysis by treatment group will 
include: 
Hematology: 
White blood cell (WBC) count, red blood cell (RBC) count, Hemoglobin, Hematocrit, 
Platelet Count, Neutrophils, Bands, Lymphocytes, Monocytes, Eosinophils, 
Basophils and ESR. 
Biochemistry: 
TSH, sodium, potassium, chloride, bicarbonate, glucose, urea, urine, creatinine, 
urate, calcium, phosphate, total protein, urine, albumin, total bilirubin, material, 
alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate 
dehydrogenase, cholesterol, triglycerides, glutamyl transferase. 
The clinical laboratory parameters (hematology and biochemistry) will be 
summarized by treatment group and visit using descriptive statistics for continuous 
data only. In addition, the change from baseline to each visit will also be 
summarized. 
The number and percentage of subjects, who have high, low, normal laboratory 
values compared to the reference ranges and clinically significant laboratory values, 
as determined by the investigators, will be summarized treatment group (each 
treatment group and the combined Multikine treated groups) and visit. Shift from 
baseline at each visit will be presented as well. 
If more than one assessment occurred at any visit (i.e. repeat samples taken), the 
last valid (non-missing) value will be used in the summaries. Unscheduled laboratory 
data will be listed but will not be included in the summary tables. 


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12.4 Vital Signs 
Summary statistics will be presented by treatment group (each treatment group and 
the combined Multikine treated groups) for each vital sign parameter: systolic and 
diastolic blood pressure, heart rate, and respiration rate and body temperature. In 
addition, the change from baseline to each visit will be presented. 
The number and percentage of subjects, who have high, low, normal vital signs 
values compared to the reference ranges and significant change as specified in the 
following table, will be summarized by treatment group and visit. 
 
 
Clinical Importance Criteria 
Vital Signs 
Unit 
Low 
High 
Decrease 
Increase 
Systolic Blood 
Pressure 
mmHg 
< 85 
> 160 
≥20 and ≥40
≥20 and ≥40 
Diastolic Blood 
Pressure 
mmHg 
< 45 
> 100 
≥10 and ≥20
≥10 and ≥20 
Heart Rate 
Bpm 
< 50 
> 110 
≥15 and ≥30
≥15 and ≥30 
 
 
12.5 Concomitant Medication 
All medications will be coded using the latest World Health Organization Drug 
Dictionary (WHODRL DEC2010, or later versions) and Anatomical Therapeutic 
Chemical (ATC) classification system. Coding will include the drug class and drug 
name. 
All medications will be classified as either prior or concomitant as follows: 
• 
Prior medication will be defined as non-study medication with a stop date before 
the first dose of study treatment; 
 
• 
Concomitant medication will be defined as non-study medication with: 
 
o Start or stop date after the date of randomization; 
 
o Start dates prior to randomization but which were ongoing after date of 
randomization (concomitant at baseline); 
 
o Partial start dates that indicate that the medication could be concomitant in 
relation to the date of randomization; 
 
o Completely missing start dates, unless their stop dates confirm otherwise 
(i.e. the stop date is before the date of randomization). 


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Prior and concomitant medication data will be presented in data listings. 
 
 
13.0 Geographic Region Analysis 
Geographic region as defined in Section 11 will also be assessed for regional 
consistency or advantage for each primary and secondary efficacy endpoint. a 
treatment-region interaction will be tested; in the event of significant treatment-region 
interactions (p<0.05), region imbalance will be addressed using proportional hazards 
analysis (for time to event endpoints) or longitudinal model analysis (QOL domains, 
Karnofsky status); see Section 11 for the specific model covariates including the 
tumor stage, tumor location, treatment, region, and treatment-region interactions. If 
there are no significant treatment-region interactions (two-sided p>0.05), the 
respective models will not include the region-treatment interactions in all proportional 
hazards models, time-dependent models, and longitudinal models; baseline 
covariates will include the tumor stage, tumor location, treatment, region. Last, the 
overall AE incidence rate will be analyzed by region with Cochran–Mantel–Haenszel 
(CMH) method4,5. 
14.0 Missing Data Conventions 
Any unresolved missing time to event data will be imputed in advance prior to 
database lock at the Biostatistics Data Review Meeting (BDRM). If only the day is 
missing, then the 15th of the month will be used. If both the month and day are 
missing, then the midpoint of that year (July 1) will be used. If all are missing, then 
a decision will be made at the BDRM meeting based on the available facts; for 
example, if the a subject’s death date is unknown, then the date that the site first 
learned of the death will be used as the surrogate date. Also see Section 7.2 for 
other censoring rules to be applied for all time to event endpoints. The same rules 
will be in place for the primary and secondary efficacy endpoints. 
There will be no imputation for missing data other than the QOL scoring according 
to the QOL endpoint scoring methodology. 
Longitudinal models for QOL and Karnofsky will use all available data without the 
need to impute any missing data. 
Similarly, as for missing time to event data, any unresolved missing adverse event 
dates will be imputed in advance prior to database lock at the BDRM. Missing AE 
dates will be imputed relative to the informed consent date as well as study and SOC 
treatment dates. First principles of imputation will be applied; for an AE with only day 
missing, if the year and month of AE onset is the same as informed consent date, 
then the AE date will be imputed with the informed consent date; otherwise, set AE 
date to the 1st day of that month. For an AE with both month and day missing, if the 
year of AE onset is the same as informed consent date, the AE date will be imputed 


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with the informed consent date; if the year of AE onset is after informed consent year, 
set AE date to the January 1 of that year. If the AE onset date is completely missing, 
set the date to the informed consent date. The BDRM will be used to discuss the 
details of imputation. 
Other considerations will also be taken into account for imputation. For example, the 
start date of any adverse event should not begin earlier than the treatment start date 
and, if that date is unknown, not earlier than the informed consent date. If the end 
date is missing, then the end date could be the next follow-up visit or contact time 
when the adverse event was known to have ended. Missing month and day could 
be imputed to be the earliest possible date after the later of the randomization date 
and the treatment start date. 
The BDRM will utilize such adverse event timing logic relative to the informed 
consent date, the treatments start-dates (study therapy as well as SOC), and the 
following timing windows: when such data are available: 
• Informed Consent to Surgery, 
• Post-surgery to RTx or CRTx, and 
• Post RTx or CRTx (i.e., after 30-60 days of last SOC treatment administration 
which is the first day of long term follow up). 
For treatment for oral carcinoma recurrence, if only the start day is missing, then the 
15th of the month will be used. If both day and month are missing, then July 1 of 
that year will be used. For complete missing date, a decision may be made at the 
BDRM meeting based on the available facts. 
 
15.0 Interim Analyses 
Interim analyses are to be performed through the study to assess Multikine safety, 
sample size assumptions, and futility as determined by the study IDMC (Independent 
Data [and Safety] Monitoring Committee). 
The first interim analysis was performed (for the IDMC) when 40 Multikine treated 
subject’s complete surgery, and an additional safety analysis performed when all 
subjects have completed the 30-day safety follow-up visit (Day 28-35). 
Subsequent interim analyses are performed (for the IDMC) as mutually agreed upon 
with the IDMC; the schedule is to perform interim analyses of safety and efficacy 
approximately every 6 months based on the study meeting enrollment objectives. 
The IDMC reviews these semi-annual safety and efficacy analyses and annual 
DSUR reports during the study to assess the feasibility of continuing the study and 
to assess the sample size according to the primary study endpoint to see if the 
sample size is adequate or requires modification (reduction or increase). This sample 
size re-estimation is conducted on blinded data, prior to any unblinding. The study 


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will not be stopped for superiority, but the study may be stopped for futility (without 
penalty). Thus, the overall significance level of the final analysis (two-sided p<0.05) 
is maintained. 
The blinded sample size adjustment follows the method discussed in Todd6. The 
method re-estimates the enrollment rate at the time of interim and the pooled survival 
rate. The survival rate at time that has not been observed in the interim data is 
adjusted from the assumed survival rate during the planning of trial. The adjustment 
is based on average difference between the observed survival rate and the assumed 
survival rate on the complementary log-log scale across different event time points 
or at the latest time point. Enrollment period and thus number of subjects needed 
can be estimated to reach the targeted number of deaths (d=298) in the combined 
comparator groups of the study. 
The IDMC can recommend that the trial may stop for futility (non-binding) if the 
conditional power based on the current trend is lower than 20%. The conditional 
power is calculated by the following as per Cui7: 
 
𝐶 (𝜃) = Φ( √𝑡∗𝐿𝑅1+𝜃(1−𝑡)−𝑧𝛼), 𝑡 = 𝑑1, 
𝑝 
√1−𝑡 
𝑑2 
 
 
where Φ is the normal cumulative distribution function, and 𝜃 = −0.5 ∗ √𝑑2 ∗ 
log(𝐻𝑅), 𝐻𝑅 is the hazard ratio (Multikine + CIZ + SOC vs. SOC alone) future data 
follow, 𝐿𝑅1 is the standardized log-rank statistics from the accumulated data up to 
the interim analysis time point, 𝑑1 is the cumulated number of deaths in both 
groups at the interim analysis. 𝑑2 = 298 is the expected number of deaths in the 
end of trial in both groups. 
Three conditional powers will be calculated assuming the future data follow, 
1) The null hypothesis 
𝐻0: 𝜃 = 0 
2) The alternative hypothesis 
 
𝐻𝛼: 𝜃 = −0.5 ∗ √𝑑2 ∗ log(𝐻𝑅) = −0.5 ∗ √298 ∗ log(0.721) = 2.82 
3) The current trend: 
𝜃 = 𝐿𝑅1_𝑜𝑏𝑠/√𝑡 
The confidence interval for the conditional power under the current trend 𝐶𝑝3 will be 
calculated assuming the observed interim data follow the current trend 


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  𝑡 
−1( ) 
 
𝐿𝑅1/√𝑡−𝑧
Since 𝐶 
 
 
 
= Φ( 𝐿𝑅1/√𝑡−𝑧𝛼), 𝑡 = 𝑑1, and 𝐿𝑅1/√𝑡−𝑧𝛼 ~𝑁(𝜃1−𝑧𝛼 ,   𝑡 ), thus p percentile of 
𝑝3 
 
 
√1−𝑡 
𝑑2 
 
 
√1−𝑡 
 
 
√1−𝑡 
 
1−𝑡 
 
 
 
 
the conditional power can be calculated by Φ(√ 
Φ 
p + 
), 
 
1−𝑡 
√1−𝑡 
 
and thus 95% CI can be produced by calculating its 2.5% and 97.5% percentile. 
 
 
16.0 COVID-19 Study Risk Analysis and Mitigation Strategy 
16.1 Background 
 
FDA 8 and other regulatory agencies 9 have issued guidance for the conduct of 
clinical trials during the COVID-19 pandemic. Challenges have emerged regarding 
to the following factors for this study to be addressed as noted below: 
• 
general or partial country quarantines 
• 
site access restrictions or closures 
• 
availability of site medical personnel and/or site staff for continuing study 
activities or study subjects becoming infected with/or die from COVID-19 
• 
subject availability due to hardships or moving to safe environments 
• 
study monitor travel restrictions. 
 
The above items lead to the following difficulties for this study: 
• acquiring subject follow-up 
• resolving data querie 
• verifying source data required to assure the integrity of trial information used 
for determining safety and efficacy. 
• completing site monitoring. 
16.2 Overall Study Analysis Strategy 
 
In 2017, the ERC was established to review all matters regarding evaluability. Any 
potentially unevaluable cases will be referred to the ERC to determine possible 
eITT exclusion. All matters impacting evaluability will be referred to the ERC. The 
ERC will complete the same forms as was followed in 2017 when they first 
reviewed evaluability data. The BDRM will review all unresolved queries and will 
assess any possible major protocol deviations to determine possible ePP 
exclusions. 
BDRM Roles and Responsibilities: 


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The BDRM will review all unresolved queries and review any possible major protocol 
deviations to identify ineligible cases. The BDRM will also review the Query 
Resolution Log. A Study Specific Procedure (SSP) will be issued by the responsible 
CRO. 
Major protocol deviations will be identified and forwarded to the BDRM by the 
responsible CRO. Major protocol deviations include the following: 
• Consent deviations 
• Ineligibility 
• SAE reporting delays 
• Missed surgeries 
• Study treatment variations. 
The BDRM will review all remaining unresolved queries due to the following reasons: 
• Site no longer operational 
• Site does not answer the query prior to database lock 
• Site has lost contact with the study subject. 
The BDRM will not impute any missing, unknown, or inconsistent data in 
accordance with GCP. The BDRM will review all unresolved queries and confirm 
the corresponding Query Resolution Log (QRL) itemizing the impact of any 
unresolved query. 
Unresolved Query Review Procedures: 
The BDRM will assess all unresolved queries. They will consider data issues 
arising from open queries unable to be resolved by sites. The general classification 
process is described below. 
The situations are as follows: 
• Data are inconsistent. Data may or may not be present to correct the query. 
• Data are missing. 
In both situations: 
• No data will be changed unless the site answers a specific query. 
• No attempts will be made to record data, impute outcomes, or resolve 
inconsistencies. 
• Do not enter NA in the absence of information. 


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• When an answer can be inferred, the most likely correct answers per query 
will be recorded in the QRL. If applicable, any possible impact will be noted 
on study endpoint conclusions, e.g. patient narrative, safety analysis, shift 
table, OS lifetable. 
Examples for decision rules: 
• A concomitant medication is administered but no adverse event is recorded: 
No imputation will be made. 
• An adverse event is mislinked to a concomitant medication: Do not correct 
the error. Use existing eCRF information to complete the QRL. 
• An adverse event end date is missing: NA will not be entered; data will be 
considered as “blank/unknown”. Record likely date range in the QRL. 
• The cause of death is unknown: Do not try to guess cause of death if 
unavailable, leave as unknown cause of death. 
• The result is unknown: Do not try to guess any missing data field. 
• A Baseline CT scan indicates longest dimension >3 cm: Do not change TNM 
classification. Record correct TNM classification in the QRL. 
• The lab units are incorrect: Review other lab data to make a reasoned 
judgement to avoid outliers / Standard ranges might be applied for MISSING 
ranges. Wrong ranges or wrong results may not be able to correct. Record 
likely correction in the QRL. 
• A tumor response calculation error is found: Recompute the tumor arithmetic 
to determine tumor response using the data (measurements) in the eCRF 
entered by the site. Record likely correction in the QRL. 
• An incorrect eligibility date is discovered: Correct a date inconsistency 
based on existing eCRF if information is available to make decision. Record 
likely correction in the QRL. 
• The eCRF contains a later survival date than appears in the LAFU form: 
Scan the eCRF for the latest survival date. Record likely correction in the 
QRL. 
Imputation Strategies: 
These considerations impact GCP since data queries are required to finalize safety 
and efficacy determinations inclusive of events and dates. Prospective rules need 


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to be in place to define data convention and analysis approaches to address 
impact areas. 
In the absence of site-specific availability, the following rules will apply using existing 
data: 
• Efficacy events only known to occur between two possible dates can be viewed 
as occurring at the most conservative outcome, at the subject-level 
• Efficacy analyses will be conducted once all queries are addressed. 
• Safety events only known to start or finish between two possible dates can be 
viewed as occurring at the earliest possible date, which give worst case 
scenarios at the subject-level 
• Safety analyses will be conducted once all queries are addressed. 
In general, a worst-case assumption using existing data will be made per impacted 
endpoint. 
Analysis Strategies: 
The following analysis strategies will be followed: 
• Eligibility: Any unconfirmed eligibility will result in inclusion in eITT and ePP 
populations 
• Time to Event Outcomes: A worst case assumption will be made; the event 
must be documented through death confirmation (OS) or by biopsy, imaging, 
or clinical (PFS, LRC) 
• Response Outcomes: A worst case assumption will be made regarding event 
timing; histopathology is required to establish pCR. 
This strategy is intended to under-estimate efficacy while maintaining GCP 
compliance and minimizing risks to trial integrity. 
Cause of death will also be obtained (as available) inclusive of COVID-19 death; 
subjects dying from COVID-19 would have otherwise lived so progression or death 
due to COVID-19 should be censored at the time of COVID-19 death. 
COVID-19 Impact: 
The COVID-19 impacted clinical study report (CSR) sections will further indicate: 
1. A risk analysis as specified in the FDA Guidance 7 (specifically: Sections C.1-3 
of the Guidance). 
2. Contingency measures implemented to manage study conduct during 
disruption of the study as a result of COVID-19 control measures. 


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3. A listing of all subjects affected by the COVID-19 related study disruption by 
unique subject number identifier per investigational site, and a description of 
how the subject’s participation was altered. 
4. As described above, conventions, contingency analyses, and corresponding 
discussions that address the impact of implemented contingency measures 
(e.g., alternative procedures used to collect critical safety and/or efficacy data) 
on the safety and efficacy results reported for the study. 
Risk Analysis Summary: 
A risk analysis follows in response to FDA Guidance Section C.1-3: 
A. Unresolved queries 
o Background: 
▪ All open queries are resolved prior to database lock or confirmed to 
be left as is 
▪ A Biostatistics Data Review Meeting (BDRM) is held to judge and 
classify any remaining open queries 
o COVID-19 Impact: 
▪ Sites may not allow staff to have access to study records to answer 
queries 
▪ Study coordinators may not be able to return to work either due to 
personal circumstances or limitation on the number of staff 
resources and availability at specific sites 
o Consequences: 
▪ New study coordinators or clinical staff may need to be trained 
▪ Site coordinators/staff may not have access to study records 
▪ Site coordinators/staff may not have access to study patients for 
survival updates 
▪ Sites may not be able to answer queries in a timely manner 
o Solutions: 
▪ Remote Monitoring 
▪ Remote query resolution (site dependent) 
▪ Source Data Verification via interview and video conference while 
maintaining patient confidentiality and adherence to HIPAA and 


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GDPR (or equivalent country-specific) rules at the same level as a 
site visit by CRAs for SDVs. 
B. Unverified source data 
o Background: 
▪ FDA expects sponsors to comply with preset source data 
verification (SDV) standards 
▪ CEL-SCI is committed to 100% SDV for all study data including 
queries but this may not be possible 
o COVID-19 Impact: 
▪ Study monitors may not be able to travel to sites 
▪ Site coordinators may not be able to host study monitors to allow 
SDV to be completed 
▪ Site coordinators may not have access to patient medical records 
o Consequences: 
▪ New study monitors may need to be trained 
▪ Delays are likely to be incurred until site coordinators resume full- 
time activities 
▪ Delays are likely until travel bans are lifted 
▪ Study monitors may be backed up to visit sites without adding 
resources 
o Solutions: 
▪ Remote Monitoring 
▪ Remote query resolution (as possible – Site dependent) 
▪ Remove Source Data Verification via interview and video 
conference (see above) 
 
C. Data analyses 
o Background: 
▪ The SAP is signed prior to database lock 
▪ The SAP includes analysis methods and table, listing, and figure 
(TLF) shells 
o COVID-19 Impact: 
▪ FDA recently issued guidelines for Sponsors to consider 


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▪ Sponsor response must be study-specific, e.g., COVID-19 deaths 
are considered to be censored at the time of death and not to be 
counted towards n=298 required number of deaths for the study 
▪ Sponsor needs to set data rules for unresolved queries, e.g. which 
ones can be resolved, which ones cannot be resolved and do not 
have material impact on the study safety or efficacy (or must await 
resolution) 
▪ Sponsor strategy must be prospectively implemented before 
database lock 
o Consequences: 
▪ COVID-19 diagnoses and deaths need to be determined 
▪ COVID-19 data rules need to be defined and implemented 
▪ COVID-19 impacted subjects need to be queried 
▪ COVID-19 TLFs need to be prospectively defined, e.g. run for 
subset with no remaining queries, run using an applied data 
convention established prospectively 
▪ COVID-19 TLFs may need to be run in multiple ways 
▪ FDA may ask Sponsor to rerun analyses once all queries can be 
resolved. 
o Solutions 
▪ Subjects with COVID-19 diagnoses will experience adverse events 
which must be reported per 21 CFR 312 standards 
▪ Any deaths attributed to COVID-19 will not be counted towards the 
final death count; instead, such subjects will be censored at the time 
of COVID-19 death for all time to event endpoints 
▪ Efficacy events only known to occur between two possible dates 
can be viewed as occurring at the most conservative outcomes, at 
the subject-level 
▪ Safety events only known to start or finish between two possible 
dates can be viewed as occurring at the earliest possible date, 
which gives a worst-case scenario at the subject-level. 


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17.0 Changes to Planned Methodology 
• ITT Evaluable (eITT) and PP Evaluable populations were added to make the 
population nesting more efficient. The PP population was dropped since it 
made sense to remove both unevaluable and ineligible patients at the same 
time. The ITT Evaluable (eITT) population will be used for the primary 
efficacy analysis. 
• Designated TCIs were added to identify the study critical intervals of 
interest. 
• Added the percent undergoing surgery following study treatment to see if 
study treatment led to a higher percent able to undergo surgery. 
• Added analyses for Karnofsky Performance Status as another QOL 
dimension. 
• Added OS, PFS, LRC analyses controlling for pre-planned covariates 
including histopathology markers 
• Conservative imputation rules were imposed to accommodate missing data. 
• Logistic and Poisson regression models have been dropped from safety 
analyses. 
• Site pooling analyses was dropped in favor of analyses of pre-defined 
geographic regions. 
 
18.0 Data Reporting Conventions 
In the presentation of descriptive summary statistics, the minimum and maximum 
will be presented to the same number of decimal places as the variable being 
reported; the mean and median will be to +1 decimal place and the SD to +2 
decimal places. 
 
18.1 Mock-up Template 
 
Refer to the TLF mockup document containing all proposed tables, listings, and 
figures. 


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19.0 References 
1. Ye Y, Li, A, Liu L, Yao B. (2012) A group sequential Holm procedure with 
multiple primary endpoints Statist Med (wileyonlinelibrary.com) DOI: 
10.1002/sim.5700. 
2. Sherman RB, Woodcock J, Norden J, Grandinetti C, Temple RJ. New FDA 
Regulation to Improve Safety Reporting in Clinical Trials N Engl J Med 2011; 
365:3-5. 
3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Head and 
Neck Cancers (2020). Version 1.2020. nccn.org 
4. Cochran WG (1954) Some methods for strengthening the common χ2 Tests". 
Biometrics. 10 (4): 417–451. doi:10.2307/3001616. JSTOR 3001616. 
5. Mantel N, Haenszel W. (1959). Statistical aspects of the analysis of data from 
retrospective studies of disease. Journal of the National Cancer Institute. 22 (4): 
719–748. doi:10.1093/jnci/22.4.719. PMID 13655060. 
6. Todd S, Valdés-Márquez E, West J. (2002). A practical comparison of blinded 
methods for sample size reviews in survival data clinical trials. Pharm Stat. 2012 
Mar-Apr; 11(2):141-8. 
7. Cui L, Hung HM, Wang SJ. (1999). Modification of Sample Size in Group 
Sequential Clinical trials. Biometrics 55:853-85. 
8. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID- 
19 Pandemic Guidance for Industry, Investigators, and Institutional Review 
Boards, March 2020. 
9. EMA (EU/ICH) Guidance for medicine developers and companies on COVID-19. 
V.3, April/May 2020.