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Trial record 1 of 1 for:    NCT01265849
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Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity (IT-MATTERS)

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.
 
ClinicalTrials.gov Identifier: NCT01265849
Recruitment Status : Active, not recruiting
First Posted : December 23, 2010
Last Update Posted : April 6, 2020
Sponsor:
Collaborators:
Teva Pharmaceutical Industries
Orient Europharma Co., Ltd.
Information provided by (Responsible Party):
CEL-SCI Corporation

Tracking Information
First Submitted Date  ICMJE December 22, 2010
First Posted Date  ICMJE December 23, 2010
Last Update Posted Date April 6, 2020
Actual Study Start Date  ICMJE December 2010
Estimated Primary Completion Date May 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2017)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
  • 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
  • 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 group 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 number and percent of subjects in the treated and untreated groups and the timing of LRC will be displayed for each group.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity
Official Title  ICMJE 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
Brief Summary 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
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].

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Squamous Cell Carcinoma of the Oral Cavity
  • Squamous Cell Carcinoma of the Soft Palate
Intervention  ICMJE
  • Biological: LI
    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.
    Other Names:
    • Multikine
    • Leukocyte interleukin, injection
  • Drug: Cyclophosphamide
    Cyclophoshamidie is administered IV bolus 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) 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
  • Drug: Indomethacin
    One 25mg capsule of indomethacin is administered orally beginning on day one of LI treatment daily until the day before surgery. for 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.
  • Dietary Supplement: Zinc
    One capsule daily beginning on day one of treatment with LI until one day before surgery
  • Procedure: Surgery
    Surgery to remove tumor
  • Drug: Cisplatin
    Cisplatin is administered 100mg/m^2 IV is administered with concurrent chemotherapy (cisplatin 100mg/m2 intravenously 1x weekly for 3 weeks on day 1 of weeks 1, 4 and 7 of radiotherapy i
  • Radiation: Radiotherapy
    60 to 70Gy in 30 to 35 fractions over 6 to 7 weeks. In 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
Study Arms  ICMJE
  • Experimental: LI + CIZ + SOC
    LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as adjuvant therapy prior to standard of care (SOC).
    Interventions:
    • Biological: LI
    • Drug: Cyclophosphamide
    • Drug: Indomethacin
    • Dietary Supplement: Zinc
    • Procedure: Surgery
    • Drug: Cisplatin
    • Radiation: Radiotherapy
  • 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.
    Interventions:
    • Procedure: Surgery
    • Drug: Cisplatin
    • Radiation: Radiotherapy
  • Experimental: LI + SOC
    LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.
    Interventions:
    • Biological: LI
    • Procedure: Surgery
    • Drug: Cisplatin
    • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 6, 2017)
928
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2010)
880
Estimated Study Completion Date  ICMJE May 15, 2020
Estimated Primary Completion Date May 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belarus,   Bosnia and Herzegovina,   Canada,   Croatia,   France,   Hungary,   India,   Israel,   Italy,   Malaysia,   Poland,   Romania,   Russian Federation,   Serbia,   Spain,   Sri Lanka,   Taiwan,   Thailand,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01265849
Other Study ID Numbers  ICMJE CS001P3
2010-019952-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There is no plan
Responsible Party CEL-SCI Corporation
Study Sponsor  ICMJE CEL-SCI Corporation
Collaborators  ICMJE
  • Teva Pharmaceutical Industries
  • Orient Europharma Co., Ltd.
Investigators  ICMJE
Study Director: Eyal Talor, PhD CEL-SCI Corporation
PRS Account CEL-SCI Corporation
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP