Squamous Cell Carcinoma of the Oral Cavity, Squamous Cell Carcinoma of the Soft Palate
Conditions
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
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.
Interventions
DIETARY_SUPPLEMENTZinc
One capsule daily self administered beginning on day one of treatment with LI until one day before surgery
PROCEDURESurgery
Excise tumor and nodes
DRUGCisplatin
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.
BIOLOGICALLI
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.
DRUGCyclophosphamide
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.
DRUGIndomethacin
One 25mg capsule of indomethacin was self administered orally (BID) beginning on day one of LI treatment daily until the day before surgery.
RADIATIONRadiotherapy
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.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Orient Europharma Co., Ltd.
CEL-SCI Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Austria, Belarus, Bosnia and Herzegovina, Canada, Croatia, France, Hungary, India, Israel, Italy, Malaysia, Poland, Romania, Russia, Serbia, Spain, Sri Lanka, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LI + CIZ + SOC LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as neoadjuvant therapy prior to standard of care (SOC). | 395 |
| 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. | 394 |
| LI + SOC LI is administered without CIZ to determine the contribution of CIZ to the effects of LI. | 134 |
| Total | 923 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 18 | 15 | 5 |
| Overall Study | Not otherwise specified | 1 | 6 | 1 |
| Overall Study | Physician Decision | 1 | 2 | 0 |
| Overall Study | Randomized//Treatment not initiated | 1 | 4 | 0 |
| Overall Study | Withdrawal by Subject | 25 | 34 | 13 |
Baseline characteristics
| Characteristic | LI + CIZ + SOC | Standard of Care (SOC) | LI + SOC | Total |
|---|---|---|---|---|
| Age, Continuous | 56.5 years | 56.9 years | 55.9 years | 56.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 190 Participants | 186 Participants | 57 Participants | 433 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 205 Participants | 208 Participants | 77 Participants | 490 Participants |
| Number of Nodes Involved Missing | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Number of Nodes Involved N0 | 190 Participants | 180 Participants | 62 Participants | 432 Participants |
| Number of Nodes Involved N1 | 108 Participants | 118 Participants | 37 Participants | 263 Participants |
| Number of Nodes Involved N2 | 96 Participants | 96 Participants | 35 Participants | 227 Participants |
| Primary Tumor Location Cheek (Buccal Mucosa) | 53 Participants | 55 Participants | 18 Participants | 126 Participants |
| Primary Tumor Location Floor of Mouth | 111 Participants | 116 Participants | 37 Participants | 264 Participants |
| Primary Tumor Location Oral Tongue | 182 Participants | 178 Participants | 63 Participants | 423 Participants |
| Primary Tumor Location Soft Palate | 49 Participants | 45 Participants | 16 Participants | 110 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 79 Participants | 76 Participants | 25 Participants | 180 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 311 Participants | 317 Participants | 108 Participants | 736 Participants |
| Region of Enrollment Belarus | 20 participants | 19 participants | 7 participants | 46 participants |
| Region of Enrollment Bosnia and Herzegovina | 16 participants | 18 participants | 6 participants | 40 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Croatia | 23 participants | 24 participants | 8 participants | 55 participants |
| Region of Enrollment France | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Hungary | 9 participants | 9 participants | 3 participants | 21 participants |
| Region of Enrollment India | 37 participants | 38 participants | 11 participants | 86 participants |
| Region of Enrollment Israel | 2 participants | 3 participants | 1 participants | 6 participants |
| Region of Enrollment Malaysia | 2 participants | 2 participants | 1 participants | 5 participants |
| Region of Enrollment Philippines | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 20 participants | 20 participants | 6 participants | 46 participants |
| Region of Enrollment Romania | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Russia | 76 participants | 76 participants | 26 participants | 178 participants |
| Region of Enrollment Serbia | 78 participants | 79 participants | 26 participants | 183 participants |
| Region of Enrollment Sri Lanka | 20 participants | 19 participants | 7 participants | 46 participants |
| Region of Enrollment Taiwan | 17 participants | 16 participants | 7 participants | 40 participants |
| Region of Enrollment Thailand | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Turkey | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Ukraine | 68 participants | 67 participants | 23 participants | 158 participants |
| Region of Enrollment United States | 1 participants | 0 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 83 Participants | 79 Participants | 29 Participants | 191 Participants |
| Sex: Female, Male Male | 312 Participants | 315 Participants | 105 Participants | 732 Participants |
| TNM Stage TNM Stage III | 218 Participants | 228 Participants | 75 Participants | 521 Participants |
| TNM Stage TNM Stage IV | 177 Participants | 166 Participants | 59 Participants | 402 Participants |
| Tumor Code T1: Tumor < 2 cm in greatest dimension | 21 Participants | 12 Participants | 4 Participants | 37 Participants |
| Tumor Code T2: Tumor > 2 and < 4 cm in greatest dimension or extension to lingual surface of epiglottis | 94 Participants | 95 Participants | 28 Participants | 217 Participants |
| Tumor Code T3: Tumor more than 4 cm in greatest dimension | 163 Participants | 191 Participants | 68 Participants | 422 Participants |
| Tumor Code T4a: Moderately advanced local disease | 117 Participants | 96 Participants | 34 Participants | 247 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 204 / 395 | 68 / 134 | 190 / 394 |
| other Total, other adverse events | 354 / 383 | 124 / 129 | 352 / 367 |
| serious Total, serious adverse events | 216 / 383 | 70 / 129 | 187 / 367 |
Outcome results
Primary
OS in Low Risk Subjects
OS was assessed using Kaplan-Meier life-table using a log rank test and confirmed further with tumor stage, tumor location, and geographic stratified log rank test. Both Stratified and unstratified log rank test are presented with the unstratified log rank test constituting the primary analysis. A two-sided p-value of 0.05 or less was considered statistically significant for comparing the two groups (i.e., Study comparator arms: LI+CIZ+SOC vs. SOC alone). Low-risk assessment and data analysis was never performed during the study and was done only after database lock.
Time frame: From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.
Population: Low Risk Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LI + CIZ + SOC | OS in Low Risk Subjects | 101.7 months |
| LI + SOC | OS in Low Risk Subjects | 68.2 months |
| Standard of Care (SOC) | OS in Low Risk Subjects | 55.2 months |
p-value: 0.0478Log Rank
p-value: 0.0137Log Rank
p-value: 0.023695% CI: [0.48, 0.95]Regression, Cox
p-value: 0.4115Log Rank
p-value: 0.2862Log Rank
p-value: 0.385995% CI: [0.52, 1.29]Regression, Cox
Primary
Overall Survival (OS)
OS was assessed using Kaplan-Meier life-table using a log rank test and confirmed further with tumor stage, tumor location, and geographic stratified log rank test. Both Stratified and unstratified log rank test are presented with the unstratified log rank test constituting the primary analysis. A two-sided p-value of 0.05 or less was considered statistically significant for comparing the two groups (i.e., Study comparator arms: LI+CIZ+SOC vs. SOC alone). Interim analyses were performed (by the iDMC) periodically throughout the study to assess safety, sample size and futility.
Time frame: From the date of treatment assignment to death or the last follow-up date. Maximum follow-up was approximately 113 months.
Population: Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LI + CIZ + SOC | Overall Survival (OS) | 46.3 months |
| LI + SOC | Overall Survival (OS) | 58.1 months |
| Standard of Care (SOC) | Overall Survival (OS) | 52.9 months |
Comparison: 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.p-value: 0.4051Log Rank
p-value: 0.5402Log Rank
p-value: 0.412895% CI: [0.89, 1.32]Regression, Cox
p-value: 0.7181Log Rank
p-value: 0.948Log Rank
p-value: 0.610195% CI: [0.81, 1.42]Regression, Cox
Secondary
EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2
The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 supplementary Head & neck cancer module (EORTC QLQ-C30 - QLQ H&N35) items 1-4 make up the symptom score for pain, items 5-8 for swallowing. The 4 pain questions score: pain in your mouth, pain in your jaw, soreness in your mouth, a painful throat? The 4 swallowing questions score problems swallowing: liquids, pureed food, solid food, choking? Item are scored as 1 (Not at all) to 4 (Very much). Each symptom scale is constructed by averaging the 4 items to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation symptom score (pain or swallowing)=100\*\[(RS-1)/3\]. A high score for these symptom scales represents a high level of symptoms.Change in symptom is calculated as Observed - Baseline, so a negative change is reduced symptomatology . Treatment comparisons are active treatment arms minus SOC, so a negative difference favors active treatment.
Time frame: Baseline [pre-randomization], Long Term Follow-up Month 2
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LI + CIZ + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 | Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 2 | -2.75 units on a scale (0-100) | Standard Error 1.66 |
| LI + CIZ + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 | Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 2 | 8.11 units on a scale (0-100) | Standard Error 1.88 |
| LI + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 | Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 2 | -2.80 units on a scale (0-100) | Standard Error 2.77 |
| LI + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 | Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 2 | 6.29 units on a scale (0-100) | Standard Error 3.13 |
| Standard of Care (SOC) | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 | Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 2 | -3.81 units on a scale (0-100) | Standard Error 1.67 |
| Standard of Care (SOC) | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 2 | Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 2 | 7.31 units on a scale (0-100) | Standard Error 1.89 |
p-value: 0.6296Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.7454Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.7452Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.771Repeated Measures ANCOVA (RMANCOVA)
Secondary
EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36
The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 supplementary Head & neck cancer module (EORTC QLQ-C30 - QLQ H&N35) items 1-4 make up the symptom score for pain, items 5-8 for swallowing. The 4 pain questions score: pain in your mouth, pain in your jaw, soreness in your mouth, a painful throat? The 4 swallowing questions score problems swallowing: liquids, pureed food, solid food, choking? Item are scored as 1 (Not at all) to 4 (Very much). Each symptom scale is constructed by averaging the 4 items to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation symptom score (pain or swallowing)=100\*\[(RS-1)/3\]. A high score for these symptom scales represents a high level of symptoms.Change in symptom is calculated as Observed - Baseline, so a negative change is reduced symptomatology . Treatment comparisons are active treatment arms minus SOC, so a negative difference favors active treatment.
Time frame: Baseline [pre-randomization], Long Term Follow-up Month 36
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LI + CIZ + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 | Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 36 | -9.47 units on a scale (0-100) | Standard Error 1.66 |
| LI + CIZ + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 | Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 36 | 6.90 units on a scale (0-100) | Standard Error 1.89 |
| LI + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 | Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 36 | -8.63 units on a scale (0-100) | Standard Error 2.61 |
| LI + SOC | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 | Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 36 | 1.66 units on a scale (0-100) | Standard Error 2.96 |
| Standard of Care (SOC) | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 | Change from Baseline in Head & Neck PAIN at Long Term Follow-up Month 36 | -8.42 units on a scale (0-100) | Standard Error 1.64 |
| Standard of Care (SOC) | EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35 at Month 36 | Change from Baseline in Head & Neck SWALLOWING at Long Term Follow-up Month 36 | 8.94 units on a scale (0-100) | Standard Error 1.86 |
p-value: 0.6337Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.945Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.4071Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.0296Repeated Measures ANCOVA (RMANCOVA)
Secondary
Local Regional Control (LRC)
LRC is defined as the number of months from randomization to the date of documented local or regional failure (recurrence or progression) or date of last follow-up or death. LRC failure includes the reappearance (recurrence) of disease (at the original tumor sites), progressive disease (but not distant metastases), or any new disease (including new disease in lymph nodes), above the clavicle, not present at baseline. This is the traditional RTOG measure of local-regional control, also referred to as Freedom from Local Progression.
Time frame: From the date of treatment assignment to LRC or the last follow-up date. Maximum follow-up was approximately 113 months.
Population: Intent to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LI + CIZ + SOC | Local Regional Control (LRC) | NA months |
| LI + SOC | Local Regional Control (LRC) | NA months |
| Standard of Care (SOC) | Local Regional Control (LRC) | NA months |
Comparison: 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.p-value: 0.7304Log Rank
p-value: 0.7171Log Rank
p-value: 0.80295% CI: [0.79, 1.36]Regression, Cox
p-value: 0.4231Log Rank
p-value: 0.6998Log Rank
p-value: 0.394495% CI: [0.81, 1.69]Regression, Cox
Secondary
LRC in Low Risk Subjects
LRC is defined as the number of months from randomization to the date of documented local or regional failure (recurrence or progression) or date of last follow-up or death. LRC failure includes the reappearance (recurrence) of disease (at the original tumor sites), progressive disease (but not distant metastases), or any new disease (including new disease in lymph nodes), above the clavicle, not present at baseline. This is the traditional RTOG measure of local-regional control, also referred to as Freedom from Local Progression. Low risk assessment and data analysis was never performed during the study and was done only after database lock.
Time frame: From the date of treatment assignment to LRC or the last follow-up date. Maximum follow-up was approximately 113 months.
Population: Low Risk Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LI + CIZ + SOC | LRC in Low Risk Subjects | NA months |
| LI + SOC | LRC in Low Risk Subjects | NA months |
| Standard of Care (SOC) | LRC in Low Risk Subjects | NA months |
p-value: 0.6142Log Rank
p-value: 0.3024Log Rank
p-value: 0.4208295% CI: [0.55, 1.28]Regression, Cox
p-value: 0.9784Log Rank
p-value: 0.8461Log Rank
p-value: 0.813195% CI: [0.53, 1.65]Regression, Cox
Secondary
PFS in Low Risk Subjects
PFS is defined as the number of months from randomization to the date of first documented, progressive disease (any tumor recurrence, any new disease above clavicle or distant metastases) or the date of last follow-up or death. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest dimension (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions. Low risk assessment and data analysis was not performed during the study and was performed only after database lock.
Time frame: From the date of treatment assignment to PFS or the last follow-up date. Maximum follow-up was approximately 113 months.
Population: Low Risk Intent to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LI + CIZ + SOC | PFS in Low Risk Subjects | 66.4 months |
| LI + SOC | PFS in Low Risk Subjects | 68.2 months |
| Standard of Care (SOC) | PFS in Low Risk Subjects | 51.5 months |
p-value: 0.1797Log Rank
p-value: 0.0159Log Rank
p-value: 0.089695% CI: [0.55, 1.04]Regression, Cox
p-value: 0.5175Log Rank
p-value: 0.453Log Rank
p-value: 0.437695% CI: [0.54, 1.3]Regression, Cox
Secondary
Progression Free Survival (PFS)
PFS is defined as the number of months from randomization to the date of first documented, progressive disease (any tumor recurrence, any new disease above clavicle or distant metastases) or the date of last follow-up or death. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest dimension (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions.
Time frame: From the date of treatment assignment to PFS or the last follow-up date. Maximum follow-up was approximately 113 months.
Population: Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LI + CIZ + SOC | Progression Free Survival (PFS) | 32.4 months |
| LI + SOC | Progression Free Survival (PFS) | 37.0 months |
| Standard of Care (SOC) | Progression Free Survival (PFS) | 45.5 months |
Comparison: This secondary endpoint PFS is analyzed similar to OS and LRC.p-value: 0.3303Log Rank
p-value: 0.6669Log Rank
p-value: 0.372895% CI: [0.9, 1.31]Regression, Cox
p-value: 0.5739Log Rank
p-value: 0.8162Log Rank
p-value: 0.472895% CI: [0.84, 1.43]Regression, Cox
Secondary
Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 2
The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 (EORTC QLQ-C30) V3.0 is composed of both multi-item scales and single-item measures. The Global Health Scale/QoL multi-item scale \[GHS\] is a comprised of two Items: Item 29 How would you rate your overall health during the past week?, and item 30: How would you rate your overall quality of life during the past week?. Both items are 7 point scales ranging from a score of 1 (very poor) to 7 (Excellent). The GHS is constructed by averaging Items 29 and 30 to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation GHS=100\*\[(RS-1)/6\]. A higher score represents a higher (better) QoL. Change in GHS is calculated as Observed - Baseline, so a positive change in GHS is improved QoL. Treatment comparisons are active treatment arms minus SOC, so a positive difference favors active treatment.
Time frame: Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 2
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LI + CIZ + SOC | Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 2 | 0.28 units on a scale (0-100) | Standard Error 1.82 |
| LI + SOC | Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 2 | 7.95 units on a scale (0-100) | Standard Error 3.03 |
| Standard of Care (SOC) | Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 2 | 3.29 units on a scale (0-100) | Standard Error 1.83 |
Comparison: 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.p-value: 0.21Repeated Measures ANCOVA (RMANCOVA)
Comparison: 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.p-value: 0.1701Repeated Measures ANCOVA (RMANCOVA)
Secondary
Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36
The European Organisation for Research and Treatment of Cancer Quality of Life Questionaire C-30 Version 3.0 (EORTC QLQ-C30) V3.0 is composed of both multi-item scales and single-item measures. The Global Health Scale/QoL multi-item scale \[GHS\] is a comprised of two Items: Item 29 How would you rate your overall health during the past week?, and item 30: How would you rate your overall quality of life during the past week?. Both items are 7 point scales ranging from a score of 1 (very poor) to 7 (Excellent). The GHS is constructed by averaging Items 29 and 30 to obtain a raw score (RS). The RS is then transformed to a 0-100 scale by the equation GHS=100\*\[(RS-1)/6\]. A higher score represents a higher (better) QoL. Change in GHS is calculated as Observed - Baseline, so a positive change in GHS is improved QoL. Treatment comparisons are active treatment arms minus SOC, so a positive difference favors active treatment.
Time frame: Global Health Status (GHS) at Baseline [pre-randomization], Long Term Follow-up Month 36
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LI + CIZ + SOC | Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36 | 7.64 units on a scale (0-100) | Standard Error 1.82 |
| LI + SOC | Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36 | 10.79 units on a scale (0-100) | Standard Error 2.85 |
| Standard of Care (SOC) | Quality of Life by EORTC QLQ-C30 Global Health Status [GHS] at Month 36 | 6.33 units on a scale (0-100) | Standard Error 1.8 |
Comparison: LI + CIZ + SOC, Standard of Care (SOC)p-value: 0.5871Repeated Measures ANCOVA (RMANCOVA)
p-value: 0.17Repeated Measures ANCOVA (RMANCOVA)
Secondary
Statistical Comparisons of Time-to-event Outcomes (OS, LRC, PFS) Were Repeated for Varying Levels of Histopathology (HP) Markers in Low Risk Subjects
HP analysis was performed in a blinded manner by a central pathology laboratory at the end of the study on available samples. To examine potential effects of HP markers on time-to-event efficacy outcomes (OS, LRC, PFS), participants were classified by HP marker levels: 20 HP markers were classified as (low, medium, high), 2 HP ratios as (low, medium, high) and 14 HP combinations as (low, high), resulting in 94 (20\*3+2\*3+2\*14) possible treatment comparisons of LI + CIZ + SOC to SOC. A total of 282 (94 x 3 efficacy outcomes) statistical tests (Cox proportional hazards regressions to test for a significant treatment effect in the model) were made. Significance (two-sided p\<0.05 favoring LI + CIZ + SOC) were reported under LI + CIZ + SOC. Significant test results favoring SOC were reported under SOC. The total number of statistical comparisons between LI + CIZ + SOC and SOC (282) is reported under both arms.
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.
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| LI + CIZ + SOC | Statistical Comparisons of Time-to-event Outcomes (OS, LRC, PFS) Were Repeated for Varying Levels of Histopathology (HP) Markers in Low Risk Subjects | 61 N of Statistically Significant Results |
| LI + SOC | Statistical Comparisons of Time-to-event Outcomes (OS, LRC, PFS) Were Repeated for Varying Levels of Histopathology (HP) Markers in Low Risk Subjects | 0 N of Statistically Significant Results |
Comparison: 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.p-value: <0.0595% CI: [17, 26.9]Regression, Cox
Post Hoc
Overall Survival by Objective Response (CR+PR) in Low Risk Subjects
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.
Population: Low risk Intent to Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LI + CIZ + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Alive | 79 participants |
| LI + CIZ + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Dead | 55 participants |
| LI + CIZ + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Alive | 21 participants |
| LI + CIZ + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Dead | 3 participants |
| LI + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Dead | 3 participants |
| LI + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Alive | 23 participants |
| LI + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Alive | 7 participants |
| LI + SOC | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Dead | 21 participants |
| Standard of Care (SOC) | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Dead | 0 participants |
| Standard of Care (SOC) | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Dead | 84 participants |
| Standard of Care (SOC) | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Alive | 0 participants |
| Standard of Care (SOC) | Overall Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Alive | 84 participants |
Comparison: 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).p-value: 0.013195% CI: [0.152, 0.801]Regression, Cox
Comparison: 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).p-value: 0.018195% CI: [0.077, 0.787]Regression, Cox
Post Hoc
Survival by Objective Response (CR+PR)
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.
Population: Intent to Treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) | Non-responder and Alive | 166 Participants |
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) | Non-responder and Dead | 197 Participants |
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) | Responder and Alive | 25 Participants |
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) | Responder and Dead | 7 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) | Responder and Dead | 3 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) | Non-responder and Alive | 56 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) | Responder and Alive | 10 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) | Non-responder and Dead | 65 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) | Responder and Dead | 0 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) | Non-responder and Dead | 190 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) | Responder and Alive | 0 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) | Non-responder and Alive | 204 Participants |
Comparison: 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.p-value: 0.0007Fisher Exact
Comparison: 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.p-value: 0.0434Fisher Exact
Comparison: 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.p-value: <0.0001Fisher Exact
Post Hoc
Survival by Objective Response (CR+PR) in Low Risk Subjects
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.
Population: Low Risk Intent to Treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Alive | 21 Participants |
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Alive | 79 Participants |
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Dead | 3 Participants |
| LI + CIZ + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Dead | 55 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Alive | 7 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Dead | 21 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Dead | 3 Participants |
| LI + SOC | Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Alive | 23 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Dead | 0 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Alive | 84 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) in Low Risk Subjects | Non-responder and Dead | 84 Participants |
| Standard of Care (SOC) | Survival by Objective Response (CR+PR) in Low Risk Subjects | Responder and Alive | 0 Participants |
Comparison: 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.p-value: 0.0101Fisher Exact
Comparison: 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.p-value: 0.4843Fisher Exact
p-value: <0.0067Fisher Exact
Post Hoc
Tumor Response by RECIST 1.0
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).
Population: Intent to Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LI + CIZ + SOC | Tumor Response by RECIST 1.0 | Partial Response (PR) | 27 participants |
| LI + CIZ + SOC | Tumor Response by RECIST 1.0 | Complete Response (CR) | 5 participants |
| LI + CIZ + SOC | Tumor Response by RECIST 1.0 | Objective Response (CR+PR) | 32 participants |
| LI + SOC | Tumor Response by RECIST 1.0 | Partial Response (PR) | 13 participants |
| LI + SOC | Tumor Response by RECIST 1.0 | Complete Response (CR) | 0 participants |
| LI + SOC | Tumor Response by RECIST 1.0 | Objective Response (CR+PR) | 13 participants |
| Standard of Care (SOC) | Tumor Response by RECIST 1.0 | Complete Response (CR) | 0 participants |
| Standard of Care (SOC) | Tumor Response by RECIST 1.0 | Objective Response (CR+PR) | 0 participants |
| Standard of Care (SOC) | Tumor Response by RECIST 1.0 | Partial Response (PR) | 0 participants |
Comparison: Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + CIZ + SOC and SOC.p-value: <0.000195% CI: [5.6, 11.2]Fisher Exact
Comparison: Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + SOC and SOC.p-value: <0.000195% CI: [4.7, 14.7]Fisher Exact
Post Hoc
Tumor Response by RECIST 1.0 in Low Risk Subjects
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).
Population: Low Risk Intent to Treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LI + CIZ + SOC | Tumor Response by RECIST 1.0 in Low Risk Subjects | Partial Response (PR) | 19 Participants |
| LI + CIZ + SOC | Tumor Response by RECIST 1.0 in Low Risk Subjects | Complete Response (CR) | 5 Participants |
| LI + CIZ + SOC | Tumor Response by RECIST 1.0 in Low Risk Subjects | Objective Response (CR+PR) | 24 Participants |
| LI + SOC | Tumor Response by RECIST 1.0 in Low Risk Subjects | Partial Response (PR) | 10 Participants |
| LI + SOC | Tumor Response by RECIST 1.0 in Low Risk Subjects | Complete Response (CR) | 0 Participants |
| LI + SOC | Tumor Response by RECIST 1.0 in Low Risk Subjects | Objective Response (CR+PR) | 10 Participants |
| Standard of Care (SOC) | Tumor Response by RECIST 1.0 in Low Risk Subjects | Complete Response (CR) | 0 Participants |
| Standard of Care (SOC) | Tumor Response by RECIST 1.0 in Low Risk Subjects | Objective Response (CR+PR) | 0 Participants |
| Standard of Care (SOC) | Tumor Response by RECIST 1.0 in Low Risk Subjects | Partial Response (PR) | 0 Participants |
Comparison: Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + CIZ + SOC and SOC.p-value: <0.000195% CI: [9.6, 20.8]Fisher Exact
Comparison: Null hypothesis is that percent (%) of participants with an objective response (CR+PR) is the same for LI + SOC and SOC.p-value: <0.000195% CI: [8.2, 28.9]Fisher Exact