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

• Progression Free Survival (PFS) in LI + CIZ + SOC vs.SOC [ Time Frame: 3 year. ] [ Designated as safety issue: Yes ]
  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 ] [ Designated as safety issue: Yes ]
  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. ] [ Designated as safety issue: Yes ]
  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.

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

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].

• Squamous Cell Carcinoma of the Oral Cavity
• Squamous Cell Carcinoma of the Soft Palate

• 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
• 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
• 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

• Experimental: LI plus CIZ
  LI plus CIZ is given as adjuvant therapy prior to standard of care (SOC).
  Intervention: Biological: LI plus CIZ
• 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.
  Intervention: Other: Standard of Care (SOC)
• Experimental: LI + SOC
  LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.
  Intervention: Biological: LI + SOC

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

• Teva Pharmaceutical Industries
• Orient Europharma Co., Ltd.