Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity

NCT01265849 | Completed Phase 3 Results DMC

• 2 other identifiers: CS001P32010-019952-35
• Study Type: interventional
• Target: 928
• Locations: 23 countries
• Sites: 102

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

Conditions

Squamous Cell Carcinoma of the Oral Cavity; Squamous Cell Carcinoma of the Soft Palate

Outcome Measures

Primary Outcomes (2)

• Overall Survival (OS)

  OS was assessed using Kaplan-Meier life-table using a log rank test and confirmed further with tumor stage, tumor location, and geographic stratified log rank test. Both Stratified and unstratified log rank test are presented with the unstratified log rank test constituting the primary analysis. A two-sided p-value of 0.05 or less was considered statistically significant for comparing the two groups (i.e., Study comparator arms: LI+CIZ+SOC vs. SOC alone). Interim analyses were performed (by the iDMC) periodically throughout the study to assess safety, sample size and futility.

  From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

• OS in Low Risk Subjects

  OS was assessed using Kaplan-Meier life-table using a log rank test and confirmed further with tumor stage, tumor location, and geographic stratified log rank test. Both Stratified and unstratified log rank test are presented with the unstratified log rank test constituting the primary analysis. A two-sided p-value of 0.05 or less was considered statistically significant for comparing the two groups (i.e., Study comparator arms: LI+CIZ+SOC vs. SOC alone). Low-risk assessment and data analysis was never performed during the study and was done only after database lock.

  From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

Secondary Outcomes (9)

• Local Regional Control (LRC)

  From the date of treatment assignment to LRC or the last follow-up date. Maximum follow-up was approximately 113 months.

• LRC in Low Risk Subjects

  From the date of treatment assignment to LRC or the last follow-up date. Maximum follow-up was approximately 113 months.

• Progression Free Survival (PFS)

  From the date of treatment assignment to PFS or the last follow-up date. Maximum follow-up was approximately 113 months.

• PFS in Low Risk Subjects

  From the date of treatment assignment to PFS or the last follow-up date. Maximum follow-up was approximately 113 months.

• Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 2

  Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 2

Study Arms (3)

LI + CIZ + SOC

EXPERIMENTAL

LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC).

Biological: LI; Drug: Cyclophosphamide; Drug: Indomethacin; Dietary Supplement: Zinc; Procedure: Surgery; Drug: Cisplatin; Radiation: Radiotherapy

Standard of Care (SOC) only

ACTIVE COMPARATOR

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.

Procedure: Surgery; Drug: Cisplatin; Radiation: Radiotherapy

LI + SOC

EXPERIMENTAL

LI was administered without CIZ to determine the contribution of CIZ to the effects of LI.

Biological: LI; Procedure: Surgery; Drug: Cisplatin; Radiation: Radiotherapy

Interventions

LI BIOLOGICAL

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.

Also known as: Multikine, Leukocyte interleukin, injection

LI + CIZ + SOC; LI + SOC

Cyclophosphamide DRUG

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.

LI + CIZ + SOC

Indomethacin DRUG

One 25mg capsule of indomethacin was self administered orally (BID) beginning on day one of LI treatment daily until the day before surgery.

LI + CIZ + SOC

Zinc DIETARY_SUPPLEMENT

One capsule daily self administered beginning on day one of treatment with LI until one day before surgery

Also known as: Multivitamins

LI + CIZ + SOC

Surgery PROCEDURE

Excise tumor and nodes

LI + CIZ + SOC; LI + SOC; Standard of Care (SOC) only

Cisplatin DRUG

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.

LI + CIZ + SOC; LI + SOC; Standard of Care (SOC) only

Radiotherapy RADIATION

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.

LI + CIZ + SOC; LI + SOC; Standard of Care (SOC) only

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Untreated SCCHN of oral cavity (anterior tongue, floor of mouth, cheek)/soft palate, categories T1N1-2M0,T2N1-2M0,T3N0-2M0,T4N0-2M0 (T4 allowed only if invasion of mandible is negligible i. e. 5mm or less) scheduled for SOC
• Primary tumor and any positive node(s) measurable in 2 dimensions
• Normal immune function
• No immunosuppressives with 1 year of entry
• KPS\>70/100
• Age\>18
• Male or Female (non-pregnant)
• Life expectancy \>6 months
• Able to take oral medication
• Able to provide informed consent

You may not qualify if:

• Subjects to be treated with other than SOC
• Tumor classifications T1N0, T2N0, T4N3, any TN classification with M1
• Active peptic ulcer (or on full-dose therapeutic anti-coagulants)
• Prior resection of jugular nodes ipsilateral to tumor
• Acute or chronic viral, bacterial immune or other disease associated with abnormal immune function
• Subjects on hemodialysis or peritoneal dialysis; or having a history of
• History of asthma, allergy to fluoroquinolone antibiotics, congestive heart failure, or on hemodialysis or peritoneal dialysis
• Any condition that in the opinion of the investigator would cause the subject to be unable to participate or tolerate the protocol regimen

Sponsors & Collaborators

• CEL-SCI Corporation: lead
• Teva Branded Pharmaceutical Products R&D, Inc.: collaborator
• Orient Europharma Co., Ltd.: collaborator

Study Sites (102)

Simmons Cancer Institute at Southern Illinois University

Springfield, Illinois, 62794, United States

Location

Henry Ford Health System Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

Location

Medical College Of South Carolina MSC550

Charleston, South Carolina, 29435, United States

Location

VA Puget Sound Healthcare System & University of WA

Seattle, Washington, 98108, United States

Location

HNO-Klinik der medizinischen Universitat Graz

Graz, 8036, Austria

Location

N.N. Alexandrov Research Istitute of Oncology and Medical Radiology

Lyasny, Minsk Oblast, 223040, Belarus

Location

Vitebsk Regional Oncology Dispensary

Vitebsk, 210603, Belarus

Location

University Clinical Centre Tuzla

Trnovac, Tuzla, 75 000, Bosnia and Herzegovina

Location

Clinical Center Banja Luka

Banja Luka, 78 000, Bosnia and Herzegovina

Location

University Clinical Hospital Mostar

Mostar, 88000, Bosnia and Herzegovina

Location

Clinical Centre University of Sarejevo Clinic for ENT

Sarajevo, 71000, Bosnia and Herzegovina

Location

St. Josephs Healthcare Department of Surgery

Hamilton, Ontario, L8N4A6, Canada

Location

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, JiH 5N4, Canada

Location

CHU de Quebec - L'Hotel Dieu de Quebec

Québec, G1R2J6, Canada

Location

CHC Osijek

Osijek, 31000, Croatia

Location

General Hospital Dr. Josip Bencevic

Slavonski Brod, 35000, Croatia

Location

CH Dubrava

Zagreb, 10000, Croatia

Location

Clinical Hospital Center Zagreb Kispaticeva 12

Zagreb, 10000, Croatia

Location

KBC Sestre Milosrdnice

Zagreb, 10000, Croatia

Location

KBC Zagreb

Zagreb, 10000, Croatia

Location

ICL 6 avenue Bourgogne CS30519

Vandœuvre-lès-Nancy, 54519, France

Location

University of Debrecen Medical and Health Scioence Centre

Debrecen, Hajdú-Bihar, krt. 98, Hungary

Location

National institute of Oncology

Budapest, Rath Gyorgy, H-1122, Hungary

Location

Semmelweis University

Budapest, 1085, Hungary

Location

University of Pecs Institute of Oncotherapy

Pécs, 7628, Hungary

Location

University of Szeged Dept of Oral and Maxillofacial Surgery

Szeged, 6725, Hungary

Location

Markusovsky Teaching Hospital

Szombathely, 9700, Hungary

Location

Bibi General Hospital and Cancer Centre

Malkapet, Andhra Pradesh, 500024, India

Location

Amrita Institute of Medical Sciences

Kochi, Kerala, 682041, India

Location

Sujan Regional Cancer Hospital & Amravati Cancer Foundation

Amravati, Maharashtra, 444606, India

Location

Government Medical College and Hospital

Aurangabad, Maharashtra, 431001, India

Location

Tata Memorial Hospital

Mumbai, Maharashtra, 400012, India

Location

Curie Manavata Cancer Center

Mumbai, Naka Nashik, 422004, India

Location

Searoc Cancer Center

Jaipur, Rajashlan, 302013, India

Location

V.N. Cancer Center G. Kuppuswamy Naidu Memorial Hospital

Coimbatore, Tamil Nadu, 641037, India

Location

Meenakshi Mission Hospital and Research Centre

Madurai, Tamil Nadu, 625107, India

Location

Regional Cancer Center

Kerola, Thiruvananthapuram, 695011, India

Location

Galaxy Cancer Center

Ghaziabad, Uttar Pradesh, 210010, India

Location

Rambam Health Care Campus

Sha‘ar Ha‘Aliya, Saint Haifa, 31906, Israel

Location

Rabin Medical Center

Petah Tikva, Tikva, 49100, Israel

Location

National Tumor Institute of Italy

Naples, 80131, Italy

Location

Ospedale S.G. Moscati Santissima Annunziata

Taranto, 74010, Italy

Location

Dept of Head and Neck Surgery School of Medical Sciences Univ. Sains

Kuantan, Pulau Pinang, 16150, Malaysia

Location

University Kabangsan Medical Center

Kuala Lumpur, 56000, Malaysia

Location

Wojewodzki Szpital Specjalistyczny im Kopernika

Lodz, Ul Paderewskiego 4, 93-509, Poland

Location

Swietokrzyskie Centrum Onkologii

Kielce, Ul. Artwinskiego 3, 25-734, Poland

Location

Centrum Onkologi-Instytut im. Marie Sklodowskiej-Curie

Warsaw, Ul. Roentgena 5, 02-781, Poland

Location

Centrum Onkologii im. Prof. Lukaszcyka

Warsaw, Ul. Roentgena 5, 02-781, Poland

Location

ul. M. Sklodowskiej-Curie 24A

Bialystok, 15-276, Poland

Location

Szpital Specialistyczny im. Ludwika Rydgiera

Krakow, 31826, Poland

Location

Samodzielny Publiczny Szpital Kliniczny Klinika Otolarryngologii I Onkologii Laryngologicznej

Lublin, 20-954, Poland

Location

Weilkopolskie Centrum Onkologii Klinika Chirurgii Glowy Szye Onkologii Laryngologiczne

Poznan, 61-866, Poland

Location

Uniwersitecki Szpital Kliniczny Klinika Otolaryngologii Chirugii Glowy i Szxyi

Wroclaw, 50-556, Poland

Location

Regional Institute of Oncology IASI

Iași, 700483, Romania

Location

Spital Clinic Judetean Mures

Târgu Mureş, 540072, Romania

Location

Sverdlovsk Regional Cancer Center

Sverdlov, Ekaterinberg, 620905, Russia

Location

Leningrad Regional Oncology Center

Saint Petersburg, Leningradskaya, 188663, Russia

Location

Kursk Regional Clinical Oncology Dispensary

Kursk, 305035, Russia

Location

Blokhin Cancer Research Center

Moscow, 115478, Russia

Location

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russia

Location

Budget Institution of Healthcare of Omsk Region Clincal Oncology Dispensary

Omsk, 644013, Russia

Location

Ryazan Clinical oncology Dispensary

Ryazan, 39011, Russia

Location

Serbia Clinic for ENT and Maxillofacial Surgery

Belgrade, Pasterova 14, 11000, Serbia

Location

Clincal Center Serbia Clinic for Oral and Maxillofacial Surgery

Belgrade, 11000, Serbia

Location

Faculty of Dental Medicine Clinic for Maxillofacial Surgery

Belgrade, 11000, Serbia

Location

Military Medical Academy Clinic for Maxillofacial Surgery

Belgrade, 11000, Serbia

Location

Clinical Center Nis center for Oncology

Niš, 18 000, Serbia

Location

Clinic for Stomatology department for maxillofacial Surgery

Niš, 18000, Serbia

Location

Clinical center Vojvodina Clinic for ORL

Novi Sad, 21000, Serbia

Location

Clinical Centre Vojvodina Clinic for Maxillofacial Surgery

Novi Sad, 21000, Serbia

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario de Princesa

Madrid, 28006, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Madrid North Universitaro de Sanchinnaro

Madrid, 28050, Spain

Location

Complejo Hospitalario Univ. de Santiago

Santiago de Compostela, 15706, Spain

Location

Consorsio Hospital General Universitario de valencia

Valencia, 46014, Spain

Location

National Cancer Institute Dept of Clinical Oncology & Radiotherapy

Colombo, 10280, Sri Lanka

Location

Oncology Unit Teaching Hospital Karapitya

Galle, Sri Lanka

Location

Kaohsiung Branch Chang Gung Memorial Hospital

Niaosong, Kaohsiung, 833, Taiwan

Location

National Cheng Kung University Hospital

Taipei, Tainan, 704, Taiwan

Location

National Taiwan Research Hospital

Chengshan, Taipei, 100, Taiwan

Location

Linkou Branch Chang Gung Memorial Hospital

Guishan, Taoyuan, 333, Taiwan

Location

Changua Christian Hospital

Chang-hua, 500, Taiwan

Location

Buddhist Tzu Chi General Hospital, Hualien Branch

Hualien City, 970, Taiwan

Location

China Medical University Hospital

Taichung, 404, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 40705, Taiwan

Location

Shin-Kong Wu Ho-Su Memorial Hospital

Taipei, 111, Taiwan

Location

Khon Kaen University Dept of Otolaryngology

Nai Muang, 40002, Thailand

Location

Haceteppe University Dept of Otolaryngology - Head and Neck Surgery

Ankara, 06100, Turkey (Türkiye)

Location

Acibadem University Maslak Hospital ENT Department

Istanbul, Turkey (Türkiye)

Location

Cherkasky Regional Oncological Dyspensary Dept. Head and Neck tumour

Cherkasy, 18009, Ukraine

Location

Clinical Diagnostic Laboratory of Dnepropetrovsk Municipal Institution City Multidisciplinary Clinical Hospital No. 4

Dnipro, 49102, Ukraine

Location

Donetsk Regional Antitumor Center

Donetsk, 83092, Ukraine

Location

Grigoriev Institute for Medical Radiology of National Academy of Medical Science of Ukraine Dept. of Remote, Combined Radiation and Complex Therapy

Kharkiv, 61024, Ukraine

Location

Kharkiv Regional Clinical Oncology Center Dept. Of Head and Neck Tumour

Kharkiv, Ukraine

Location

Kiev City Clinical Oncology Center of the Main Health Care Dept of Kiev Day Hospital Radiotherapy Dept.

Kiev, Ukraine

Location

Kiev City Clinical Oncology Center of the Main Health Care Dept. of the Kiev Day Hospital

Kiev, Ukraine

Location

Lviv State OncologyRegional treatment and Diagnostic Center

Lviv, 79031, Ukraine

Location

Sumy Regional Clinical Oncology Dyspensary

Sumy, 40004, Ukraine

Location

Zaporiz'ka Regional Clinical Oncology Dispensary

Zaporiz'ka Oblast', 69040, Ukraine

Location

Aintree University Hospital

Liverpool, L9 7AL, United Kingdom

Location

Related Publications (1)

• Talor E, Timar J, Lavin P, Cipriano J, Markovic D, Ladanyi A, Karpenko A, Bondarenko I, Stosic S, Sobat H, Zhukavets A, Imamovic N, Chien CY, Bankowska-Wozniak M, Kisely M, Jovic R, Young JEM, Hao SP. Neoadjuvant leukocyte interleukin injection immunotherapy improves overall survival in low-risk locally advanced head and neck squamous cell carcinoma -the IT-MATTERS study. Pathol Oncol Res. 2025 Mar 21;31:1612084. doi: 10.3389/pore.2025.1612084. eCollection 2025.

  PMID: 40191245 DERIVED

Related Links

• Click here for more information about this study: Phase 3 Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity (IT-MATTERS)

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

Injections; Cyclophosphamide; Indomethacin; Zinc; Geritol; Surgical Procedures, Operative; Cisplatin; Radiotherapy

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Chlorine Compounds; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: John Cipriano, Senior VP Regulatory Affairs, Eyal Talor Chief Scientific Officer
• Organization: CEL-SCI Corporation

jcipriano@cel-sci.com

(205) 586-6947

Study Officials

• Eyal Talor, PhD

  CEL-SCI Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2010
• First Posted: December 23, 2010
• Study Start: December 1, 2010
• Primary Completion: May 15, 2020
• Study Completion: December 4, 2020
• Last Updated: August 19, 2022
• Results First Posted: August 19, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

CR (6); AU (1); MY (2); TW (9); IL (2); TH (1); US (5); BE (2); RU (7); IN (11); SE (8); HU (6); ES (6); BO (4); SR (2); FR (1); IT (2); TU (2); GB (1); UA (10); PL (9); CA (3); RO (2)