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

• Sponsor: CEL-SCI Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01265849
• Collaborator: Teva Branded Pharmaceutical Products R&D, Inc. (Industry), Orient Europharma Co., Ltd. (Industry)
• Enrollment: 928
• Locations: 102
• Arms: 3
• Actual Duration (Months): 120.1
• Patients Per Site: 9.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Oral Cavity; Squamous Cell Carcinoma of the Soft Palate	Biological: LI; Drug: Cyclophosphamide; Drug: Indomethacin; Dietary Supplement: Zinc; Procedure: Surgery; Drug: Cisplatin; Radiation: Radiotherapy	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 928 participants
• 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
• Actual Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: May 15, 2020
• Actual Study Completion Date: Dec 4, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Simmons Cancer Institute at Southern Illinois University	Springfield	Illinois	United States	62794
2	Henry Ford Health System Henry Ford Hospital	Detroit	Michigan	United States	48202
3	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
4	Medical College Of South Carolina MSC550	Charleston	South Carolina	United States	29435
5	VA Puget Sound Healthcare System & University of WA	Seattle	Washington	United States	98108
6	HNO-Klinik der medizinischen Universitat Graz	Graz		Austria	8036
7	N.N. Alexandrov Research Istitute of Oncology and Medical Radiology	Lesnoy 2	Minsk	Belarus	223040
8	Vitebsk Regional Oncology Dispensary	Vitebsk		Belarus	210603
9	University Clinical Centre Tuzla	Trnovac	Tuzla	Bosnia and Herzegovina	75 000
10	Clinical Center Banja Luka	Banja Luka		Bosnia and Herzegovina	78 000
11	University Clinical Hospital Mostar	Mostar		Bosnia and Herzegovina	88000
12	Clinical Centre University of Sarejevo Clinic for ENT	Sarajevo		Bosnia and Herzegovina	71000
13	St. Josephs Healthcare Department of Surgery	Hamilton	Ontario	Canada	L8N4A6
14	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec	Canada	JiH 5N4
15	CHU de Quebec - L'Hotel Dieu de Quebec	Quebec		Canada	G1R2J6
16	CHC Osijek	Osijek		Croatia	31000
17	General Hospital Dr. Josip Bencevic	Slavonski Brod		Croatia	35000
18	CH Dubrava	Zagreb		Croatia	10000
19	Clinical Hospital Center Zagreb Kispaticeva 12	Zagreb		Croatia	10000
20	KBC Sestre Milosrdnice	Zagreb		Croatia	10000
21	KBC Zagreb	Zagreb		Croatia	10000
22	ICL 6 avenue Bourgogne CS30519	Vandoeuvre les Nancy		France	54519
23	University of Debrecen Medical and Health Scioence Centre	Debrecen	Hajdu Bihar	Hungary	krt. 98
24	National institute of Oncology	Budapest	Rath Gyorgy	Hungary	H-1122
25	Semmelweis University	Budapest		Hungary	1085
26	University of Pecs Institute of Oncotherapy	Pecs		Hungary	7628
27	University of Szeged Dept of Oral and Maxillofacial Surgery	Szeged		Hungary	6725
28	Markusovsky Teaching Hospital	Szombathely		Hungary	9700
29	Bibi General Hospital and Cancer Centre	Malkapet	Andhra Pradesh	India	500024
30	Amrita Institute of Medical Sciences	Kochi	Kerala	India	682041
31	Sujan Regional Cancer Hospital & Amravati Cancer Foundation	Amravati	Maharashtra	India	444606
32	Government Medical College and Hospital	Aurangabad	Maharashtra	India	431001
33	Tata Memorial Hospital	Mumbai	Maharashtra	India	400012
34	Curie Manavata Cancer Center	Mumbai	Naka Nashik	India	422004
35	Searoc Cancer Center	Jaipur	Rajashlan	India	302013
36	V.N. Cancer Center G. Kuppuswamy Naidu Memorial Hospital	Coimbatore	Tamil Nadu	India	641037
37	Meenakshi Mission Hospital and Research Centre	Madurai	Tamil Nadu	India	625107
38	Regional Cancer Center	Kerola	Thiruvananthapuram	India	695011
39	Galaxy Cancer Center	Ghaziabad	Uttar Pradesh	India	210010
40	Rambam Health Care Campus	Sha'ar Ha'Aliya	Saint Haifa	Israel	31906
41	Rabin Medical Center	Petaẖ Tiqwa	Tikva	Israel	49100
42	National Tumor Institute of Italy	Naples		Italy	80131
43	Ospedale S.G. Moscati Santissima Annunziata	Taranto		Italy	74010
44	Dept of Head and Neck Surgery School of Medical Sciences Univ. Sains	Kuantan	Penang	Malaysia	16150
45	University Kabangsan Medical Center	Kuala Lumpur		Malaysia	56000
46	Wojewodzki Szpital Specjalistyczny im Kopernika	Lodz	Ul Paderewskiego 4	Poland	93-509
47	Swietokrzyskie Centrum Onkologii	Kielce	Ul. Artwinskiego 3	Poland	25-734
48	Centrum Onkologii im. Prof. Lukaszcyka	Warsaw	Ul. Roentgena 5	Poland	02-781
49	Centrum Onkologi-Instytut im. Marie Sklodowskiej-Curie	Warszawa	Ul. Roentgena 5	Poland	02-781
50	ul. M. Sklodowskiej-Curie 24A	Bialystok		Poland	15-276
51	Szpital Specialistyczny im. Ludwika Rydgiera	Krakow		Poland	31826
52	Samodzielny Publiczny Szpital Kliniczny Klinika Otolarryngologii I Onkologii Laryngologicznej	Lublin		Poland	20-954
53	Weilkopolskie Centrum Onkologii Klinika Chirurgii Glowy Szye Onkologii Laryngologiczne	Poznan		Poland	61-866
54	Uniwersitecki Szpital Kliniczny Klinika Otolaryngologii Chirugii Glowy i Szxyi	Wroclaw		Poland	50-556
55	Regional Institute of Oncology IASI	Iasi		Romania	700483
56	Spital Clinic Judetean Mures	Targu Mures		Romania	540072
57	Sverdlovsk Regional Cancer Center	Sverdlov	Ekaterinberg	Russian Federation	620905
58	Leningrad Regional Oncology Center	St. Petersburg	Leningradskaya	Russian Federation	188663
59	Kursk Regional Clinical Oncology Dispensary	Kursk		Russian Federation	305035
60	Blokhin Cancer Research Center	Moscow		Russian Federation	115478
61	N.N. Blokhin Russian Cancer Research Center	Moscow		Russian Federation	115478
62	Budget Institution of Healthcare of Omsk Region Clincal Oncology Dispensary	Omsk		Russian Federation	644013
63	Ryazan Clinical oncology Dispensary	Ryazan		Russian Federation	39011
64	Serbia Clinic for ENT and Maxillofacial Surgery	Belgrade	Pasterova 14	Serbia	11000
65	Clincal Center Serbia Clinic for Oral and Maxillofacial Surgery	Belgrade		Serbia	11000
66	Faculty of Dental Medicine Clinic for Maxillofacial Surgery	Belgrade		Serbia	11000
67	Military Medical Academy Clinic for Maxillofacial Surgery	Belgrade		Serbia	11000
68	Clinical Center Nis center for Oncology	Nis		Serbia	18 000
69	Clinic for Stomatology department for maxillofacial Surgery	Nis		Serbia	18000
70	Clinical center Vojvodina Clinic for ORL	Novi Sad		Serbia	21000
71	Clinical Centre Vojvodina Clinic for Maxillofacial Surgery	Novi Sad		Serbia	21000
72	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
73	Hospital Universitario de Princesa	Madrid		Spain	28006
74	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
75	Hospital Madrid North Universitaro de Sanchinnaro	Madrid		Spain	28050
76	Complejo Hospitalario Univ. de Santiago	Santiago de Compostela		Spain	15706
77	Consorsio Hospital General Universitario de valencia	Valencia		Spain	46014
78	National Cancer Institute Dept of Clinical Oncology & Radiotherapy	Colombo		Sri Lanka	10280
79	Oncology Unit Teaching Hospital Karapitya	Galle		Sri Lanka
80	Kaohsiung Branch Chang Gung Memorial Hospital	Niaosong	Kaohsiung	Taiwan	833
81	National Cheng Kung University Hospital	Taipei	Tainan	Taiwan	704
82	National Taiwan Research Hospital	Chengshan	Taipei	Taiwan	100
83	Linkou Branch Chang Gung Memorial Hospital	Guishan	Taoyuan	Taiwan	333
84	Changua Christian Hospital	Chang-hua		Taiwan	500
85	Buddhist Tzu Chi General Hospital, Hualien Branch	Hualien City		Taiwan	970
86	China Medical University Hospital	Taichung		Taiwan	404
87	Taichung Veterans General Hospital	Taichung		Taiwan	40705
88	Shin-Kong Wu Ho-Su Memorial Hospital	Taipei		Taiwan	111
89	Khon Kaen University Dept of Otolaryngology	Nai- Muang		Thailand	40002
90	Haceteppe University Dept of Otolaryngology - Head and Neck Surgery	Ankara		Turkey	06100
91	Acibadem University Maslak Hospital ENT Department	Istanbul		Turkey
92	Cherkasky Regional Oncological Dyspensary Dept. Head and Neck tumour	Cherkasy		Ukraine	18009
93	Clinical Diagnostic Laboratory of Dnepropetrovsk Municipal Institution City Multidisciplinary Clinical Hospital No. 4	Dnepropetrovsk		Ukraine	49102
94	Donetsk Regional Antitumor Center	Donetsk		Ukraine	83092
95	Grigoriev Institute for Medical Radiology of National Academy of Medical Science of Ukraine Dept. of Remote, Combined Radiation and Complex Therapy	Kharkiv		Ukraine	61024
96	Kharkiv Regional Clinical Oncology Center Dept. Of Head and Neck Tumour	Kharkiv		Ukraine
97	Kiev City Clinical Oncology Center of the Main Health Care Dept of Kiev Day Hospital Radiotherapy Dept.	Kiev		Ukraine
98	Kiev City Clinical Oncology Center of the Main Health Care Dept. of the Kiev Day Hospital	Kiev		Ukraine
99	Lviv State OncologyRegional treatment and Diagnostic Center	Lviv		Ukraine	79031
100	Sumy Regional Clinical Oncology Dyspensary	Sumy		Ukraine	40004
101	Zaporiz'ka Regional Clinical Oncology Dispensary	Zaporiz'ka Oblast'		Ukraine	69040
102	Aintree University Hospital	Liverpool		United Kingdom	L9 7AL

Sponsors and Collaborators

• CEL-SCI Corporation
• Teva Branded Pharmaceutical Products R&D, Inc.
• Orient Europharma Co., Ltd.

Investigators

• Study Director: Eyal Talor, PhD, CEL-SCI Corporation

Study Documents (Full-Text)

• Study Protocol - Jun 27, 2014
• Statistical Analysis Plan: SAP main text - Nov 27, 2020
• Statistical Analysis Plan: CS001P3 Note to File 1 - Dec 28, 2020
• Statistical Analysis Plan: CS001P3 Note to file 2 - Jan 12, 2021
• Statistical Analysis Plan: Note to file 3 - Mar 28, 2021
• Statistical Analysis Plan: Note to file 4 - Mar 30, 2021
• Statistical Analysis Plan: Note to file 5 - Apr 29, 2021

More Information

Additional Information:

• Click here for more information about this study: Phase 3 Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity (IT-MATTERS)

Publications

None provided.

• Responsible Party: CEL-SCI Corporation
• ClinicalTrials.gov Identifier: NCT01265849
• Other Study ID Numbers: CS001P3; 2010-019952-35
• First Posted: Dec 23, 2010
• Last Update Posted: Aug 19, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Indomethacin; Cyclophosphamide

Study Results

Participant Flow

Arm/Group Title	LI + CIZ + SOC	Standard of Care (SOC)	LI + SOC
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as adjuvant therapy prior to 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 recurrence determined at surgery.	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.
Period Title: Overall Study
STARTED	396	398	134
COMPLETED	350	337	115
NOT COMPLETED	46	61	19

Baseline Characteristics

Arm/Group Title	LI + CIZ + SOC	Standard of Care (SOC)	LI + SOC	Total
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to 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.	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	Total of all reporting groups
Overall Participants	395	394	134	923
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	56.5	56.9	55.9	56.6
Sex: Female, Male (Count of Participants)
Female	83 21%	79 20.1%	29 21.6%	191 20.7%
Male	312 79%	315 79.9%	105 78.4%	732 79.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	190 48.1%	186 47.2%	57 42.5%	433 46.9%
Unknown or Not Reported	205 51.9%	208 52.8%	77 57.5%	490 53.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	79 20%	76 19.3%	25 18.7%	180 19.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 0.5%	0 0%	0 0%	2 0.2%
White	311 78.7%	317 80.5%	108 80.6%	736 79.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 0.8%	1 0.3%	1 0.7%	5 0.5%
Region of Enrollment (participants) [Number]
Malaysia	2 0.5%	2 0.5%	1 0.7%	5 0.5%
Philippines	1 0.3%	1 0.3%	0 0%	2 0.2%
Taiwan	17 4.3%	16 4.1%	7 5.2%	40 4.3%
Thailand	1 0.3%	1 0.3%	0 0%	2 0.2%
India	37 9.4%	38 9.6%	11 8.2%	86 9.3%
Israel	2 0.5%	3 0.8%	1 0.7%	6 0.7%
Sri Lanka	20 5.1%	19 4.8%	7 5.2%	46 5%
Bosnia and Herzegovina	16 4.1%	18 4.6%	6 4.5%	40 4.3%
Serbia	78 19.7%	79 20.1%	26 19.4%	183 19.8%
Turkey	1 0.3%	0 0%	0 0%	1 0.1%
Belarus	20 5.1%	19 4.8%	7 5.2%	46 5%
Russia	76 19.2%	76 19.3%	26 19.4%	178 19.3%
Ukraine	68 17.2%	67 17%	23 17.2%	158 17.1%
Canada	1 0.3%	1 0.3%	1 0.7%	3 0.3%
Croatia	23 5.8%	24 6.1%	8 6%	55 6%
France	1 0.3%	0 0%	0 0%	1 0.1%
Hungary	9 2.3%	9 2.3%	3 2.2%	21 2.3%
Poland	20 5.1%	20 5.1%	6 4.5%	46 5%
Romania	1 0.3%	1 0.3%	0 0%	2 0.2%
United States	1 0.3%	0 0%	1 0.7%	2 0.2%
Primary Tumor Location (Count of Participants)
Cheek (Buccal Mucosa)	53 13.4%	55 14%	18 13.4%	126 13.7%
Floor of Mouth	111 28.1%	116 29.4%	37 27.6%	264 28.6%
Oral Tongue	182 46.1%	178 45.2%	63 47%	423 45.8%
Soft Palate	49 12.4%	45 11.4%	16 11.9%	110 11.9%
Tumor Code (Count of Participants)
T1: Tumor < 2 cm in greatest dimension	21 5.3%	12 3%	4 3%	37 4%
T2: Tumor > 2 and < 4 cm in greatest dimension or extension to lingual surface of epiglottis	94 23.8%	95 24.1%	28 20.9%	217 23.5%
T3: Tumor more than 4 cm in greatest dimension	163 41.3%	191 48.5%	68 50.7%	422 45.7%
T4a: Moderately advanced local disease	117 29.6%	96 24.4%	34 25.4%	247 26.8%
Number of Nodes Involved (Count of Participants)
Missing	1 0.3%	0 0%	0 0%	1 0.1%
N0	190 48.1%	180 45.7%	62 46.3%	432 46.8%
N1	108 27.3%	118 29.9%	37 27.6%	263 28.5%
N2	96 24.3%	96 24.4%	35 26.1%	227 24.6%
TNM Stage (Count of Participants)
TNM Stage III	218 55.2%	228 57.9%	75 56%	521 56.4%
TNM Stage IV	177 44.8%	166 42.1%	59 44%	402 43.6%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	395	134	394
Median (95% Confidence Interval) [months]	46.3	58.1	52.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	The primary objective was to compare overall survival in the LI + CIZ + SOC group to that in the SOC alone group for superiority of the former.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4051
	Comments	For the primary efficacy measure a two-sided p-value of 0.05 or less is considered to be statistically significant in comparing the LI+CIZ+SOC treatment vs. SOC alone for superiority.
	Method	Log Rank
	Comments	Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5402
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4128
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7181
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9480
	Comments
	Method	Log Rank
	Comments	This log Rank p-value is based on a stratified analysis.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6101
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	A hazard Ratio < 1.0 would favor LI + SOC.

2. Primary Outcome

Title	OS in Low Risk Subjects
Description	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.
Time Frame	From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Low Risk Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	158	54	168
Median (95% Confidence Interval) [months]	101.7	68.2	55.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0478
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0137
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0236
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4115
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2862
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.
Other Statistical Analysis		This HR is presented as (LI + SOC) / SOC. A HR < 1.0 favors LI+SOC. Wald p-value for this HR is 0.3859.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3859
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + SOC.

3. Secondary Outcome

Title	Local Regional Control (LRC)
Description	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.
Time Frame	From the date of treatment assignment to LRC or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	395	134	394
Median (95% Confidence Interval) [months]	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	The secondary endpoint LRC failure is analyzed similar to the primary OS endpoint. The primary comparison is LI+CIZ+SOC vs SOC; LI+SOC vs SOC results are also reported.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7304
	Comments	P-values are not adjusted for multiple comparisons.
	Method	Log Rank
	Comments	This Log Rank P-value is based on an unstratified analysis.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7171
	Comments	P-values are reported unadjusted for multiplicity.
	Method	Log Rank
	Comments	The Log Rank statistic is based on a stratified analysis.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8020
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4231
	Comments
	Method	Log Rank
	Comments	The Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6998
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3944
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + SOC.

4. Secondary Outcome

Title	LRC in Low Risk Subjects
Description	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.
Time Frame	From the date of treatment assignment to LRC or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Low Risk Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	158	54	168
Median (95% Confidence Interval) [months]	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6142
	Comments
	Method	Log Rank
	Comments	The Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3024
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.42082
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9784
	Comments
	Method	Log Rank
	Comments	The Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8461
	Comments	This Log Rank statistic is based on a stratified analysis.
	Method	Log Rank
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8131
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio of < 1.0 would favor LI + SOC.

5. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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.
Time Frame	From the date of treatment assignment to PFS or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	395	134	394
Median (95% Confidence Interval) [months]	32.4	37.0	45.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	This secondary endpoint PFS is analyzed similar to OS and LRC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3303
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is from an unstratified analysis.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6669
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3728
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5739
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8162
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4728
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + SOC.

6. Secondary Outcome

Title	PFS in Low Risk Subjects
Description	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.
Time Frame	From the date of treatment assignment to PFS or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Low Risk Intent to treat population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of CIZ.	SOC for previously untreated SCCHN patients is currently surgery followed by either radiotherapy or combined radiochemotherapy.
Measure Participants	158	54	168
Median (95% Confidence Interval) [months]	66.4	68.2	51.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1797
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0159
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0896
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio of < 1.0 would favor LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5175
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on an unstratified analysis.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4530
	Comments
	Method	Log Rank
	Comments	This Log Rank statistic is based on a stratified analysis.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4376
	Comments
	Method	Regression, Cox
	Comments	The Cox Proportional Hazards Model included terms for treatment, tumor stage, tumor location, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Hazard Ratio < 1.0 would favor LI + SOC.

7. Secondary Outcome

Title	Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 2
Description	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.
Time Frame	Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 2

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed is the total number of subjects in the longitudinal model. The number of participants analyzed is the number of subjects assessed at each visit. This study is not powered for quality of life comparisons.

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	117	37	119
Least Squares Mean (Standard Error) [units on a scale (0-100)]	0.28 (1.82)	7.95 (3.03)	3.29 (1.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	Approximately 30% of participants completed the QOL instrument at first administration (Month2), thus the study did not have the power for QoL comparisons. These completer analyses are descriptive only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2100
	Comments	This p-value for Long Term Follow-up at Month 2 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.00
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.395
	Estimation Comments	Positive value for the difference (Mean Difference (Net)) favors LI + CIZ + SOC.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments	Approximately 30% of participants completed the QOL instrument at last administration (Month 36), thus the study did not have power for QoL comparisons. These completer analyses are descriptive only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1701
	Comments	This p-value for Long Term Follow-up at Month 2 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.67
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.401
	Estimation Comments	Positive value for the difference (Mean Difference (Net)) favors LI + SOC.

8. Secondary Outcome

Title	Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36
Description	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.
Time Frame	Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 36

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed is the total number of subjects with data at this visit. The number of participants analyzed is the number of subjects assessed at each visit. This study is not powered for quality of life comparisons.

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	112	44	119
Least Squares Mean (Standard Error) [units on a scale (0-100)]	7.64 (1.82)	10.79 (2.85)	6.33 (1.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	LI + CIZ + SOC, Standard of Care (SOC)
	Type of Statistical Test	Superiority
	Comments	This p-value for Long Term Follow-up at Month 36 is not adjusted for multiplicity.
Statistical Test of Hypothesis	p-Value	0.5871
	Comments	This p-value for Long Term Follow-up at Month 36 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.397
	Estimation Comments	Positive value for the difference (Mean Difference (Net)) favors LI + CIZ + SOC.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1700
	Comments	This p-value for Long Term Follow-up at Month 36 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.46
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.247
	Estimation Comments	Positive value for the difference (Mean Difference (Net)) favors LI + SOC.

9. Secondary Outcome

Title	EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2
Description	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.
Time Frame	Baseline [pre-randomization], Long Term Follow-up Month 2

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed is the total number of subjects in data at that visit. The number of participants analyzed is the number of subjects assessed at each visit. This study is not powered for quality of life comparisons.

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI was administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	117	37	120
Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 2	-2.75 (1.66)	-2.80 (2.77)	-3.81 (1.67)
Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 2	8.11 (1.88)	6.29 (3.13)	7.31 (1.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6296
	Comments	This p-value for head and neck pain at Long Term Follow-up Month 2 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed effects of treatment, visit, treatment by visit, tumor location & stage, geographic region, and baseline with compound symmetry.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.183
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + CIZ + SOC.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7454
	Comments	This p-value for head and neck pain at Long Term Follow-up Month 2 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed effects of treatment, visit, treatment by visit, tumor location & stage, geographic region, and baseline with compound symmetry.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.103
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + SOC.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7452
	Comments	This p-value for Long Term Follow-up for swallowing at month 2 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed effects of treatment, visit, treatment by visit, tumor location & stage, geographic region, and baseline with compound symmetry.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.465
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7710
	Comments	This p-value for Long Term Follow-up for swallowing at Month 2 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed effects of treatment, visit, treatment by visit, and baseline with compound symmetry.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.496
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + SOC.

10. Secondary Outcome

Title	EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36
Description	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.
Time Frame	Baseline [pre-randomization], Long Term Follow-up Month 36

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed is the total number of subjects with data at this visit. The number of participants analyzed is the number of subjects assessed at each visit. This study is not powered for quality of life comparisons.

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI was administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	112	44	120
Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 36	-9.47 (1.66)	-8.63 (2.61)	-8.42 (1.64)
Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 36	6.90 (1.89)	1.66 (2.96)	8.94 (1.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6337
	Comments	This p-value for Long Term Follow-up for head and neck pain at Month 36 is not adjusted for multiplicity
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.185
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + CIZ + SOC.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9450
	Comments	This p-value for Long Term Follow-up for head and neck pain at Month 36 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.962
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + SOC.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4071
	Comments	This p-value for Long Term Follow-up for Swallowing at Month 36 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.04
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.465
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI+ CIZ + SOC.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0296
	Comments	This p-value for Long Term Follow-up for Swallowing at Month 36 is not adjusted for multiplicity.
	Method	Repeated Measures ANCOVA (RMANCOVA)
	Comments	RMANCOVA with fixed stratification factors, trt, visit, trt*visit, and baseline, with a compound symmetry correlation structure.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.29
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.347
	Estimation Comments	Negative value for the difference (Mean Difference (Net)) favors LI + SOC.

11. Secondary Outcome

Title	Statistical Comparisons of Time-to-event Outcomes (OS, LRC, PFS) Were Repeated for Varying Levels of Histopathology (HP) Markers in Low Risk Subjects
Description	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.
Time Frame	From the date of treatment assignment to event (LRC,PFS,OS) or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

The analysis population is the Low Risk Intent to treat Population who had HP marker levels assessed and were in either treatment arm LI + CIZ + SOC or SOC. This includes 82 subjects in LI + CIZ + SOC and 95 subjects in standard of care (SOC). No statistical comparisons were made for the 33 Low Risk subjects with HP markers in treatment arm LI + SOC. No data were collected for this Outcome Measure for treatment arm LI + SOC..

Arm/Group Title	LI + CIZ + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to 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.
Measure Participants	82	95
Measure Number of statistical tests	282	282
Number [N of Statistically Significant Results]	61	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, LI + SOC
	Comments	Treatment comparisons of LI+CIZ+SOC v. SOC were repeated at all levels of HP, HP ratios, and HP combinations for endpoints OS, PFS, and LRC. Significant outcomes for the treatment term in the model (two-sided p<0.05) were accumulated.
	Type of Statistical Test	Superiority
	Comments	Statistical tests were for a significant treatment effect in the Cox Proportional Hazards model including treatment, disease stage, tumor location, and geographical region.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Under the null hypothesis of no effect the expected number of significant test results would be balanced between treatments. The expected number (%) of statistically significant results would be approximately 14 (5%) of 282.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	% of significant test results
	Estimated Value	21.6
	Confidence Interval	(2-Sided) 95%; 17.0 to 26.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Post-Hoc Outcome

Title	Tumor Response by RECIST 1.0
Description	Tumor response is evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) and confirmed by pathology at surgery. For target lesions as assessed by MRI or CT: Complete Response (CR) is disappearance of all target and non-target lesions, no new tumors, and normalization of tumor marker level. Partial Response (PR), >=30% decrease in the sum of the longest diameter (LD) of target lesions taken as a reference the baseline sum of LDs, and no new tumors. Objective response = CR + PR. Response was assessed to LI treatment and compared to controls (SOC) from randomization to surgery in the ITT population for recurrence.
Time Frame	From treatment assignment to planned surgery, 29-38 days for LI treated groups and as soon as practicable with within 8 - 38 days for the SOC group (median 33 days).

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	395	134	394
Complete Response (CR)	5 1.3%	0 0%	0 0%
Partial Response (PR)	27 6.8%	13 3.3%	0 0%
Objective Response (CR+PR)	32 8.1%	13 3.3%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + CIZ + SOC and SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Percent (%) of Participants
	Estimated Value	8.1
	Confidence Interval	(2-Sided) 95%; 5.6 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments	Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + SOC and SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Percent (%) of Participants
	Estimated Value	9.7
	Confidence Interval	(2-Sided) 95%; 4.7 to 14.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Post-Hoc Outcome

Title	Tumor Response by RECIST 1.0 in Low Risk Subjects
Description	Tumor response was evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). For target lesions as assessed by MRI or CT: Complete Response (CR) is disappearance of all target and non-target lesions, no new tumors, and normalization of tumor marker level. Partial Response (PR), >=30% decrease in the sum of the longest diameter (LD) of target lesions taken as a reference the baseline sum of LDs, and no new tumors. Objective response = CR + PR. Response was assessed to LI treatment and compared to controls (SOC) from randomization to surgery in the lower risk ITT population for recurrence.
Time Frame	From treatment assignment to planned surgery, 29-38 days for LI treated groups and as soon as practicable with within 8 - 38 days for the SOC group (median 33 days).

Outcome Measure Data

Analysis Population Description

Low Risk Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	158	54	168
Complete Response (CR)	5 1.3%	0 0%	0 0%
Partial Response (PR)	19 4.8%	10 2.5%	0 0%
Objective Response (CR+PR)	24 6.1%	10 2.5%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, Standard of Care (SOC)
	Comments	Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + CIZ + SOC and SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Percent (%) of Participants
	Estimated Value	15.2
	Confidence Interval	(2-Sided) 95%; 9.6 to 20.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC, Standard of Care (SOC)
	Comments	Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + SOC and SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Percent (%) of Participants
	Estimated Value	18.5
	Confidence Interval	(2-Sided) 95%; 8.2 to 28.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Post-Hoc Outcome

Title	Survival by Objective Response (CR+PR)
Description	Survival is assessed as dead or alive at last follow-up. Tumor response is evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). For target lesions as assessed by MRI or CT: Complete Response (CR) is disappearance of all target and non-target lesions, no new tumors, and normalization of tumor marker level. Partial Response (PR), >=30% decrease in the sum of the longest diameter (LD) of target lesions taken as a reference the baseline sum of LDs, and no new tumors. Objective response = CR + PR.
Time Frame	Objective Response: from treatment assignment to surgery: 29-38 days for LI-treated & 8-38 days for SOC (median 33 days). Survival from treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	395	134	394
Non-responder and Alive	166 42%	56 14.2%	204 152.2%
Non-responder and Dead	197 49.9%	65 16.5%	190 141.8%
Responder and Alive	25 6.3%	10 2.5%	0 0%
Responder and Dead	7 1.8%	3 0.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC
	Comments	The null hypothesis that survival is unrelated to objective response versus the alternative hypothesis that objective response is predictive of increased survival for participants receiving LI + CIZ + SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC
	Comments	The null hypothesis is that survival is unrelated to objective response versus the alternative that response is predictive of increased survival in subjects receiving LI + SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0434
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, LI + SOC
	Comments	The null hypothesis is that survival is unrelated to objective response versus the alternative hypothesis that objective response is predictive of increased survival for participants receiving LI, considering both treatment groups combined.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

15. Post-Hoc Outcome

Title	Survival by Objective Response (CR+PR) in Low Risk Subjects
Description	OS is assessed as dead or alive at last follow-up. Tumor response is evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). For target lesions as assessed by MRI or CT: Complete Response (CR) is disappearance of all target and non-target lesions, no new tumors, and normalization of tumor marker level. Partial Response (PR), >=30% decrease in the sum of the longest diameter (LD) of target lesions taken as a reference the baseline sum of LDs, and no new tumors. Objective response = CR + PR.
Time Frame	Objective Response: from treatment assignment to surgery: 29-38 days for LI-treated & 8-38 days for SOC (median 33 days). Survival from treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Low Risk Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	158	54	168
Non-responder and Alive	79 20%	23 5.8%	84 62.7%
Non-responder and Dead	55 13.9%	21 5.3%	84 62.7%
Responder and Alive	21 5.3%	7 1.8%	0 0%
Responder and Dead	3 0.8%	3 0.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC
	Comments	The null hypothesis that survival is unrelated to objective response versus the alternative hypothesis that objective response is predictive of increased survival for low risk participants receiving LI + CIZ + SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0101
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + SOC
	Comments	The null hypothesis that survival is unrelated to objective response versus the alternative hypothesis that objective response is predictive of increased survival for low risk participants receiving LI + SOC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4843
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, LI + SOC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0067
	Comments	The null hypothesis is that survival is unrelated to objective response versus the alternative hypothesis that objective response is predictive of increased survival for participants receiving LI, considering both treatment groups combined.
	Method	Fisher Exact
	Comments

16. Post-Hoc Outcome

Title	Overall Survival by Objective Response (CR+PR) in Low Risk Subjects
Description	OS is assessed using Kaplan-Meier life-table using an unstratified log rank test and a stratified log rank test, stratified by tumor stage, tumor location, and geographic region. Alive at last follow-up was was censored. Tumor response is evaluated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). For target lesions as assessed by MRI or CT: Complete Response (CR) is disappearance of all target and non-target lesions, no new tumors, and normalization of tumor marker level. Partial Response (PR), >=30% decrease in the sum of the longest diameter (LD) of target lesions taken as a reference the baseline sum of LDs, and no new tumors. Objective response = CR + PR.
Time Frame	Objective Response: from treatment assignment to surgery: 29-38 days for LI-treated & 8-38 days for SOC (median 33 days). Survival from treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.

Outcome Measure Data

Analysis Population Description

Low risk Intent to Treat Population

Arm/Group Title	LI + CIZ + SOC	LI + SOC	Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC).	LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.	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.
Measure Participants	158	54	168
Non-responder and Alive	79 20%	23 5.8%	84 62.7%
Non-responder and Dead	55 13.9%	21 5.3%	84 62.7%
Responder and Alive	21 5.3%	7 1.8%	0 0%
Responder and Dead	3 0.8%	3 0.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC, LI + SOC
	Comments	Null hypothesis is that the Hazard Ratio (HR) for low risk subjects responding to LI (combined arms LI + CIZ + SOC, LI + SOC) is >=1.0 versus the alternative hypothesis that subjects responding to LI are at reduced risk of death (HR < 1.0).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0131
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.348
	Confidence Interval	(2-Sided) 95%; 0.152 to 0.801
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LI + CIZ + SOC
	Comments	Null hypothesis is that the Hazard Ratio (HR) for low risk subjects responding to LI + CIZ + SOC is >=1.0 versus the alternative hypothesis that subjects responding to LI + CIZ + SOC are at reduced risk of death (HR < 1.0).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0181
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.246
	Confidence Interval	(2-Sided) 95%; 0.077 to 0.787
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were reported from the signing of informed consent to the end of the study treatment follow-up. Participants were followed through 60 days after the last radio/chemoradiotherapy. Median last day of radiation-only was 122 days (IQR 106, 132 days). Median last day of chemotherapy for participants receiving both radiation and chemotherapy was 112 days (IQR 96, 129 days). Median AE follow-up was approximately six months post radiotherapy/chemoradiotherapy.
Adverse Event Reporting Description	All-cause mortality reports 462 deaths in the ITT population (at risk N=923). All-cause mortality includes the 5 deaths for the 44 subjects excluded from the safety population because they were not treated in this study. Adverse events were reported for the safety population (at risk N=879). Five (5) deaths are reported in all-cause mortality that are not reported in the adverse event module.
Arm/Group Title	LI + CIZ + SOC		LI + SOC		Standard of Care (SOC)
Arm/Group Description	LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as adjuvant therapy prior to standard of care (SOC).		LI is administered without CIZ to determine the contribution of CIZ to the effects of LI.		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.
All Cause Mortality
	LI + CIZ + SOC		LI + SOC		Standard of Care (SOC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	204/395 (51.6%)		68/134 (50.7%)		190/394 (48.2%)
Serious Adverse Events
	LI + CIZ + SOC		LI + SOC		Standard of Care (SOC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	216/383 (56.4%)		70/129 (54.3%)		187/367 (51%)
Blood and lymphatic system disorders
Anaemia	3/383 (0.8%)		0/129 (0%)		5/367 (1.4%)
Febrile neutropenia	2/383 (0.5%)		0/129 (0%)		1/367 (0.3%)
Lymphadenopathy	0/383 (0%)		1/129 (0.8%)		2/367 (0.5%)
Cardiac disorders
Cardiac arrest	2/383 (0.5%)		2/129 (1.6%)		3/367 (0.8%)
Acute myocardial infarction	1/383 (0.3%)		1/129 (0.8%)		2/367 (0.5%)
Cardio-respiratory arrest	3/383 (0.8%)		0/129 (0%)		1/367 (0.3%)
Myocardial infarction	1/383 (0.3%)		1/129 (0.8%)		1/367 (0.3%)
Atrial fibrillation	0/383 (0%)		2/129 (1.6%)		0/367 (0%)
Cardiopulmonary failure	0/383 (0%)		2/129 (1.6%)		0/367 (0%)
Acute coronary syndrome	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Cardiac failure	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Cardiovascular disorder	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Coronary artery disease	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Pericardial effusion	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Ventricular arrhythmia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Ventricular fibrillation	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Ventricular tachycardia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Ear and labyrinth disorders
Deafness unilateral	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Vertigo	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Eye disorders
Blindness unilateral	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Diplopia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Gastrointestinal disorders
Oral cavity fistula	6/383 (1.6%)		1/129 (0.8%)		3/367 (0.8%)
Stomatitis	2/383 (0.5%)		0/129 (0%)		4/367 (1.1%)
Duodenal ulcer perforation	2/383 (0.5%)		0/129 (0%)		0/367 (0%)
Gastric perforation	0/383 (0%)		1/129 (0.8%)		1/367 (0.3%)
Tongue movement disturbance	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Tongue necrosis	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Vomiting	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Abdominal pain upper	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Anal fistula	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Ascites	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Constipation	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Diarrhoea	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Dysphagia	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Enteritis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Gastric haemorrhage	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Gingival bleeding	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Glossitis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Haemorrhoids	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Hypoaesthesia oral	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Incarcerated inguinal hernia	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Intestinal haemorrhage	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Intestinal obstruction	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Mouth ulceration	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Odynophagia	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Oesophageal compression	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Oral mucosal hypertrophy	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Oroantral fistula	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Small intestinal haemorrhage	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Submaxillary gland enlargement	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Tongue disorder	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Tongue oedema	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Upper gastrointestinal haemorrhage	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
General disorders
Death	18/383 (4.7%)		4/129 (3.1%)		17/367 (4.6%)
General physical health deterioration	0/383 (0%)		0/129 (0%)		5/367 (1.4%)
Mucosal inflammation	1/383 (0.3%)		1/129 (0.8%)		2/367 (0.5%)
Sudden death	0/383 (0%)		1/129 (0.8%)		3/367 (0.8%)
Complication associated with device	0/383 (0%)		1/129 (0.8%)		1/367 (0.3%)
Accidental death	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Asthenia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Face oedema	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Fatigue	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Impaired healing	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Implant site ulcer	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Localised oedema	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Multiple organ dysfunction syndrome	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Organ failure	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Pyrexia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Sudden cardiac death	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Hepatobiliary disorders
Chronic hepatic failure	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Hepatic failure	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Infections and infestations
Pneumonia	9/383 (2.3%)		2/129 (1.6%)		11/367 (3%)
Cellulitis	5/383 (1.3%)		2/129 (1.6%)		2/367 (0.5%)
Sepsis	4/383 (1%)		1/129 (0.8%)		3/367 (0.8%)
Postoperative wound infection	2/383 (0.5%)		1/129 (0.8%)		4/367 (1.1%)
Abscess neck	2/383 (0.5%)		0/129 (0%)		1/367 (0.3%)
Wound infection	2/383 (0.5%)		0/129 (0%)		1/367 (0.3%)
Osteomyelitis	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Peritonitis	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Septic shock	2/383 (0.5%)		0/129 (0%)		0/367 (0%)
Subcutaneous abscess	2/383 (0.5%)		0/129 (0%)		0/367 (0%)
Abscess	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Cystitis	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Hepatitis B	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Lower respiratory tract infection	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Ludwig angina	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Lung abscess	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Lymph gland infection	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Oral infection	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Osteomyelitis acute	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Periorbital cellulitis	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Pseudomonas infection	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Pulmonary mycosis	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Pulmonary tuberculosis	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Rectal abscess	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Sepsis syndrome	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Sinusitis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Streptococcal sepsis	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Tooth infection	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Urinary tract infection	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Wound abscess	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Injury, poisoning and procedural complications
Post procedural haemorrhage	4/383 (1%)		2/129 (1.6%)		4/367 (1.1%)
Wound dehiscence	3/383 (0.8%)		1/129 (0.8%)		2/367 (0.5%)
Osteoradionecrosis	1/383 (0.3%)		2/129 (1.6%)		2/367 (0.5%)
Jaw fracture	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Post procedural complication	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Postoperative wound complication	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Radiation mucositis	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Alcohol poisoning	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Flap necrosis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Humerus fracture	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Postoperative adhesion	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Radiation skin injury	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Rib fracture	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Scar	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Seroma	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Skin flap necrosis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Skin graft contracture	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Skin laceration	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Investigations
Oxygen saturation decreased	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Weight decreased	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Metabolism and nutrition disorders
Dehydration	1/383 (0.3%)		1/129 (0.8%)		2/367 (0.5%)
Hypercalcaemia	1/383 (0.3%)		0/129 (0%)		2/367 (0.5%)
Hypernatraemia	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Hypoalbuminaemia	0/383 (0%)		1/129 (0.8%)		1/367 (0.3%)
Hypokalaemia	0/383 (0%)		0/129 (0%)		2/367 (0.5%)
Hyponatraemia	0/383 (0%)		1/129 (0.8%)		1/367 (0.3%)
Cachexia	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Hypertriglyceridaemia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Hyperuricaemia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Hypoglycaemia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Hypomagnesaemia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Hypophagia	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Malnutrition	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Musculoskeletal and connective tissue disorders
Trismus	1/383 (0.3%)		0/129 (0%)		2/367 (0.5%)
Arthritis	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Costochondritis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Muscle contracture	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Osteonecrosis of jaw	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	100/383 (26.1%)		32/129 (24.8%)		74/367 (20.2%)
Lip and/or oral cavity cancer recurrent	18/383 (4.7%)		6/129 (4.7%)		18/367 (4.9%)
Metastases to lymph nodes	6/383 (1.6%)		1/129 (0.8%)		9/367 (2.5%)
Metastases to lung	8/383 (2.1%)		2/129 (1.6%)		5/367 (1.4%)
Tumour haemorrhage	4/383 (1%)		0/129 (0%)		3/367 (0.8%)
Oral cavity cancer metastatic	2/383 (0.5%)		0/129 (0%)		4/367 (1.1%)
Lung neoplasm malignant	2/383 (0.5%)		1/129 (0.8%)		2/367 (0.5%)
Lung cancer metastatic	3/383 (0.8%)		0/129 (0%)		1/367 (0.3%)
Tongue cancer recurrent	1/383 (0.3%)		1/129 (0.8%)		2/367 (0.5%)
Lip and/or oral cavity cancer	2/383 (0.5%)		1/129 (0.8%)		0/367 (0%)
Metastases to central nervous system	1/383 (0.3%)		2/129 (1.6%)		0/367 (0%)
Oesophageal carcinoma	2/383 (0.5%)		0/129 (0%)		1/367 (0.3%)
Tongue neoplasm malignant stage unspecified	0/383 (0%)		2/129 (1.6%)		1/367 (0.3%)
Metastases to bone	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Metastases to liver	0/383 (0%)		1/129 (0.8%)		1/367 (0.3%)
Metastatic neoplasm	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Small cell lung cancer	0/383 (0%)		0/129 (0%)		2/367 (0.5%)
Squamous cell carcinoma of lung	1/383 (0.3%)		0/129 (0%)		1/367 (0.3%)
Squamous cell carcinoma of the oral cavity	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Tonsil cancer	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Adenoma benign	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Basal cell carcinoma	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Colon cancer	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Epiglottic cancer	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Hepatic cancer	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Laryngeal cancer	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Lip and/or oral cavity cancer stage IV	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Malignant melanoma	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Malignant pleural effusion	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Metastases to salivary gland	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Nasal cavity cancer	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Nasal sinus cancer	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Neoplasm progression	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Non-small cell lung cancer	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Oesophageal squamous cell carcinoma	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Prostate cancer	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Second primary malignancy	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Squamous cell carcinoma of skin	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Squamous cell carcinoma of the hypopharynx	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Tongue cancer metastatic	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Tracheal cancer	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Nervous system disorders
Cerebrovascular accident	1/383 (0.3%)		1/129 (0.8%)		0/367 (0%)
Cerebral infarction	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Cranial nerve palsies multiple	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Ischaemic stroke	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Seizure	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Syncope	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Psychiatric disorders
Completed suicide	3/383 (0.8%)		0/129 (0%)		0/367 (0%)
Delirium	0/383 (0%)		1/129 (0.8%)		1/367 (0.3%)
Renal and urinary disorders
Acute kidney injury	3/383 (0.8%)		0/129 (0%)		1/367 (0.3%)
Azotaemia	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Renal failure	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/383 (0.5%)		1/129 (0.8%)		2/367 (0.5%)
Pulmonary embolism	2/383 (0.5%)		0/129 (0%)		3/367 (0.8%)
Respiratory failure	2/383 (0.5%)		1/129 (0.8%)		1/367 (0.3%)
Pneumonia aspiration	2/383 (0.5%)		0/129 (0%)		1/367 (0.3%)
Upper airway obstruction	2/383 (0.5%)		1/129 (0.8%)		0/367 (0%)
Acute pulmonary oedema	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Acute respiratory failure	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Dysphonia	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Epistaxis	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Obstructive airways disorder	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Oropharyngeal swelling	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Pneumothorax	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Pulmonary oedema	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Vascular disorders
Arterial haemorrhage	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Deep vein thrombosis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Jugular vein thrombosis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Lymphoedema	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Lymphorrhoea	0/383 (0%)		1/129 (0.8%)		0/367 (0%)
Peripheral artery thrombosis	1/383 (0.3%)		0/129 (0%)		0/367 (0%)
Venous thrombosis	0/383 (0%)		0/129 (0%)		1/367 (0.3%)
Other (Not Including Serious) Adverse Events
	LI + CIZ + SOC		LI + SOC		Standard of Care (SOC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	354/383 (92.4%)		124/129 (96.1%)		352/367 (95.9%)
Blood and lymphatic system disorders
Anaemia	64/383 (16.7%)		26/129 (20.2%)		68/367 (18.5%)
Leukopenia	36/383 (9.4%)		12/129 (9.3%)		32/367 (8.7%)
Neutropenia	33/383 (8.6%)		8/129 (6.2%)		36/367 (9.8%)
Gastrointestinal disorders
Constipation	29/383 (7.6%)		9/129 (7%)		22/367 (6%)
Dry mouth	40/383 (10.4%)		11/129 (8.5%)		48/367 (13.1%)
Dysphagia	48/383 (12.5%)		17/129 (13.2%)		40/367 (10.9%)
Nausea	38/383 (9.9%)		16/129 (12.4%)		34/367 (9.3%)
Oral pain	31/383 (8.1%)		18/129 (14%)		32/367 (8.7%)
Stomatitis	50/383 (13.1%)		22/129 (17.1%)		63/367 (17.2%)
Vomiting	29/383 (7.6%)		14/129 (10.9%)		24/367 (6.5%)
General disorders
Asthenia	29/383 (7.6%)		16/129 (12.4%)		39/367 (10.6%)
Mucosal inflammation	121/383 (31.6%)		43/129 (33.3%)		117/367 (31.9%)
Pyrexia	43/383 (11.2%)		16/129 (12.4%)		36/367 (9.8%)
Injury, poisoning and procedural complications
Incision site pain	31/383 (8.1%)		13/129 (10.1%)		37/367 (10.1%)
Radiation injury	47/383 (12.3%)		13/129 (10.1%)		49/367 (13.4%)
Radiation mucositis	28/383 (7.3%)		15/129 (11.6%)		30/367 (8.2%)
Radiation skin injury	71/383 (18.5%)		31/129 (24%)		77/367 (21%)
Investigations
Blood creatinine increased	27/383 (7%)		8/129 (6.2%)		25/367 (6.8%)
Lymphocyte count decreased	23/383 (6%)		6/129 (4.7%)		26/367 (7.1%)
Weight decreased	169/383 (44.1%)		56/129 (43.4%)		168/367 (45.8%)
Metabolism and nutrition disorders
Decreased appetite	18/383 (4.7%)		7/129 (5.4%)		21/367 (5.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	48/383 (12.5%)		13/129 (10.1%)		11/367 (3%)
Psychiatric disorders
Insomnia	25/383 (6.5%)		5/129 (3.9%)		21/367 (5.7%)
Respiratory, thoracic and mediastinal disorders
Cough	25/383 (6.5%)		4/129 (3.1%)		17/367 (4.6%)
Skin and subcutaneous tissue disorders
Dermatitis	48/383 (12.5%)		12/129 (9.3%)		43/367 (11.7%)
Scar pain	28/383 (7.3%)		7/129 (5.4%)		20/367 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

See Clinical Protocol Section 13.0 Publication Plan