Results of a 9.5-year pivotal, open-label randomized multi-center controlled Phase 3 clinical study (NCT01265849) of leukocyte interleukin injection (Multikine®; CEL-SCI Corporation), an investigational immunotherapy known to contain 14 natural human cytokines, including glycosylated interleukin-2 (IL-2), demonstrated significant overall survival (OS) benefit for patients treated for advanced (stages III and IV) or primary (previously untreated) squamous cell carcinoma of the head and neck (SCCHN) who received this treatment regimen followed by surgery and radiotherapy, compared to patients who received chemotherapy added to the same treatment.

According to the World Health Organization (WHO), the annual incidence of head and neck cancers worldwide is more than 550,000 cases with approximately 300,000 deaths each year. [1]* Male to female ratio ranges from 2:1 to 4:1. About 90% of all head and neck cancers are SCCHN, which is considered the sixth leading cancer by incidence worldwide.

Most SCCHN arise in the epithelial lining of the oral cavity, oropharynx, larynx, and hypopharynx [2][3]. These cancers are strongly associated with certain environmental and lifestyle risks factors like tobacco (smoking) and heavy alcohol consumption. However, more recently a new disease has emerged related to several strains of human papillomavirus (HPV16,18). [4] The prognosis of patients diagnosed with HPV-related SCCHN is substantially better than those associated with tobacco and alcohol.

The five-year overall survival rate of patients with SCCHN is about 40-50%. About one-third of patients present with early-stage disease (T1-2, N0). Treatment for early SCCHN usually involves single-modality therapy with either surgery or radiation. Early-stage cancers have a very favorable prognosis with high cure rates with surgery or radiation alone and chemotherapy or concurrent chemotherapy/radiation is not indicated for this group of patients.

Furthermore, on average, the recurrence rate following the currently available standard of care  is high for patients diagnosed with SCCHN with about one out of every two patients will die within three to five years

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Study design
Patients participating in the IT-MATTERS trial, treated with the leukocyte interleukin injection treatment regimen followed by surgery and radiotherapy (without chemotherapy) demonstrated statistically significant overall survival (Intent To Treat, p=0.0236, HR= 0.68) advantage vs. standard of care alone.  The 3-year survival advantage shown in this study was 4.9% (72.4% vs 67.5%). In addition, the analyses of long-term data showed a 5-year survival advantage of 14.1% (62.7% vs 48.6%) for the pre-defined population receiving no chemotherapy. The leukocyte interleukin injection treatment regimen followed by surgery and radiotherapy (without chemotherapy) exhibited a consistent OS advantage. Median follow-up time was greater than 7 years for patients last alive.

The Overall Survival benefit increased over time. This group represents about 155,000 patients worldwide or about 40% of all advanced primary head and neck cancer cases annually. Patients treated with the same leukocyte interleukin injection treatment regimen prior to surgery and radiotherapy, but who also received chemotherapy, did not exhibit this survival advantage. The chemotherapy, cisplatin, was given intravenously and may have negated the survival benefit imparted by leukocyte interleukin injection immunotherapy in these patients.

The global trial enrolled 928 stage III and IVa patients through 78 sites on 3 continents. The intent to treat population included 923 patients, as 5 randomized patients were never treated. The two main comparator arms of the study included the leukocyte interleukin injection treatment regimen (leukocyte interleukin injection + CIZ: cyclophosphamide; indomethacin; zinc- multivitamins) + standard of care vs. standard of care alone. In each of these comparator arms, patients were determined by pathology following surgery to receive radiotherapy only or concurrent radio-chemotherapy. These treatments were prescribed by the protocol and are based on the National Comprehensive Cancer Network (NCCN-) Guidelines for the treatment of SCCHN patients. The data were analyzed per the protocol and the Statistical Analysis Plan.

Regulatory approval
Results for the patients who did not receive chemotherapy treatment as part of their standard of care, the group for which CEL-SCI plans to seek approval from the U.S. Food and Drug Administration, includes:

  • Patients treated with the leukocyte interleukin injection treatment regimen plus SOC vs. SOC alone had an overall survival benefit of 14.1% at 5 years which exceeded the pre-defined 10% overall survival benefit set out for the study population as a whole. This result was statistically significant (ITT; p =0.0236, HR=0.68) with a robust and durable duration effect exceeding 5 years.
  • In this group of patients, the corresponding overall survival at 3 years and 5 years for each study treatment group were as follows: leukocyte interleukin injection treatment regimen (leukocyte interleukin injection plus CIZ: cyclophosphamide; indomethacin, zinc- multivitamins) plus standard of care was 72.4% at 3 years, 62.7% at 5 years; leukocyte interleukin injection (without CIZ) plus standard of care was 78.8% at 3 years, 55.5% at 5 years. The results of the standard of care alone treatment were 67.5% at 3 years and 48.6% at 5 years. The primary survival comparison was pre-defined only between the first and last groups.
  • The study results showed that the Overal Survival advantage increased over time and was evident from the inception of the study participants for this group of patients through the end of the follow-up period with a median follow-up time greater than 7 years for those still alive.
  • Finally, no safety issues for leukocyte interleukin injection were found during or as a result of its administration, including no late effects, in the overall treated patient population.

Primary endpoint
When the complete study population to which the leukocyte interleukin injection treatment regimen was administered (i.e., the combined lower risk without no chemotherapy and higher risk with chemotherapy added) was compared to control, the study did not achieve its primary endpoint of a 10% improvement in overall survival. However, the OS benefit of 14.1% at 5 years for the lower risk subgroup, which included patients treated without chemotherapy, exceeded the 10% OS benefit set out for the study population as a whole. In addition, as the OS results for the lower risk of recurrence patients (no chemotherapy) are significant (two-sided p=0.0236, HR=0.68) and the effect is robust, durable, and increasing over time, CEL-SCI plans to seek FDA approval for leukocyte interleukin injection cancer immunotherapy in this underserved patient population.

Geerts R. Kersten, JD, Chief Executive Officer and a member of the board of directors of Cel Sci.

Major unmet medical need
This indication represents a dire unmet medical need with the last FDA approval being many decades ago. CEL-SCI has Orphan Drug designation from the FDA for the neoadjuvant therapy in patients with squamous cell carcinoma of the head and neck – the patient population treated in this Phase 3 study.

The analysis of this separate group is expected to meet regulatory requirements for FDA submission based on the protocol and Statistical Analysis Plan, which were prospectively concluded before database lock and unblinding.

“The leukocyte interleukin injection treatment demonstrated a significant survival benefit in the group whose standard of care did not include chemotherapy and a favorable safety profile across the entire patient population,” noted Geert R. Kersten, JD, Chief Executive Officer of CEL-SCI.

“Based on this landmark study data, we intend to seek FDA approval for what could become the first treatment in newly diagnosed advanced primary head and neck cancer in many decades. If approved, leukocyte interleukin injection treatment would address the needs of approximately 155,000 patients diagnosed annually worldwide who are currently slated for surgery plus radiotherapy and would significantly increase their chances of overall survival,” he explained.

“Our aim with leukocyte interleukin injection was to develop a treatment that will extend survival, and clearly, this has been achieved in this patient population. In addition, we wanted to develop a treatment that does not add toxicity and does not make other cancer treatments more difficult to bear. We appear to have achieved this goal as well. We are grateful to all the patients and their families who volunteered to participate in the world’s largest and most rigorous Phase 3 study in advanced primary head and neck cancer,” Kersten explained.

“We are confident that the robust overall survival benefit shown in this pivotal study along with the safety profile of leukocyte interleukin injection clearly demonstrates the benefit of neoadjuvant immunotherapy in this patient population and may lead to a new way to treat advanced primary head and neck cancer,” he concluded.

Long-term overall survival
“These data, combined with what we know of leukocyte interleukin injection’s mechanism of action, demonstrate [the potential of leukocyte interleukin injection] to impart long term overall survival advantage and a beneficial effect on the anti-tumor immune response in patients who have not been treated with chemotherapy (cisplatin) which is known to be highly toxic,” commented Eyal Talor, Ph.D., Chief Scientific Officer of CEL-SCI and the developer of Multikine.

“In patients not indicated to receive chemotherapy as part of their standard of care, treatment with [this neoadjuvant leukocyte interleukin injection regimen] demonstrated a statistically significant, robust, and durable overall survival benefit. The data possibly indicate that the leukocyte interleukin injection treatment regimen is capable of altering the course of disease in this population. Perhaps most impressive in the leukocyte interleukin injection treated group not receiving chemotherapy was the fact that the overall survival benefit imparted by leukocyte interleukin injection increased over time as compared to overall survival in control, suggesting that the [neoadjuvant leukocyte interleukin injection immunotherapy] stands to add great benefit to the intent to cure – the current standard of care,” he concluded.

Talor believes that the positive results of the study in this group of patients mark the first-ever success of neoadjuvant cancer immunotherapy in advanced primary head and neck cancer.

Note
* In the US there are about 37,000 new cases of head and neck cancer annually with approximately 90% of all cases being advanced primary squamous cell carcinoma (SCCHN). Approximately 2/3 of SCCHN patients present on their first visit with locally advanced disease. The median 3-year overall survival for these patients with existing standard of care therapies, which includes surgery followed by radiotherapy or combined radiochemotherapy, is between 52 and 55%; the 5-year overall survival is 43%.

Clinical study
Efficacy and Safety Study of Leukocyte Interleukin, Injection (LI) to Treat Cancer of the Oral Cavity (IT-MATTERS) – NCT01265849

Highlights of Prescribing Information
Cyclophosphamide [Prescribing Information]
Indomethacin (Indocin®)[Prescribing Information]
Cisplatin [Perscription Information]

Reference
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[2] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43. PMID: 17237035.
[3] Boyle P, Bernard Levin. World Cancer Report 2008. International Agency for Research on Cancer.
[4] Kreimer, A, Clifford G, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev 2005, 14:467-475
[5] Tímár J, Forster-Horváth C, Lukits J, Döme B, Ladányi A, Remenár E, Kásler M, Bencsik M, Répássy G, Szabó G, Velich N, Suba Z, Elõ J, Balatoni Z, Bajtai A, Chretien P, Talor E. The effect of leukocyte interleukin injection (Multikine) treatment on the peritumoral and intratumoral subpopulation of mononuclear cells and on tumor epithelia: a possible new approach to augmenting sensitivity to radiation therapy and chemotherapy in oral cancer–a multicenter phase I/II clinical Trial. Laryngoscope. 2003 Dec;113(12):2206-17. doi: 10.1097/00005537-200312000-00031. PMID: 14660929.
[6] Chirigos MA, Talor E, Sidwell RW, Burger RA, Warren RP. Leukocyte Interleukin, Inj. (LI) augmentation of natural killer cells and cytolytic T-lymphocytes. Immunopharmacol Immunotoxicol. 1995 May;17(2):247-64. doi: 10.3109/08923979509019749. PMID: 7650289.

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