Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity (IT-MATTERS)
|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 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|
- 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.
- 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.
|Study Start Date:||December 2010|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
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.
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
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.
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].
Please refer to this study by its ClinicalTrials.gov identifier: NCT01265849
|Contact: Eyal Talor, PhDfirstname.lastname@example.org|
|Contact: John Cipriano, M.S.||email@example.com|
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|Study Director:||Eyal Talor, PhD||CEL-SCI Corporation|