CS001P3

CEL-SCI Corporation

: 8229 Boone Boulevard, Suite 802, Vienna/Virginia, United States, 22182

John Cipriano, CEL-SCI Corporation, 001 703-506-9460, jcipriano@cel-sci.com

Eyal Talor, CEL-SCI Corporation, 001 410-358-6866, etalor@cel-sci.com

No

No

No

Final

19 Aug 2022

Yes

15 May 2020

Yes

04 Dec 2020

No

The primary endpoint of the study is OS. After Multikine injection (with or without CIZ (cyclophosphamide indometacin and zinc)) followed by standard of care (SOC) treatment, subjects will be monitored on a regular basis by clinical and radiographic criteria and will be followed for 30-36 months after completion of study drug + SOC until the required number of deaths are observed.

all treatments for minimizing pain and distress to subjects per medical standard of care

15 Dec 2010

No

Yes

Malaysia: 5

Philippines: 2

Taiwan: 40

Thailand: 2

India: 86

Israel: 6

Sri Lanka: 46

Bosnia and Herzegovina: 40

Serbia: 183

Turkey: 1

Belarus: 46

Russian Federation: 178

Ukraine: 158

Canada: 3

France: 1

Hungary: 21

Poland: 46

United States: 2

Croatia: 55

Romania: 2

923

125

0

0

0

0

0

0

720

202

1

Overall study (overall period)

Randomised - controlled

Yes

LI 400 IU

Multikine

Injection

Intralymphatic use, Peritumoral use, Subcutaneous use

Multikine is provided frozen in a vial containing 2.2 mL of drug at 200 IU (as IL-2) per mL for peritumoral, intra-tumoral, peri-lymphatic or subcutaneous administration. The drug is stored frozen in the pharmacy at –20o C until needed. The vial contents may be thawed at ambient temperature just before use, and the drug is allowed to reach ambient temperature before injection. If thawed at ambient temperature, the drug must be injected within 4 hours. Subjects randomized to one of the Multikine treatment groups, Multikine, 400 IU (2 mL) is injected each day of study drug administration, 1/2 dose (1 mL) peri-tumorally and 1/2 dose (1 mL) peri-lymphatically at the jugular lymphatic chain ipsilaterally to the injected tumor site inferior to the tip of the mastoid process in the area of the sternomastoid muscle sequentially and during the same visit.Both injections (peri-tumorally and peri-lymphatically) are administered 5 times per week for 3 weeks.

cyclophosphamide

Powder for solution for injection

Intravenous use

Cyclophosphamidie is 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 squamouscell carcinoma of the head and neck is currently surgery followed by radiotherapy (60-70Gy in30 to 35 fractions over 6 to 7 weeks) for higher risk subjects (subjects determined at surgery to have adverse features per the 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 (cisplatin100mg/m^2 intravenously 1x weekly for 3 weeks on day 1 of weeks 1, 4 and 7 of radiotherapy

indometacine

Capsule

Oral use

One 25mg capsule of indomethacin is administered orally beginning on day one of LI treatment daily until the day before surgery

Zinc

multivatimines

Capsule

Oral use

One capsule daily beginning on day one of treatment with LI until one day before surgery

cisplatin

Concentrate for solution for injection

Intravenous use

Cisplatin is administered 100mg/m^2 IV concurrent with radiotherapy. The chemotherapy agent(cisplatin 100mg/m^2) is administered intravenously 1x weekly for 3 weeks on day 1 of weeks1, 4 and 7 of radiotherapy

LI 400 IU

Multikine

Injection

Intralymphatic use, Peritumoral use, Subcutaneous use

Multikine is provided frozen in a vial containing 2.2 mL of drug at 200 IU (as IL-2) per mL for peritumoral, intra-tumoral, peri-lymphatic or subcutaneous administration. The drug is stored frozen in the pharmacy at –20o C until needed. The vial contents may be thawed at ambient temperature just before use, and the drug is allowed to reach ambient temperature before injection. If thawed at ambient temperature, the drug must be injected within 4 hours. Subjects randomized to one of the Multikine treatment groups, Multikine, 400 IU (2 mL) is injected each day of study drug administration, 1/2 dose (1 mL) peri-tumorally and 1/2 dose (1 mL) peri-lymphatically at the jugular lymphatic chain ipsilaterally to the injected tumor site inferior to the tip of the mastoid process in the area of the sternomastoid muscle sequentially and during the same visit.Both injections (peri-tumorally and peri-lymphatically) are administered 5 times per week for 3 weeks.

cisplatin

Concentrate for solution for injection

Intravenous use

Cisplatin is administered 100mg/m^2 IV concurrent with radiotherapy. The chemotherapy agent(cisplatin 100mg/m^2) is administered intravenously 1x weekly for 3 weeks on day 1 of weeks1, 4 and 7 of radiotherapy

cisplatin

Concentrate for solution for injection

Intravenous use

Cisplatin is administered 100mg/m^2 IV concurrent with radiotherapy. The chemotherapy agent(cisplatin 100mg/m^2) is administered intravenously 1x weekly for 3 weeks on day 1 of weeks1, 4 and 7 of radiotherapy

LI+CIZ+SOC

LI+SOC

Standard of care

LI+CIZ+SOC

LI+SOC

Standard of care

SOC low risk

Per the NCCN Guidelines lower risk subjects to receive radiotherapy randomized to SOC

LI+CIZ+SOC low risk

Per the NCCN Guidelines lower risk subjects to receive radiotherapy randomized to LI+CIZ+SOC

LI+SOC low risk

Per the NCCN Guidelines lower risk subjects to receive radiotherapy randomized to LI+SOC

OS is assessed using Kaplan-Meier life-table and compared using a log rank test and confirmed further with tumor stage location and geographic stratified log rank tests. 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 is considered statistically significant for comparing the two groups (i.e., Study comparator arms: LI+CIZ+SOC vs. SOC alone). Interim analyses is performed (by the iDMC) throughout the study to assess safety, sample size and futility

Primary

3-5 years

The primary objective is to compare overall survival in the Multikine (LI) + CIZ + SOC group to that in the SOC alone group for superiority of the former

LI+CIZ+SOC v Standard of care

789

Pre-specified

1.09

2-sided

The LI+SOC vs SOC comparison is not a part of the primary (OS) analysis

LI+SOC v Standard of care

528

Pre-specified

1.07

2-sided

The primary analysis is repeated for the 326 (41%) of subjects meeting the NCCN guideline for low risk.

SOC low risk v LI+CIZ+SOC low risk

326

Pre-specified

0.68

2-sided

LI+SOC low risk v SOC low risk

222

Pre-specified

0.82

2-sided

PFS will be assessed using Kaplan-Meier life-table and compared using a logrank test and confirmed further with stage location and geographic stratified log rank tests. Both stratified and unstratified logrank test results are presented with the unstratified log rank test representing the primary analysis. A two-sided p-value of 0.05 or less will be considered statistically significant in comparing the groups. The Holm closed-sequential procedure will be used to control type 1 error probability to at most 0.05.

Secondary

3-5 years

The secondary endpoint PFS is analyzed similar to OS and LRC.

LI+CIZ+SOC v Standard of care

789

Pre-specified

1.09

2-sided

The p-values for LI+SOC to SOC comparison for unstratified and stratified logrank are 0.5739 and 0.8162, respectively. Hazard ratio (95%CI) for this comparison is 1.10 (0.84, 1.43)

LI+SOC v Standard of care

528

Pre-specified

1.1

2-sided

The population for this PFS analysis is low risk subjects by NCCN guidelines.

SOC low risk v LI+CIZ+SOC low risk

326

Pre-specified

0.76

2-sided

The population for this PFS analysis is low risk subjects by NCCN guidelines

LI+SOC low risk v SOC low risk

222

Pre-specified

0.84

2-sided

LRC is assessed by classifying the first evidence of progression in local (defined as any reappearance or new disease above the clavicle) but not distal sites for the control groups and for the LI treated group. LRC failure includes progression of tumor(s) and nodes or appearance of new disease above the clavicle (but not distant metastases) the reappearance of tumor in the original tumor bed, development of cervical node metastases and new disease above the clavicle other than distant metastases not present at baseline. The total number and corresponding percent of subjects in each of the treated and untreated control groups as well as the time to LRC in days for each group will also be displayed for each group.

Secondary

2-3 years

The secondary endpoint LRC failure is analyzed similar to the primary OS endpoint. The primary comparison is LI+CIZ+SOC vs SOC.

LI+CIZ+SOC v Standard of care

789

Pre-specified

1.04

2-sided

The secondary endpoint LRC failure is analyzed similar to the primary OS endpoint. The comparison is LI+SOC vs SOC results are reported.

LI+SOC v Standard of care

528

Pre-specified

1.17

2-sided

Population is low-risk subjects by NCCN Guidelines. Median time-to-LRC failure has not yet been reach for any of the treatments.

SOC low risk v LI+CIZ+SOC low risk

326

Pre-specified

0.84

2-sided

Median time-to-LRC failure has not yet been reach for any of the treatments. Population is low-risk subjects by NCCN Guidelines.

SOC low risk v LI+SOC low risk

222

Pre-specified

0.93

2-sided

EORTC Quality of Life Questionnaire (QLQ) - Head & Neck Cancer Module: QLQ-H&N35. Pain item on the QLQ-H&N35 ranges from 0 to 100 with lower scores representing better (less) Head and Neck pain. If reporting a score on a scale, please include the unabbreviated scale title, the minimum and maximum values, and whether higher scores mean a better or worse outcome. Approximately 30% of participants completed this QoL instrument.

Secondary

3 years

P-values are not adjusted for multiplicity. This is a repeated measures ANCOVA with the fixed effects of treatment, visit, treatment by visit interaction, tumor location, tumor stage, geographic region, and baseline score. Results are reported for the first (Month 2) and last (Month 36) administration of this QoL instrument.For H&N pain a lower score is better. Planned analysis focus is on LI+CIZ+SOC.

LI+CIZ+SOC v Standard of care

237

Pre-specified

0.8

2-sided

Standard error of the mean

2.465

EORTC QOQ-C30 was completed by approximately 30% of participants. This is a completer analysis. If reporting a score on a scale, please include the unabbreviated scale title, the minimum and maximum values, and whether higher scores mean a better or worse outcome

Secondary

3 years

Approximately 30% of participants completed the QOL instrument at first (Month2) and last (Month 36) administration. This study was not powered for QoL comparisons. These completer analyses are descriptive only.

LI+CIZ+SOC v Standard of care

236

Pre-specified

-3

2-sided

Standard error of the mean

2.395

Difficulty swallowing item on the QLQ-H&N35 ranges from 0 to 100 with lower scores representing better (less) difficulty swallowing. If reporting a score on a scale, please include the unabbreviated scale title, the minimum and maximum values, and whether higher scores mean a better or worse outcome.

Secondary

3 years

Approximately 30% of the participants completed this QoL instrument. This is a completer analysis.

LI+CIZ+SOC v Standard of care

237

Pre-specified

0.8

2-sided

Standard error of the mean

2.465

OS, PFS, and LRC were examined using a proportional hazards model to assess the interactions between HP levels, risk group (low, high), and treatment (LI+CIZ+SOC, SOC Alone). Twenty (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 possible treatment comparisons for OS, PFS and LRC. Significance (two-sided p<0.05 always favoring Group 1 vs Group 3) was observed for OS (14/60, 2/6, and 9/28), PFS (11/60, 1/6, and 5/28), and LRC (9/60, 1/6, and 6/28) in support of robust efficacy outcomes, only seen in the low risk population. Combined, significance was reached for 20.9% (59/282) possible comparisons; the one-sided 97.5% confidence bound on the fraction significant was 16.3% which exceeds 5% chance alone.

Secondary

Duration of the study

LI plus CIZ (cyclophosphamide, indomethacin and zinc) is given as adjuvant therapy prior to standard of care (SOC).

Standard of care v LI+CIZ+SOC

789

Pre-specified

20.1

2-sided

Pre-surgery tumor response was assessed by RECIST 1.0 criteria, see Protocol Appendix 10.

Post-hoc

Initation of treatment through surgery

Pre-surgery tumor response was assessed by RECIST 1.0 criteria, see Protocol Appendix 10.

LI+CIZ+SOC v LI+SOC v Standard of care

923

Post-hoc

8.1

2-sided

Intent-to-treat population who are low risk by NCCN guideline

SOC low risk v LI+CIZ+SOC low risk v LI+SOC low risk

380

Post-hoc

16

2-sided

Survival was assessed for subjects responding (RECIST 1.0) to Multikine treatment

Post-hoc

Duration of the study

The null hypothesis that survival is unrelated to MK response versus the alternative hypothesis that MK response is predictive of survival.

LI+CIZ+SOC v LI+SOC v Standard of care

923

Post-hoc

The null hypothesis that survival is unrelated to MK response versus the alternative hypothesis that MK response is predictive of survival for low risk participants

LI+CIZ+SOC v LI+SOC v Standard of care

923

Post-hoc

From the signing of the ICF to the end of the study treatment follow up in each group and through the end of the study. For this study, there was an end of study follow-up for AEs 30 and 60 days following the last study treatment component.

All AEs occurring during the study period were recorded. The clinical course of each event was followed until resolution, stabilization, or until it was determined that the study treatment or participation was not the cause. All unresolved SAEs were followed by the investigator until the events were resolved, the subject was lost to follow-up.

23

Li+CIZ+SOC

Standard of Care (SOC)

LI + SOC