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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01265849
First Posted: December 23, 2010
Last Update Posted: December 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Teva Pharmaceutical Industries
Orient Europharma Co., Ltd.
Information provided by (Responsible Party):
CEL-SCI Corporation
  Purpose
The purpose of this study is to determine whether LI administered in combination with cyclophosphamide, indomethacin and zinc (CIZ) in a multivitamin 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 squamous cell carcinoma of the oral cavity or soft palate at a median of 3 years

Condition Intervention Phase
Squamous Cell Carcinoma of the Oral Cavity Squamous Cell Carcinoma of the Soft Palate Biological: LI plus CIZ Other: Standard of Care (SOC) Biological: LI + SOC Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Study of LI [Multikine®] Plus SOC (Surgery + Radiotherapy or Surgery + Concurrent Radiochemotherapy) in Subjects With Advanced Primary Squamous Cell Carcinoma of the Oral Cavity/Soft Palate vs. SOC Only

Further study details as provided by CEL-SCI Corporation:

Primary Outcome Measures:
  • Overall Survival (OS) in LI + CIZ + SOC vs. SOC [ Time Frame: 3 year ]
    OS will be assessed using Kaplan-Meier life-table and compared using a logrank test and confirmed further with tumor stage location and geographic stratified log rank tests. The unstratified logrank test constitutes the primary analysis. A two-sided p-value of 0.05 or less will be considered statistically significant for comparing the two groups. Interim analyses will be performed throughout the study to assess safety, sample size and futility.


Secondary Outcome Measures:
  • Local regional control (LRC) in LI + CIZ + SOC vs. SOC [ Time Frame: 2 years ]
    LRC is assessed by classifying the first evidence of progression in local and distal sites for the control groups and for the LI treated group. LRC failure includes progression of tumor(s) and nodes or appearance of new disease above the clavicle (but not distant metastases) the reappearance of tumor in the original tumor bed, development of cervical node metastases and new disease above the clavicle other than distant metastases not present at baseline. The total number and corresponding percent of subjects in each of the treated and untreated control groups as well as the time to LRC in days for each group will also be displayed for each group.

  • Progression Free Survival (PFS) in LI + CIZ + SOC vs.SOC [ Time Frame: 3 year. ]
    PFS will be assessed using Kaplan-Meier life-table and compared using a logrank test and confirmed further with stage location and geographic stratified log rank tests. The unstratified logrank test constitutes the primary analysis.A two sided p-value of 0.05 or less will be considered statistically significant in comparing the groups. The Holm closed-sequential procedure will be used to control type 1 error probability to at most 0.05

  • Quality of Life (QOL) in LI + CIZ + SOC vs. SOC [ Time Frame: 3 yr. ]
    QOL will be based on the EORTC QLOQ-C30 and EORTC QLQ-H&N35. QOL data will be assessed for change in QOL from baseline within and between treatment groups.Between group comparisons will be performed using ANOVA or Wilcoxon rank sum test. Within treatment group change from baseline will be performed using a paired t-test or a signed rank test. Two-sided t-test will be used with no adjustment for type I error. An exact binomial test of each treatment group will be used to assess a 10 point improvement between treatments. A Fisher Exact Test will be used for between group comparisons.


Estimated Enrollment: 928
Study Start Date: December 2010
Study Completion Date: December 2017
Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LI plus CIZ
LI plus CIZ is given as adjuvant therapy prior to standard of care (SOC).
Biological: LI plus CIZ
LI 400IU (2.0mL total daily) 1.0 mL peritumoral, 1.0 mL perilymphatic 5x weekly x3 weeks administered in combination with cyclophosphamide indomethacin and zinc (CIZ) as adjuvant therapy prior to SOC, surgery followed by radiation or concurrent radiochemotherapy with cisplatin 100mg/m^2 intravenously to determine if LI plus CIZ affects the overall survival of subjects at median 3 years. Cyclophosphamide 300mg/m^2 is administered intravenously bolus 3 days prior to treatment with LI. Indomethacin 25mg capsules are administered orally beginning on day 1 of LI treatment up to 1 day prior to surgery. Multivitamin tablets or capsules with zinc (> or = to 15mg but not > 40mg) are administered orally beginning on day 1 of LI treatment up to 1 day prior to surgery.
Other Names:
  • BB IND 5677
  • Multikine
  • CS001P3
Active Comparator: Standard of Care (SOC)
SOC for previously untreated SCCHN patients is currently surgery followed by either radiotherapy or combined radiochemotherapy depending the patient's risk status for relapse determined at surgery.
Other: Standard of Care (SOC)
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) or for higher risk subjects (subjects determined at surgery to have positive surgical margins, 2 or more clinically positive nodes or extracapsular nodal spread) radiotherapy is combined with concurrent chemotherapy (cisplatin 100mg/m2 intravenously 1x weekly for 3 weeks on day 1 of weeks 1, 4 and 7 of radiotherapy
Other Names:
  • BB IND 5677
  • Multikine
  • CS001P3
Experimental: LI + SOC
LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.
Biological: LI + SOC
LI is administered 400 IU (2.0mL) 1/2 peritumorally and 1/2 perilymphatically 5 times a week for three weeks prior to SOC to determine the contribution of CIZ on LI activity.
Other Names:
  • BB IND 5677
  • Multikine
  • CS001P3

Detailed Description:

Head and neck carcinomas constitute about 5% of all cancers annually worldwide. In the US there are about 37,000 new cases annually. Ninety percent are advanced primary squamous cell carcinoma (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 combined radiochemotherapy - is between 52 and 55%; the 5 year OS is 43%. There are clearly a large number 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 1 and 2 clinical trials. LI was 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 is being 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 Arms for, Overall Survival, the Primary End Point of this Study].

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Untreated SCCHN of oral cavity/soft palate, categories T1N1-2M0,T2N1-2M0,T3N0-2M0,T4N0-2M0 (T4 allowed only if invasion of mandible is negligible) scheduled for SOC
  • Primary tumor and any positive node(s)measurable in 2 dimensions
  • normal immune function
  • no immunosuppressives with 1 year
  • KPS>70
  • Age>18
  • Male or Female (non-pregnant)
  • Life expectancy >6mo.
  • Able to take oral medication
  • Able to provide informed consent

Exclusion Criteria:

  • Subjects to be treated with other than SOC
  • Tumor invasion of bone (also see inclusion criteria)
  • Tumor classifications T1N0, T2N0, T4N3, any TN classification with M1
  • Tumors in locations other than those specified in inclusion criteria
  • Active peptic ulcer
  • 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
  • History of asthma
  • Any condition that in the opinion of the investigator would cause the subject to be unable to participate or tolerate the protocol regimen
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01265849


  Hide Study Locations
Locations
United States, Illinois
Simmons Cancer Institute at Southern Illinois University
Springfield, Illinois, United States, 62794
United States, Michigan
Henry Ford Health System Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, Ohio
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45219
United States, South Carolina
Medical College Of South Carolina MSC550
Charleston, South Carolina, United States, 29435
United States, Washington
VA Puget Sound Healthcare System & University of WA
Seattle, Washington, United States, 98108
Austria
HNO-Klinik der medizinischen Universitat Graz
Graz, Austria, 8036
Belarus
N.N. Alexandrov Research Istitute of Oncology and Medical Radiology
Lesnoy 2, Minsk, Belarus, 223040
Vitebsk Regional Oncology Dispensary
Vitebsk, Belarus, 210603
Bosnia and Herzegovina
University Clinical Centre Tuzla
Trnovac, Tuzla, Bosnia and Herzegovina, 75 000
Clinical Center Banja Luka
Banja Luka, Bosnia and Herzegovina, 78 000
University Clinical Hospital Mostar
Mostar, Bosnia and Herzegovina, 88000
Clinical Centre University of Sarejevo Clinic for ENT
Sarajevo, Bosnia and Herzegovina, 71000
Canada, Ontario
St. Josephs Healthcare Department of Surgery
Hamilton, Ontario, Canada, L8N4A6
Canada, Quebec
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, Canada, JiH 5N4
Canada
CHU de Quebec - L'Hotel Dieu de Quebec
Quebec, Canada, G1R2J6
Croatia
CHC Osijek
Osijek, Croatia, 31000
General Hospital Dr. Josip Bencevic
Slavonski Brod, Croatia, 35000
CH Dubrava
Zagreb, Croatia, 10000
Clinical Hospital Center Zagreb Kispaticeva 12
Zagreb, Croatia, 10000
KBC Sestre Milosrdnice
Zagreb, Croatia, 10000
KBC Zagreb
Zagreb, Croatia, 10000
France
ICL 6 avenue Bourgogne CS30519
Vandoeuvre les Nancy, France, 54519
Hungary
University of Debrecen Medical and Health Scioence Centre
Debrecen, Hajdu Bihar, Hungary, krt. 98
National institute of Oncology
Budapest, Rath Gyorgy, Hungary, H-1122
Semmelweis University
Budapest, Hungary, 1085
University of Pecs Institute of Oncotherapy
Pecs, Hungary, 7628
University of Szeged Dept of Oral and Maxillofacial Surgery
Szeged, Hungary, 6725
Markusovsky Teaching Hospital
Szombathely, Hungary, 9700
India
Bibi General Hospital and Cancer Centre
Malkapet, Andhra Pradesh, India, 500024
Amrita Institute of Medical Sciences
Kochi, Kerala, India, 682041
Sujan Regional Cancer Hospital & Amravati Cancer Foundation
Amravati, Maharashtra, India, 444606
Government Medical College and Hospital
Aurangabad, Maharashtra, India, 431001
Tata Memorial Hospital
Mumbai, Maharashtra, India, 400012
Curie Manavata Cancer Center
Mumbai, Naka Nashik, India, 422004
Searoc Cancer Center
Jaipur, Rajashlan, India, 302013
V.N. Cancer Center G. Kuppuswamy Naidu Memorial Hospital
Coimbatore, Tamil Nadu, India, 641037
Meenakshi Mission Hospital and Research Centre
Madurai, Tamil Nadu, India, 625107
Regional Cancer Center
Kerola, Thiruvananthapuram, India, 695011
Galaxy Cancer Center
Ghaziabad, Uttar Pradesh, India, 210010
Israel
Rambam Health Care Campus
Sha`ar Ha`Aliya, Saint Haifa, Israel, 31906
Rabin Medical Center
Petaẖ Tiqwa, Tikva, Israel, 49100
Italy
National Tumor Institute of Italy
Naples, Italy, 80131
Ospedale S.G. Moscati Santissima Annunziata
Taranto, Italy, 74010
Malaysia
Dept of Head and Neck Surgery School of Medical Sciences Univ. Sains
Kuantan, Penang, Malaysia, 16150
University Kabangsan Medical Center
Kuala Lumpur, Malaysia, 56000
Poland
Wojewodzki Szpital Specjalistyczny im Kopernika
Lodz, Ul Paderewskiego 4, Poland, 93-509
Swietokrzyskie Centrum Onkologii
Kielce, Ul. Artwinskiego 3, Poland, 25-734
Centrum Onkologii im. Prof. Lukaszcyka
Warsaw, Ul. Roentgena 5, Poland, 02-781
Centrum Onkologi-Instytut im. Marie Sklodowskiej-Curie
Warszawa, Ul. Roentgena 5, Poland, 02-781
ul. M. Sklodowskiej-Curie 24A
Bialystok, Poland, 15-276
Szpital Specialistyczny im. Ludwika Rydgiera
Krakow, Poland, 31826
Samodzielny Publiczny Szpital Kliniczny Klinika Otolarryngologii I Onkologii Laryngologicznej
Lublin, Poland, 20-954
Weilkopolskie Centrum Onkologii Klinika Chirurgii Glowy Szye Onkologii Laryngologiczne
Poznan, Poland, 61-866
Uniwersitecki Szpital Kliniczny Klinika Otolaryngologii Chirugii Glowy i Szxyi
Wroclaw, Poland, 50-556
Romania
Regional Institute of Oncology IASI
Iasi, Romania, 700483
Spital Clinic Judetean Mures
Targu Mures, Romania, 540072
Russian Federation
Sverdlovsk Regional Cancer Center
Sverdlov, Ekaterinberg, Russian Federation, 620905
Leningrad Regional Oncology Center
St. Petersburg, Leningradskaya, Russian Federation, 188663
Kursk Regional Clinical Oncology Dispensary
Kursk, Russian Federation, 305035
Blokhin Cancer Research Center
Moscow, Russian Federation, 115478
N.N. Blokhin Russian Cancer Research Center
Moscow, Russian Federation, 115478
Budget Institution of Healthcare of Omsk Region Clincal Oncology Dispensary
Omsk, Russian Federation, 644013
Ryazan Clinical oncology Dispensary
Ryazan, Russian Federation, 39011
Serbia
Serbia Clinic for ENT and Maxillofacial Surgery
Belgrade, Pasterova 14, Serbia, 11000
Clincal Center Serbia Clinic for Oral and Maxillofacial Surgery
Belgrade, Serbia, 11000
Faculty of Dental Medicine Clinic for Maxillofacial Surgery
Belgrade, Serbia, 11000
Military Medical Academy Clinic for Maxillofacial Surgery
Belgrade, Serbia, 11000
Clinical Center Nis center for Oncology
Nis, Serbia, 18 000
Clinic for Stomatology department for maxillofacial Surgery
Nis, Serbia, 18000
Clinical center Vojvodina Clinic for ORL
Novi Sad, Serbia, 21000
Clinical Centre Vojvodina Clinic for Maxillofacial Surgery
Novi Sad, Serbia, 21000
Spain
hospiatl Universitari Vall d'Hebron
Barcelona, Spain, 08035
Hospital Universitario de Princesa
Madrid, Spain, 28006
Hospital Universitario Ramon y Cajal
Madrid, Spain, 28034
Complejo Hospitalario Univ. de Santiago
Santiago de Compostela, Spain, 15706
Consorsio Hospital General Universitario de valencia
Valencia, Spain, 46014
Sri Lanka
National Cancer Institute Dept of Clinical Oncology & Radiotherapy
Colombo, Sri Lanka, 10280
Oncology Unit Teaching Hospital Karapitya
Galle, Sri Lanka
Taiwan
Kaohsiung Branch Chang Gung Memorial Hospital
Niaosong, Kaohsiung, Taiwan, 833
National Cheng Kung University Hospital
Taipei, Tainan, Taiwan, 704
National Taiwan Research Hospital
Chengshan, Taipei, Taiwan, 100
Linkou Branch Chang Gung Memorial Hospital
Guishan, Taoyuan, Taiwan, 333
Changua Christian Hospital
Chang-hua, Taiwan, 500
Buddhist Tzu Chi General Hospital, Hualien Branch
Hualien City, Taiwan, 970
China Medical University Hospital
Taichung, Taiwan, 404
Taichung Veterans General Hospital
Taichung, Taiwan, 40705
Shin-Kong Wu Ho-Su Memorial Hospital
Taipei, Taiwan, 111
Thailand
Khon Kaen University Dept of Otolaryngology
Nai- Muang, Thailand, 40002
Turkey
Haceteppe University Dept of Otolaryngology - Head and Neck Surgery
Ankara, Turkey, 06100
Acibadem University Maslak Hospital ENT Department
Istanbul, Turkey
Ukraine
Cherkasky Regional Oncological Dyspensary Dept. Head and Neck tumour
Cherkasy, Ukraine, 18009
Clinical Diagnostic Laboratory of Dnepropetrovsk Municipal Institution City Multidisciplinary Clinical Hospital No. 4
Dnepropetrovsk, Ukraine, 49102
Donetsk Regional Antitumor Center
Donetsk, Ukraine, 83092
Grigoriev Institute for Medical Radiology of National Academy of Medical Science of Ukraine Dept. of Remote, Combined Radiation and Complex Therapy
Kharkiv, Ukraine, 61024
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 Ceneter
Lviv, Ukraine, 79031
Sumy Regional Clinical Oncology Dyspensary
Sumy, Ukraine, 40004
Zaporiz'ka Regional Clinical Oncology Dispensary
Zaporiz'ka Oblast', Ukraine, 69040
United Kingdom
Aintree University Hospital
Liverpool, United Kingdom, L9 7AL
Sponsors and Collaborators
CEL-SCI Corporation
Teva Pharmaceutical Industries
Orient Europharma Co., Ltd.
Investigators
Study Director: Eyal Talor, PhD CEL-SCI Corporation
  More Information

Additional Information:
Responsible Party: CEL-SCI Corporation
ClinicalTrials.gov Identifier: NCT01265849     History of Changes
Other Study ID Numbers: CS001P3
2010-019952-35 ( EudraCT Number )
First Submitted: December 22, 2010
First Posted: December 23, 2010
Last Update Posted: December 8, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell