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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Squamous Cell Carcinoma of the Oral Cavity, Squamous Cell Carcinoma of the Soft Palate

Intervention / Treatment
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* Biological: LI
* Drug: Cyclophosphamide
* Drug: Indomethacin
* Dietary Supplement: Zinc
* Procedure: Surgery
* Drug: Cisplatin
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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. |