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

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

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

Study Overview

• Status: Completed
• Conditions: Squamous Cell Carcinoma of the Oral Cavity; Squamous Cell Carcinoma of the Soft Palate
• Intervention / Treatment: Biological: LI; Drug: Cyclophosphamide; Drug: Indomethacin; Dietary supplement: Zinc; Procedure: Surgery; Drug: Cisplatin; Radiation: Radiotherapy

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.

• Study Type: Interventional
• Enrollment (Actual): 928
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • HNO-Klinik der medizinischen Universitat Graz
• Belarus
  • Vitebsk, Belarus, 210603
    • Vitebsk Regional Oncology Dispensary
  • Minsk
    • Lesnoy 2, Minsk, Belarus, 223040
      • N.N. Alexandrov Research Istitute of Oncology and Medical Radiology
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78 000
    • Clinical Center Banja Luka
  • Mostar, Bosnia and Herzegovina, 88000
    • University Clinical Hospital Mostar
  • Sarajevo, Bosnia and Herzegovina, 71000
    • Clinical Centre University of Sarejevo Clinic for ENT
  • Tuzla
    • Trnovac, Tuzla, Bosnia and Herzegovina, 75 000
      • University Clinical Centre Tuzla
• Canada
  • Quebec, Canada, G1R2J6
    • CHU de Quebec - L'Hotel Dieu de Quebec
  • Ontario
    • Hamilton, Ontario, Canada, L8N4A6
      • St. Josephs Healthcare Department of Surgery
  • Quebec
    • Sherbrooke, Quebec, Canada, JiH 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
• Croatia
  • Osijek, Croatia, 31000
    • CHC Osijek
  • Slavonski Brod, Croatia, 35000
    • General Hospital Dr. Josip Bencevic
  • Zagreb, Croatia, 10000
    • KBC Zagreb
  • Zagreb, Croatia, 10000
    • CH Dubrava
  • Zagreb, Croatia, 10000
    • Clinical Hospital Center Zagreb Kispaticeva 12
  • Zagreb, Croatia, 10000
    • KBC Sestre milosrdnice
• France
  • Vandoeuvre les Nancy, France, 54519
    • ICL 6 avenue Bourgogne CS30519
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis University
  • Pecs, Hungary, 7628
    • University of Pecs Institute of Oncotherapy
  • Szeged, Hungary, 6725
    • University of Szeged Dept of Oral and Maxillofacial Surgery
  • Szombathely, Hungary, 9700
    • Markusovsky Teaching Hospital
  • Hajdu Bihar
    • Debrecen, Hajdu Bihar, Hungary, krt. 98
      • University of Debrecen Medical and Health Scioence Centre
  • Rath Gyorgy
    • Budapest, Rath Gyorgy, Hungary, H-1122
      • National Institute of Oncology
• India
  • Andhra Pradesh
    • Malkapet, Andhra Pradesh, India, 500024
      • Bibi General Hospital and Cancer Centre
  • Kerala
    • Kochi, Kerala, India, 682041
      • Amrita Institute of Medical Sciences
  • Maharashtra
    • Amravati, Maharashtra, India, 444606
      • Sujan Regional Cancer Hospital & Amravati Cancer Foundation
    • Aurangabad, Maharashtra, India, 431001
      • Government Medical College and Hospital
    • Mumbai, Maharashtra, India, 400012
      • Tata Memorial Hospital
  • Naka Nashik
    • Mumbai, Naka Nashik, India, 422004
      • Curie Manavata Cancer Center
  • Rajashlan
    • Jaipur, Rajashlan, India, 302013
      • Searoc Cancer Center
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India, 641037
      • V.N. Cancer Center G. Kuppuswamy Naidu Memorial Hospital
    • Madurai, Tamil Nadu, India, 625107
      • Meenakshi mission hospital and research centre
  • Thiruvananthapuram
    • Kerola, Thiruvananthapuram, India, 695011
      • Regional Cancer Center
  • Uttar Pradesh
    • Ghaziabad, Uttar Pradesh, India, 210010
      • Galaxy Cancer Center
• Israel
  • Saint Haifa
    • Sha'ar Ha'Aliya, Saint Haifa, Israel, 31906
      • Rambam Health Care Campus
  • Tikva
    • Petaẖ Tiqwa, Tikva, Israel, 49100
      • Rabin Medical Center
• Italy
  • Naples, Italy, 80131
    • National Tumor Institute of Italy
  • Taranto, Italy, 74010
    • Ospedale S.G. Moscati Santissima Annunziata
• Malaysia
  • Kuala Lumpur, Malaysia, 56000
    • University Kabangsan Medical Center
  • Penang
    • Kuantan, Penang, Malaysia, 16150
      • Dept of Head and Neck Surgery School of Medical Sciences Univ. Sains
• Poland
  • Bialystok, Poland, 15-276
    • ul. M. Sklodowskiej-Curie 24A
  • Krakow, Poland, 31826
    • Szpital Specialistyczny im. Ludwika Rydgiera
  • Lublin, Poland, 20-954
    • Samodzielny Publiczny Szpital Kliniczny Klinika Otolarryngologii I Onkologii Laryngologicznej
  • Poznan, Poland, 61-866
    • Weilkopolskie Centrum Onkologii Klinika Chirurgii Glowy Szye Onkologii Laryngologiczne
  • Wroclaw, Poland, 50-556
    • Uniwersitecki Szpital Kliniczny Klinika Otolaryngologii Chirugii Glowy i Szxyi
  • Ul Paderewskiego 4
    • Lodz, Ul Paderewskiego 4, Poland, 93-509
      • Wojewodzki Szpital Specjalistyczny im Kopernika
  • Ul. Artwinskiego 3
    • Kielce, Ul. Artwinskiego 3, Poland, 25-734
      • Swietokrzyskie Centrum Onkologii
  • Ul. Roentgena 5
    • Warsaw, Ul. Roentgena 5, Poland, 02-781
      • Centrum Onkologii im. Prof. Lukaszcyka
    • Warszawa, Ul. Roentgena 5, Poland, 02-781
      • Centrum Onkologi-Instytut im. Marie Sklodowskiej-Curie
• Romania
  • Iasi, Romania, 700483
    • Regional Institute of Oncology Iasi
  • Targu Mures, Romania, 540072
    • Spital Clinic Judetean Mures
• Russian Federation
  • Kursk, Russian Federation, 305035
    • Kursk Regional Clinical Oncology Dispensary
  • Moscow, Russian Federation, 115478
    • N.N. Blokhin Russian Cancer Research Center
  • Moscow, Russian Federation, 115478
    • Blokhin Cancer Research Center
  • Omsk, Russian Federation, 644013
    • Budget Institution of Healthcare of Omsk Region Clincal Oncology Dispensary
  • Ryazan, Russian Federation, 39011
    • Ryazan Clinical oncology Dispensary
  • Ekaterinberg
    • Sverdlov, Ekaterinberg, Russian Federation, 620905
      • Sverdlovsk Regional Cancer Center
  • Leningradskaya
    • St. Petersburg, Leningradskaya, Russian Federation, 188663
      • Leningrad Regional Oncology Center
• Serbia
  • Belgrade, 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
  • Nis, Serbia, 18 000
    • Clinical Center Nis center for Oncology
  • Nis, Serbia, 18000
    • Clinic for Stomatology department for maxillofacial Surgery
  • Novi Sad, Serbia, 21000
    • Clinical center Vojvodina Clinic for ORL
  • Novi Sad, Serbia, 21000
    • Clinical Centre Vojvodina Clinic for Maxillofacial Surgery
  • Pasterova 14
    • Belgrade, Pasterova 14, Serbia, 11000
      • Serbia Clinic for ENT and Maxillofacial Surgery
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28006
    • Hospital Universitario de Princesa
  • Madrid, Spain, 28050
    • Hospital Madrid North Universitaro de Sanchinnaro
  • Santiago de Compostela, Spain, 15706
    • Complejo Hospitalario Univ. De Santiago
  • Valencia, Spain, 46014
    • Consorsio Hospital General Universitario de valencia
• Sri Lanka
  • Colombo, Sri Lanka, 10280
    • National Cancer Institute Dept of Clinical Oncology & Radiotherapy
  • Galle, Sri Lanka
    • Oncology Unit Teaching Hospital Karapitya
• Taiwan
  • Chang-hua, Taiwan, 500
    • Changua Christian Hospital
  • Hualien City, Taiwan, 970
    • Buddhist Tzu Chi General Hospital, Hualien Branch
  • Taichung, Taiwan, 404
    • China Medical University Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 111
    • Shin-Kong Wu Ho-Su Memorial Hospital
  • Kaohsiung
    • Niaosong, Kaohsiung, Taiwan, 833
      • Kaohsiung Branch Chang Gung Memorial Hospital
  • Tainan
    • Taipei, Tainan, Taiwan, 704
      • National Cheng Kung University Hospital
  • Taipei
    • Chengshan, Taipei, Taiwan, 100
      • National Taiwan Research Hospital
  • Taoyuan
    • Guishan, Taoyuan, Taiwan, 333
      • Linkou Branch Chang Gung Memorial Hospital
• Thailand
  • Nai- Muang, Thailand, 40002
    • Khon Kaen University Dept of Otolaryngology
• Turkey
  • Ankara, Turkey, 06100
    • Haceteppe University Dept of Otolaryngology - Head and Neck Surgery
  • Istanbul, Turkey
    • Acibadem University Maslak Hospital ENT Department
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Cherkasky Regional Oncological Dyspensary Dept. Head and Neck tumour
  • Dnepropetrovsk, Ukraine, 49102
    • Clinical Diagnostic Laboratory of Dnepropetrovsk Municipal Institution City Multidisciplinary Clinical Hospital No. 4
  • Donetsk, Ukraine, 83092
    • Donetsk Regional Antitumor Center
  • Kharkiv, Ukraine, 61024
    • 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
  • Kiev, 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
  • Lviv, Ukraine, 79031
    • Lviv State OncologyRegional treatment and Diagnostic Center
  • Sumy, Ukraine, 40004
    • Sumy Regional Clinical Oncology Dyspensary
  • Zaporiz'ka Oblast', Ukraine, 69040
    • Zaporiz'ka Regional Clinical Oncology Dispensary
• United Kingdom
  • Liverpool, United Kingdom, L9 7AL
    • Aintree University Hospital
• United States
  • Illinois
    • Springfield, Illinois, United States, 62794
      • Simmons Cancer Institute at Southern Illinois University
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System Henry Ford Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29435
      • Medical College Of South Carolina MSC550
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Healthcare System & University of WA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (main):

• 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

Exclusion Criteria (main):

• 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 (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
• Failure to meet inclusion criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LI + CIZ + SOC; LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC).	Biological: 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.; Other Names: Multikine; Leukocyte interleukin, injection; Drug: 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.; Drug: Indomethacin; One 25mg capsule of indomethacin was self administered orally (BID) beginning on day one of LI treatment daily until the day before surgery.; Dietary supplement: Zinc; One capsule daily self administered beginning on day one of treatment with LI until one day before surgery; Other Names: Multivitamins; Procedure: Surgery; Excise tumor and nodes; Drug: 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.; Radiation: 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.
Active Comparator: 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.	Procedure: Surgery; Excise tumor and nodes; Drug: 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.; Radiation: 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.
Experimental: LI + SOC; LI was administered without CIZ to determine the contribution of CIZ to the effects of LI.	Biological: 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.; Other Names: Multikine; Leukocyte interleukin, injection; Procedure: Surgery; Excise tumor and nodes; Drug: 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.; Radiation: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local Regional Control (LRC)	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 present at baseline. This is the traditional RTOG measure of local-regional control, also referred to as Freedom from Local Progression.	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	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 present at baseline. This is the traditional RTOG measure of local-regional control, also referred to as Freedom from Local Progression. 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 LRC or the last follow-up date. Maximum follow-up was approximately 113 months.
Progression Free Survival (PFS)	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. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest dimension (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions.	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	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. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest dimension (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions. Low risk assessment and data analysis was not performed during the study and was performed only after database lock.	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	The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 (EORTC QLQ-C30) V3.0 is composed of both multi-item scales and single-item measures. The Global Health Scale/QoL multi-item scale [GHS] is a comprised of two Items: Item 29 "How would you rate your overall health during the past week?", and item 30: "How would you rate your overall quality of life during the past week?". Both items are 7 point scales ranging from a score of 1 (very poor) to 7 (Excellent). The GHS is constructed by averaging Items 29 and 30 to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation GHS=100*[(RS-1)/6]. A higher score represents a higher ("better") QoL. Change in GHS is calculated as Observed - Baseline, so a positive change in GHS is improved QoL. Treatment comparisons are active treatment arms minus SOC, so a positive difference favors active treatment.	Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 2
Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36	The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 (EORTC QLQ-C30) V3.0 is composed of both multi-item scales and single-item measures. The Global Health Scale/QoL multi-item scale [GHS] is a comprised of two Items: Item 29 "How would you rate your overall health during the past week?", and item 30: "How would you rate your overall quality of life during the past week?". Both items are 7 point scales ranging from a score of 1 (very poor) to 7 (Excellent). The GHS is constructed by averaging Items 29 and 30 to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation GHS=100*[(RS-1)/6]. A higher score represents a higher ("better") QoL. Change in GHS is calculated as Observed - Baseline, so a positive change in GHS is improved QoL. Treatment comparisons are active treatment arms minus SOC, so a positive difference favors active treatment.	Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 36
EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2	The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 supplementary Head & neck cancer module (EORTC QLQ-C30 - QLQ H&N35) items 1-4 make up the symptom score for pain, items 5-8 for swallowing. The 4 pain questions score: "pain in your mouth, pain in your jaw, soreness in your mouth, a painful throat?" The 4 swallowing questions score "problems swallowing: liquids, pureed food, solid food, choking? Item are scored as 1 (Not at all) to 4 (Very much). Each symptom scale is constructed by averaging the 4 items to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation symptom score (pain or swallowing)=100*[(RS-1)/3]. A high score for these symptom scales represents a high level of symptoms.Change in symptom is calculated as Observed - Baseline, so a negative change is reduced symptomatology . Treatment comparisons are active treatment arms minus SOC, so a negative difference favors active treatment.	Baseline [pre-randomization], Long Term Follow-up Month 2
EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36	The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 supplementary Head & neck cancer module (EORTC QLQ-C30 - QLQ H&N35) items 1-4 make up the symptom score for pain, items 5-8 for swallowing. The 4 pain questions score: "pain in your mouth, pain in your jaw, soreness in your mouth, a painful throat?" The 4 swallowing questions score "problems swallowing: liquids, pureed food, solid food, choking? Item are scored as 1 (Not at all) to 4 (Very much). Each symptom scale is constructed by averaging the 4 items to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation symptom score (pain or swallowing)=100*[(RS-1)/3]. A high score for these symptom scales represents a high level of symptoms.Change in symptom is calculated as Observed - Baseline, so a negative change is reduced symptomatology . Treatment comparisons are active treatment arms minus SOC, so a negative difference favors active treatment.	Baseline [pre-randomization], Long Term Follow-up Month 36
Statistical Comparisons of Time-to-event Outcomes (OS, LRC, PFS) Were Repeated for Varying Levels of Histopathology (HP) Markers in Low Risk Subjects	HP analysis was performed in a blinded manner by a central pathology laboratory at the end of the study on available samples. To examine potential effects of HP markers on time-to-event efficacy outcomes (OS, LRC, PFS), participants were classified by HP marker levels: 20 HP markers were classified as (low, medium, high), 2 HP ratios as (low, medium, high) and 14 HP combinations as (low, high), resulting in 94 (20*3+2*3+2*14) possible treatment comparisons of LI + CIZ + SOC to SOC. A total of 282 (94 x 3 efficacy outcomes) statistical tests (Cox proportional hazards regressions to test for a significant treatment effect in the model) were made. Significance (two-sided p<0.05 favoring LI + CIZ + SOC) were reported under LI + CIZ + SOC. Significant test results favoring SOC were reported under SOC. The total number of statistical comparisons between LI + CIZ + SOC and SOC (282) is reported under both arms.	From the date of treatment assignment to event (LRC,PFS,OS) or the last follow-up date. Maximum follow-up was approximately 113 months.

Collaborators and Investigators

• Sponsor: CEL-SCI Corporation
• Collaborators: Teva Branded Pharmaceutical Products R&D, Inc.; Orient Europharma Co., Ltd.
• Investigators: Study Director: Eyal Talor, PhD, CEL-SCI Corporation

Publications and helpful links

Helpful 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)

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2010
• Primary Completion (Actual): May 15, 2020
• Study Completion (Actual): December 4, 2020

Study Registration Dates

• First Submitted: December 22, 2010
• First Submitted That Met QC Criteria: December 22, 2010
• First Posted (Estimate): December 23, 2010

Study Record Updates

• Last Update Posted (Actual): August 19, 2022
• Last Update Submitted That Met QC Criteria: August 17, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Cyclophosphamide; Indomethacin
• Other Study ID Numbers: CS001P3; 2010-019952-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan