Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity
NCT ID: NCT01265849
Last Updated: 2022-08-19
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
928 participants
INTERVENTIONAL
2010-12-31
2020-12-04
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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LI + CIZ + SOC
LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC).
LI
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.
Cyclophosphamide
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.
Indomethacin
One 25mg capsule of indomethacin was self administered orally (BID) beginning on day one of LI treatment daily until the day before surgery.
Zinc
One capsule daily self administered beginning on day one of treatment with LI until one day before surgery
Surgery
Excise tumor and nodes
Cisplatin
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.
Radiotherapy
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.
Standard of Care (SOC) only
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.
Surgery
Excise tumor and nodes
Cisplatin
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.
Radiotherapy
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 + SOC
LI was administered without CIZ to determine the contribution of CIZ to the effects of LI.
LI
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.
Surgery
Excise tumor and nodes
Cisplatin
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.
Radiotherapy
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.
Interventions
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LI
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.
Cyclophosphamide
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.
Indomethacin
One 25mg capsule of indomethacin was self administered orally (BID) beginning on day one of LI treatment daily until the day before surgery.
Zinc
One capsule daily self administered beginning on day one of treatment with LI until one day before surgery
Surgery
Excise tumor and nodes
Cisplatin
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.
Radiotherapy
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
Exclusion Criteria
18 Years
ALL
No
Sponsors
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Teva Branded Pharmaceutical Products R&D, Inc.
INDUSTRY
Orient Europharma Co., Ltd.
INDUSTRY
CEL-SCI Corporation
INDUSTRY
Responsible Party
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Principal Investigators
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Eyal Talor, PhD
Role: STUDY_DIRECTOR
CEL-SCI Corporation
Locations
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Simmons Cancer Institute at Southern Illinois University
Springfield, Illinois, United States
Henry Ford Health System Henry Ford Hospital
Detroit, Michigan, United States
University of Cincinnati Medical Center
Cincinnati, Ohio, United States
Medical College Of South Carolina MSC550
Charleston, South Carolina, United States
VA Puget Sound Healthcare System & University of WA
Seattle, Washington, United States
HNO-Klinik der medizinischen Universitat Graz
Graz, , Austria
N.N. Alexandrov Research Istitute of Oncology and Medical Radiology
Lyasny, Minsk Oblast, Belarus
Vitebsk Regional Oncology Dispensary
Vitebsk, , Belarus
University Clinical Centre Tuzla
Trnovac, Tuzla, Bosnia and Herzegovina
Clinical Center Banja Luka
Banja Luka, , Bosnia and Herzegovina
University Clinical Hospital Mostar
Mostar, , Bosnia and Herzegovina
Clinical Centre University of Sarejevo Clinic for ENT
Sarajevo, , Bosnia and Herzegovina
St. Josephs Healthcare Department of Surgery
Hamilton, Ontario, Canada
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, Canada
CHU de Quebec - L'Hotel Dieu de Quebec
Québec, , Canada
CHC Osijek
Osijek, , Croatia
General Hospital Dr. Josip Bencevic
Slavonski Brod, , Croatia
CH Dubrava
Zagreb, , Croatia
Clinical Hospital Center Zagreb Kispaticeva 12
Zagreb, , Croatia
KBC Sestre Milosrdnice
Zagreb, , Croatia
KBC Zagreb
Zagreb, , Croatia
ICL 6 avenue Bourgogne CS30519
Vandœuvre-lès-Nancy, , France
University of Debrecen Medical and Health Scioence Centre
Debrecen, Hajdú-Bihar, Hungary
National institute of Oncology
Budapest, Rath Gyorgy, Hungary
Semmelweis University
Budapest, , Hungary
University of Pecs Institute of Oncotherapy
Pécs, , Hungary
University of Szeged Dept of Oral and Maxillofacial Surgery
Szeged, , Hungary
Markusovsky Teaching Hospital
Szombathely, , Hungary
Bibi General Hospital and Cancer Centre
Malkapet, Andhra Pradesh, India
Amrita Institute of Medical Sciences
Kochi, Kerala, India
Sujan Regional Cancer Hospital & Amravati Cancer Foundation
Amravati, Maharashtra, India
Government Medical College and Hospital
Aurangabad, Maharashtra, India
Tata Memorial Hospital
Mumbai, Maharashtra, India
Curie Manavata Cancer Center
Mumbai, Naka Nashik, India
Searoc Cancer Center
Jaipur, Rajashlan, India
V.N. Cancer Center G. Kuppuswamy Naidu Memorial Hospital
Coimbatore, Tamil Nadu, India
Meenakshi Mission Hospital and Research Centre
Madurai, Tamil Nadu, India
Regional Cancer Center
Kerola, Thiruvananthapuram, India
Galaxy Cancer Center
Ghaziabad, Uttar Pradesh, India
Rambam Health Care Campus
Sha‘ar Ha‘Aliya, Saint Haifa, Israel
Rabin Medical Center
Petah Tikva, Tikva, Israel
National Tumor Institute of Italy
Naples, , Italy
Ospedale S.G. Moscati Santissima Annunziata
Taranto, , Italy
Dept of Head and Neck Surgery School of Medical Sciences Univ. Sains
Kuantan, Pulau Pinang, Malaysia
University Kabangsan Medical Center
Kuala Lumpur, , Malaysia
Wojewodzki Szpital Specjalistyczny im Kopernika
Lodz, Ul Paderewskiego 4, Poland
Swietokrzyskie Centrum Onkologii
Kielce, Ul. Artwinskiego 3, Poland
Centrum Onkologi-Instytut im. Marie Sklodowskiej-Curie
Warsaw, Ul. Roentgena 5, Poland
Centrum Onkologii im. Prof. Lukaszcyka
Warsaw, Ul. Roentgena 5, Poland
ul. M. Sklodowskiej-Curie 24A
Bialystok, , Poland
Szpital Specialistyczny im. Ludwika Rydgiera
Krakow, , Poland
Samodzielny Publiczny Szpital Kliniczny Klinika Otolarryngologii I Onkologii Laryngologicznej
Lublin, , Poland
Weilkopolskie Centrum Onkologii Klinika Chirurgii Glowy Szye Onkologii Laryngologiczne
Poznan, , Poland
Uniwersitecki Szpital Kliniczny Klinika Otolaryngologii Chirugii Glowy i Szxyi
Wroclaw, , Poland
Regional Institute of Oncology IASI
Iași, , Romania
Spital Clinic Judetean Mures
Târgu Mureş, , Romania
Sverdlovsk Regional Cancer Center
Sverdlov, Ekaterinberg, Russia
Leningrad Regional Oncology Center
Saint Petersburg, Leningradskaya, Russia
Kursk Regional Clinical Oncology Dispensary
Kursk, , Russia
Blokhin Cancer Research Center
Moscow, , Russia
N.N. Blokhin Russian Cancer Research Center
Moscow, , Russia
Budget Institution of Healthcare of Omsk Region Clincal Oncology Dispensary
Omsk, , Russia
Ryazan Clinical oncology Dispensary
Ryazan, , Russia
Serbia Clinic for ENT and Maxillofacial Surgery
Belgrade, Pasterova 14, Serbia
Clincal Center Serbia Clinic for Oral and Maxillofacial Surgery
Belgrade, , Serbia
Faculty of Dental Medicine Clinic for Maxillofacial Surgery
Belgrade, , Serbia
Military Medical Academy Clinic for Maxillofacial Surgery
Belgrade, , Serbia
Clinical Center Nis center for Oncology
Niš, , Serbia
Clinic for Stomatology department for maxillofacial Surgery
Niš, , Serbia
Clinical center Vojvodina Clinic for ORL
Novi Sad, , Serbia
Clinical Centre Vojvodina Clinic for Maxillofacial Surgery
Novi Sad, , Serbia
Hospital Universitari Vall d'Hebron
Barcelona, , Spain
Hospital Universitario de Princesa
Madrid, , Spain
Hospital Universitario Ramon y Cajal
Madrid, , Spain
Hospital Madrid North Universitaro de Sanchinnaro
Madrid, , Spain
Complejo Hospitalario Univ. de Santiago
Santiago de Compostela, , Spain
Consorsio Hospital General Universitario de valencia
Valencia, , Spain
National Cancer Institute Dept of Clinical Oncology & Radiotherapy
Colombo, , Sri Lanka
Oncology Unit Teaching Hospital Karapitya
Galle, , Sri Lanka
Kaohsiung Branch Chang Gung Memorial Hospital
Niaosong, Kaohsiung, Taiwan
National Cheng Kung University Hospital
Taipei, Tainan, Taiwan
National Taiwan Research Hospital
Chengshan, Taipei, Taiwan
Linkou Branch Chang Gung Memorial Hospital
Guishan, Taoyuan, Taiwan
Changua Christian Hospital
Chang-hua, , Taiwan
Buddhist Tzu Chi General Hospital, Hualien Branch
Hualien City, , Taiwan
China Medical University Hospital
Taichung, , Taiwan
Taichung Veterans General Hospital
Taichung, , Taiwan
Shin-Kong Wu Ho-Su Memorial Hospital
Taipei, , Taiwan
Khon Kaen University Dept of Otolaryngology
Nai Muang, , Thailand
Haceteppe University Dept of Otolaryngology - Head and Neck Surgery
Ankara, , Turkey (Türkiye)
Acibadem University Maslak Hospital ENT Department
Istanbul, , Turkey (Türkiye)
Cherkasky Regional Oncological Dyspensary Dept. Head and Neck tumour
Cherkasy, , Ukraine
Clinical Diagnostic Laboratory of Dnepropetrovsk Municipal Institution City Multidisciplinary Clinical Hospital No. 4
Dnipro, , Ukraine
Donetsk Regional Antitumor Center
Donetsk, , Ukraine
Grigoriev Institute for Medical Radiology of National Academy of Medical Science of Ukraine Dept. of Remote, Combined Radiation and Complex Therapy
Kharkiv, , Ukraine
Kharkiv Regional Clinical Oncology Center Dept. Of Head and Neck Tumour
Kharkiv, , Ukraine
Kiev City Clinical Oncology Center of the Main Health Care Dept of Kiev Day Hospital Radiotherapy Dept.
Kiev, , Ukraine
Kiev City Clinical Oncology Center of the Main Health Care Dept. of the Kiev Day Hospital
Kiev, , Ukraine
Lviv State OncologyRegional treatment and Diagnostic Center
Lviv, , Ukraine
Sumy Regional Clinical Oncology Dyspensary
Sumy, , Ukraine
Zaporiz'ka Regional Clinical Oncology Dispensary
Zaporiz'ka Oblast', , Ukraine
Aintree University Hospital
Liverpool, , United Kingdom
Countries
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References
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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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan: SAP main text
Document Type: Statistical Analysis Plan: CS001P3 Note to File 1
Document Type: Statistical Analysis Plan: CS001P3 Note to file 2
Document Type: Statistical Analysis Plan: Note to file 3
Document Type: Statistical Analysis Plan: Note to file 4
Document Type: Statistical Analysis Plan: Note to file 5
Related Links
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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)
Other Identifiers
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2010-019952-35
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
CS001P3
Identifier Type: -
Identifier Source: org_study_id
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