Clinical Trial Status of Investigational Therapy Multikine® (Leukocyte Interleukin, Injection)

Multikine (Leukocyte Interleukin, Injection) is the full name of this investigational therapy, which, for simplicity, is referred to in the remainder of this page as Multikine*.

The first indication being pursued for Multikine:

The first indication we are pursuing for our Multikine investigational product candidate is an indication for the neoadjuvant therapy in patients with squamous cell carcinoma of the head and neck, or SCCHN. The Phase III clinical trial of the Multikine investigational neoadjuvant therapy in SCCHN. SCCHN is a type of head and neck cancer that, in the aggregate, represents a large, unmet medical need among head and neck cancer patients. To the best of our knowledge, the last FDA approval of a therapy indicated for the treatment of advanced primary head and neck cancer was decades ago. In the aggregate, head and neck cancer represents about 6% of the world’s cancer cases, with approximately 890,000 patients diagnosed worldwide each year, and nearly 60,000 patients diagnosed annually in the United States. Multikine investigational immunotherapy was granted Orphan Drug designation for neoadjuvant therapy in patients with SCCHN by the FDA in the United States.

The recurrence rate following currently available conventional treatment is high for patients diagnosed with SCCHN and about one out of every two patients will die within three to five years. The current standard of care, or SOC, treatment regimen for advanced primary head and neck cancer patients consists of surgical resection of the tumor and involved lymph nodes, followed by either radiotherapy alone or radiotherapy and concurrent chemotherapy which is recommended by the NCCN Clinical Practice Guidelines for Oncology – published by the National Comprehensive Cancer Network. The current SOC appears not to be able to completely arrest the disease because these treatments are unable to completely remove or kill all of the cancer cells in the advanced primary disease cases. The persistence of these residual cells is thought to be partly responsible for the cancer’s recurrence or metastasis.

In a number of Phase I and II studies, and in the recently completed global pivotal Phase III clinical trial, Multikine investigational therapy was injected five times a week for three weeks around the tumor (peri-tumorally) as well as in the vicinity of the local draining lymph nodes (peri-lymphatically) prior to the patient’s tumor being removed surgically and the patient receiving any other therapy because these are the areas in which the cancer is thought to most likely recur and from which metastases would therefore be most likely to develop.

The current underlying understanding of Multikine’s apparent mode of action, which presently is based on data from animal (Chirigos et al Immunopharm. and Immunotox. 1995) and human (Timar et al JCO 2005) studies to date, is that it appears to activate the immune system to potentially mount an anti-tumor immune response against the specific individual tumor within each subject treated. This opens up the potential (to be explored in future clinical development) for this investigational therapy to possibly treat other solid tumors in addition to its potential role in head and neck cancer.

Multikine has already preliminarily shown the potential for biological activity (in early clinical trials) in cervical dysplasia / neoplasia (pre-cancer and cancer of the cervix) and prostate cancer.

Other potential indications in which development likely would be pursued for Multikine if it is determined by FDA to be safe and effective based upon the entirety of the developmental data including that from the recently completed Phase III clinical study in advanced primary head and neck cancer may include: breast cancer, skin cancer, cervical cancer, anal warts (potential precursor to anal cancer) in HIV/HPV co-infected men and women, melanoma and enhancement of radiation. The potential for the possible enhancement of radiation is a particularly important field to investigate because it may open the potential to reduce the amounts of radiation given to patients.

o Summary of results from our last Phase II clinical trial of the investigational therapy Multikine in head and neck cancer patients with advanced primary disease**:

• In a follow-up analysis of the Phase II clinical study population, which used the same dosage and treatment regimen as is being used in the Phase III study, head and neck cancer patients with locally advanced primary disease who received our investigational therapy Multikine as first-line investigational therapy, followed by surgery and radiotherapy, were reported by the clinical investigators to have had a 63.2% overall survival (OS) rate at a median of 3.33 years from surgery. This percentage of OS was arrived at as follows: of the 21 subjects enrolled in the Phase II study, the consent for the survival follow-up portion of the study was received from 19 subjects. OS was calculated using the entire treatment population that consented to the follow-up portion of the study (19 subjects), including two subjects who, as later determined by three pathologists blinded to the study, did not have oral squamous cell carcinoma (OSCC). These two subjects were thus not evaluable per the protocol and were not included in the pathology portion of the study for purposes of calculating complete response rate, as described below, but were included in the OS calculation. The overall survival rate of subjects receiving the investigational therapy in this study was compared to the overall survival rate that was calculated based upon a review of 55 clinical trials conducted in the same cancer population (with a total of 7,294 patients studied) and reported in the peer reviewed scientific literature between 1987 and 2007. Review of this literature showed an approximate survival rate of 47.5% at 3.5 years from treatment. Therefore, the results of CEL-SCI’s final Phase II study were considered to be potentially favorable in terms of overall survival, recognizing the limitations of this early-phase study. It should be noted that an earlier investigational therapy Multikine study appears to lend support to the overall survival findings described above – Feinmesser et al Arch Otolaryngol. Surg. 2003. However, no definitive conclusions can be drawn from these data about the potential efficacy or safety profile of this investigational therapy.
• Data from the Final Phase II study after only 3-weeks of the Multikine treatment regimen has also shown the following:
• Reported average of 50% reduction in tumor cells in Phase II trial (based on 19 patients evaluable by pathology, having OSCC):The clinical investigators who administered the three-week Multikine treatment regimen used in the Phase II study reported that, as was determined in a controlled pathology study, Multikine administration appeared to have caused, on average, the disappearance of about half of the cancer cells present at surgery (as determined by histopathology assessing the area of Stroma/Tumor (Mean+/- Standard Error of the Mean of the number of cells counted per filed)) even before the start of standard therapy surgery, radiation and chemotherapy (Timar et al JCO 2005).
• Reported 10.5% complete response in the Phase II trial (based on 19 patients evaluable by pathology, having OSCC):The clinical investigators who administered the three-week Multikine investigational treatment regimen used in the Phase II study reported that, as was determined in a controlled pathology study, the tumor apparently was no longer present (as determined by histopathology) in approximately 10.5% of evaluable patients with OSCC (Timar et al JCO 2005). In the original study, 21 subjects received Multikine, two of which were later excluded, as subsequent analysis by three pathologists blinded to the study revealed that these two patients did not have OSCC. Two subjects in this study had a complete response, leaving a reported complete response rate of two out of 19 assessable subjects with OSCC (or 10.5%) (Timar et al, JCO 2005). Subsequently, an analysis on the 21 subjects originally treated with Multikine in the study to evaluate overall survival was conducted, as described above. In connection with the follow-up portion of the study for overall survival, we also conducted an unreported post-hoc analysis of complete response rate in the study population, which included subjects who provided consent for the follow-up and who also had OSCC. Two out of the 21 subjects did not re-consent for follow-up, and two of the remaining 19 subjects were excluded from the post-hoc complete response rate analysis as they had previously been determined by pathology analysis to not have OSCC. The two complete responders with OSCC both consented to the follow-up study. Therefore, the post-hoc analysis of complete response was based on a calculation of the two complete responders out of 17 evaluable subjects who consented to the follow-up analysis and who also had OSCC (or 11.8%). Furthermore, we reported an overall objective response rate of 42.1% based on the number of evaluable patients who experienced a favorable response to the treatment, including those who experienced minor, major and complete responses. Out of the 19 evaluable patients, two experienced a complete response, two experienced a major response, and four experienced a minor response to treatment. Thus, we calculated the number of patients experiencing a favorable response as eight patients out of 19 (or 42.1%) (Timar et al, JCO 2005).

o Topline Phase III study results: 

Our completed Phase III trial is the largest ever in head and neck cancer with 928 patients enrolled. The top line data read out in June 2021 showed that when the Multikine treatment regimen was given after diagnosis before surgery and radiation (the first of two possible treatment arms determined by the treating physicians following the National Comprehensive Cancer Network (NCCN) guidelines) the 5-year OS benefit of patients treated with Multikine in this study arm was 14.1% (absolute advantage), (62.7% treated vs. 48.6% control) exceeding the protocol required 10% or better. The p-value for this treatment arm was 0.0236, exceeding the protocol required p-value of <0.05. The Hazard Ratio [HR] of the Multikine treatment regimen plus surgery and radiotherapy arm vs Control (Surgery plus radiotherapy) arm was 0.68, exceeding the protocol required 0.721. No safety issues arose during or after the study directed treatments in the Multikine treated arms of the study as compared to control.

Adverse events reported in clinical trials: In clinical trials conducted to date with the Multikine investigational therapy, adverse events which have been reported by the clinical investigators as possibly or probably related to Multikine administration included pain at the injection site, local minor bleeding and edema at the injection site, diarrhea, headache, nausea, and constipation. The Phase III study showed no safety issues with Multikine administration and Multikine treatment regimen did not produce an adverse safety signal in this study.

* Multikine is the trademark that CEL-SCI has registered for this investigational therapy, and this proprietary name is subject to FDA review in connection with our future anticipated regulatory submission for approval.

** Multikine has not been licensed or approved for sale, barter or exchange by the FDA or by any other regulatory agency. Similarly, its safety or efficacy has not been established for any use. Moreover, no definitive conclusions can be drawn from the early-phase, clinical-trials data summarized on this page or elsewhere on this website involving the investigational therapy Multikine (Leukocyte Interleukin, Injection).