Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity
- Conditions
- Squamous Cell Carcinoma of the Oral CavitySquamous Cell Carcinoma of the Soft Palate
- Interventions
- Biological: LIDietary Supplement: ZincProcedure: SurgeryRadiation: Radiotherapy
- Registration Number
- NCT01265849
- Lead Sponsor
- CEL-SCI Corporation
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 928
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description LI + CIZ + SOC LI LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). LI + CIZ + SOC Indomethacin LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). LI + CIZ + SOC Zinc LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). LI + CIZ + SOC Surgery LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). LI + CIZ + SOC Cisplatin LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). LI + CIZ + SOC Radiotherapy LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC). Standard of Care (SOC) only Surgery 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. Standard of Care (SOC) only Cisplatin 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. Standard of Care (SOC) only Radiotherapy 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. LI + SOC LI LI was administered without CIZ to determine the contribution of CIZ to the effects of LI. LI + SOC Surgery LI was administered without CIZ to determine the contribution of CIZ to the effects of LI. LI + SOC Cisplatin LI was administered without CIZ to determine the contribution of CIZ to the effects of LI. LI + SOC Radiotherapy LI was administered without CIZ to determine the contribution of CIZ to the effects of LI. LI + CIZ + SOC Cyclophosphamide LI plus CIZ (cyclophosphamide, indomethacin and zinc-multivitamins) was given as neoadjuvant therapy prior to standard of care (SOC).
- Primary Outcome Measures
Name Time Method Overall Survival (OS) From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months. 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.
OS in Low Risk Subjects From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months. 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.
- Secondary Outcome Measures
Name Time Method 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. 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.
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 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.
Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36 Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up 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.
EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 Baseline [pre-randomization], Long Term Follow-up 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.
EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 Baseline [pre-randomization], Long Term Follow-up 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.
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 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.
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. 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.
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 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.
Statistical Comparisons of Time-to-event Outcomes (OS, LRC, PFS) Were Repeated for Varying Levels of Histopathology (HP) Markers in Low Risk Subjects From the date of treatment assignment to event (LRC,PFS,OS) or the last follow-up date. Maximum follow-up was approximately 113 months. 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.
Trial Locations
- Locations (102)
Linkou Branch Chang Gung Memorial Hospital
🇨🇳Guishan, Taoyuan, Taiwan
Meenakshi Mission Hospital and Research Centre
🇮🇳Madurai, Tamil Nadu, India
St. Josephs Healthcare Department of Surgery
🇨🇦Hamilton, Ontario, Canada
CHU de Quebec - L'Hotel Dieu de Quebec
🇨🇦Quebec, Canada
Simmons Cancer Institute at Southern Illinois University
🇺🇸Springfield, Illinois, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
Henry Ford Health System Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
HNO-Klinik der medizinischen Universitat Graz
🇦🇹Graz, Austria
Medical College Of South Carolina MSC550
🇺🇸Charleston, South Carolina, United States
VA Puget Sound Healthcare System & University of WA
🇺🇸Seattle, Washington, United States
CHC Osijek
ðŸ‡ðŸ‡·Osijek, Croatia
General Hospital Dr. Josip Bencevic
ðŸ‡ðŸ‡·Slavonski Brod, Croatia
National institute of Oncology
ðŸ‡ðŸ‡ºBudapest, Rath Gyorgy, Hungary
University of Debrecen Medical and Health Scioence Centre
ðŸ‡ðŸ‡ºDebrecen, Hajdu Bihar, Hungary
ICL 6 avenue Bourgogne CS30519
🇫🇷Vandoeuvre les Nancy, France
University of Szeged Dept of Oral and Maxillofacial Surgery
ðŸ‡ðŸ‡ºSzeged, Hungary
Semmelweis University
ðŸ‡ðŸ‡ºBudapest, Hungary
Curie Manavata Cancer Center
🇮🇳Mumbai, Naka Nashik, India
Markusovsky Teaching Hospital
ðŸ‡ðŸ‡ºSzombathely, Hungary
Bibi General Hospital and Cancer Centre
🇮🇳Malkapet, Andhra Pradesh, India
V.N. Cancer Center G. Kuppuswamy Naidu Memorial Hospital
🇮🇳Coimbatore, Tamil Nadu, India
Searoc Cancer Center
🇮🇳Jaipur, Rajashlan, India
Galaxy Cancer Center
🇮🇳Ghaziabad, Uttar Pradesh, India
Szpital Specialistyczny im. Ludwika Rydgiera
🇵🇱Krakow, Poland
Ospedale S.G. Moscati Santissima Annunziata
🇮🇹Taranto, Italy
Swietokrzyskie Centrum Onkologii
🇵🇱Kielce, Ul. Artwinskiego 3, Poland
Centrum Onkologii im. Prof. Lukaszcyka
🇵🇱Warsaw, Ul. Roentgena 5, Poland
N.N. Blokhin Russian Cancer Research Center
🇷🇺Moscow, Russian Federation
Leningrad Regional Oncology Center
🇷🇺St. Petersburg, Leningradskaya, Russian Federation
Ryazan Clinical oncology Dispensary
🇷🇺Ryazan, Russian Federation
Clinical Center Nis center for Oncology
🇷🇸Nis, Serbia
Military Medical Academy Clinic for Maxillofacial Surgery
🇷🇸Belgrade, Serbia
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario de Princesa
🇪🇸Madrid, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Haceteppe University Dept of Otolaryngology - Head and Neck Surgery
🇹🇷Ankara, Turkey
Acibadem University Maslak Hospital ENT Department
🇹🇷Istanbul, Turkey
Cherkasky Regional Oncological Dyspensary Dept. Head and Neck tumour
🇺🇦Cherkasy, Ukraine
Lviv State OncologyRegional treatment and Diagnostic Center
🇺🇦Lviv, Ukraine
Clinical Centre University of Sarejevo Clinic for ENT
🇧🇦Sarajevo, Bosnia and Herzegovina
CH Dubrava
ðŸ‡ðŸ‡·Zagreb, Croatia
KBC Sestre Milosrdnice
ðŸ‡ðŸ‡·Zagreb, Croatia
KBC Zagreb
ðŸ‡ðŸ‡·Zagreb, Croatia
University of Pecs Institute of Oncotherapy
ðŸ‡ðŸ‡ºPecs, Hungary
Government Medical College and Hospital
🇮🇳Aurangabad, Maharashtra, India
Amrita Institute of Medical Sciences
🇮🇳Kochi, Kerala, India
Regional Cancer Center
🇮🇳Kerola, Thiruvananthapuram, India
Rambam Health Care Campus
🇮🇱Sha'ar Ha'Aliya, Saint Haifa, Israel
National Tumor Institute of Italy
🇮🇹Naples, Italy
Rabin Medical Center
🇮🇱Petaẖ Tiqwa, Tikva, Israel
Wojewodzki Szpital Specjalistyczny im Kopernika
🇵🇱Lodz, Ul Paderewskiego 4, Poland
Dept of Head and Neck Surgery School of Medical Sciences Univ. Sains
🇲🇾Kuantan, Penang, Malaysia
Samodzielny Publiczny Szpital Kliniczny Klinika Otolarryngologii I Onkologii Laryngologicznej
🇵🇱Lublin, Poland
ul. M. Sklodowskiej-Curie 24A
🇵🇱Bialystok, Poland
Weilkopolskie Centrum Onkologii Klinika Chirurgii Glowy Szye Onkologii Laryngologiczne
🇵🇱Poznan, Poland
Spital Clinic Judetean Mures
🇷🇴Targu Mures, Romania
Sverdlovsk Regional Cancer Center
🇷🇺Sverdlov, Ekaterinberg, Russian Federation
Budget Institution of Healthcare of Omsk Region Clincal Oncology Dispensary
🇷🇺Omsk, Russian Federation
Blokhin Cancer Research Center
🇷🇺Moscow, Russian Federation
Serbia Clinic for ENT and Maxillofacial Surgery
🇷🇸Belgrade, Pasterova 14, Serbia
Faculty of Dental Medicine Clinic for Maxillofacial Surgery
🇷🇸Belgrade, Serbia
Clincal Center Serbia Clinic for Oral and Maxillofacial Surgery
🇷🇸Belgrade, Serbia
Regional Institute of Oncology IASI
🇷🇴Iasi, Romania
Clinical center Vojvodina Clinic for ORL
🇷🇸Novi Sad, Serbia
Clinical Centre Vojvodina Clinic for Maxillofacial Surgery
🇷🇸Novi Sad, Serbia
Complejo Hospitalario Univ. de Santiago
🇪🇸Santiago de Compostela, Spain
Hospital Madrid North Universitaro de Sanchinnaro
🇪🇸Madrid, Spain
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
Changua Christian Hospital
🇨🇳Chang-hua, Taiwan
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
National Taiwan Research Hospital
🇨🇳Chengshan, Taipei, Taiwan
Khon Kaen University Dept of Otolaryngology
🇹ðŸ‡Nai- Muang, Thailand
Donetsk Regional Antitumor Center
🇺🇦Donetsk, Ukraine
Clinical Diagnostic Laboratory of Dnepropetrovsk Municipal Institution City Multidisciplinary Clinical Hospital No. 4
🇺🇦Dnepropetrovsk, 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
Sumy Regional Clinical Oncology Dyspensary
🇺🇦Sumy, Ukraine
Zaporiz'ka Regional Clinical Oncology Dispensary
🇺🇦Zaporiz'ka Oblast', Ukraine
Aintree University Hospital
🇬🇧Liverpool, United Kingdom
Consorsio Hospital General Universitario de valencia
🇪🇸Valencia, Spain
Kursk Regional Clinical Oncology Dispensary
🇷🇺Kursk, Russian Federation
Tata Memorial Hospital
🇮🇳Mumbai, Maharashtra, India
N.N. Alexandrov Research Istitute of Oncology and Medical Radiology
🇧🇾Lesnoy 2, Minsk, Belarus
University Kabangsan Medical Center
🇲🇾Kuala Lumpur, Malaysia
University Clinical Centre Tuzla
🇧🇦Trnovac, Tuzla, Bosnia and Herzegovina
Clinical Hospital Center Zagreb Kispaticeva 12
ðŸ‡ðŸ‡·Zagreb, Croatia
Vitebsk Regional Oncology Dispensary
🇧🇾Vitebsk, Belarus
Buddhist Tzu Chi General Hospital, Hualien Branch
🇨🇳Hualien City, Taiwan
China Medical University Hospital
🇨🇳Taichung, Taiwan
Sujan Regional Cancer Hospital & Amravati Cancer Foundation
🇮🇳Amravati, Maharashtra, India
Shin-Kong Wu Ho-Su Memorial Hospital
🇨🇳Taipei, Taiwan
Clinical Center Banja Luka
🇧🇦Banja Luka, Bosnia and Herzegovina
University Clinical Hospital Mostar
🇧🇦Mostar, Bosnia and Herzegovina
Clinic for Stomatology department for maxillofacial Surgery
🇷🇸Nis, Serbia
National Cancer Institute Dept of Clinical Oncology & Radiotherapy
🇱🇰Colombo, Sri Lanka
Centrum Onkologi-Instytut im. Marie Sklodowskiej-Curie
🇵🇱Warszawa, Ul. Roentgena 5, Poland
Uniwersitecki Szpital Kliniczny Klinika Otolaryngologii Chirugii Glowy i Szxyi
🇵🇱Wroclaw, Poland
Grigoriev Institute for Medical Radiology of National Academy of Medical Science of Ukraine Dept. of Remote, Combined Radiation and Complex Therapy
🇺🇦Kharkiv, Ukraine
Kiev City Clinical Oncology Center of the Main Health Care Dept. of the Kiev Day Hospital
🇺🇦Kiev, Ukraine
Centre Hospitalier Universitaire de Sherbrooke
🇨🇦Sherbrooke, Quebec, Canada