Investigational Therapy Multikine (Leukocyte Interleukin, Injection) Phase III Clinical Trial Design and Status

The end game is near: The final stages of clinical trials: Multikine (Leukocyte Interleukin, Injection) has been cleared for a global Phase III trial in advanced primary head and neck cancer. It has received a go-ahead from 24 Regulatory Agencies including leading regulators in the U.S., Canada and the United Kingdom. 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*. Multikine has not been licensed or approved 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 this investigational therapy.

Because of Multikine's orphan drug status in the USA, it currently is anticipated that only one pivotal study is expected to be necessary for Multikine's approval. Advanced primary, not yet treated, head and neck cancer represents a recognized unmet medical need. The current statistics indicate that about 50% of the patients diagnosed with the disease will die within three years following the current standard of care, or SOC, treatment with minimal progress over the last 50 years.

The Multikine open-label, randomized, controlled, multi-center Phase III study will enroll approximately 880 subjects with advanced primary (not yet treated) head and neck cancer, in order to have approximately 784 evaluable subjects,. This pivotal Phase III study will be conducted in approximately 100 centers in about 25 countries in 3 continents.

In 2013, CEL-SCI was faced with a major challenge. We were forced to transfer the management of the Phase III trial for Multikine in the treatment of head and neck cancer to two new Clinical Research organizations (CROs). In April 2013, CEL-SCI had to dismiss the prior CRO that had this responsibility because, among other things, they did not achieve the rate of patient enrollment in our study assumed by our contract, and they had a high internal rate of turnover among their personnel which negatively affected the conduct of our Phase III trial. CEL-SCI believes that the new CRO team is now effectively managing the Phase III trial, and the CRO's goal is to reach full enrollment in the Phase III study by about March 2016.

The current standard of care (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 as defined by the National Comprehensive Cancer Network, or NCCN guidelines. Our ongoing Phase 3 trial is testing the hypothesis that Multikine treatment, administered prior to such SOC treatment regimen, will extend overall survival, enhance the local/regional control of the disease and reduce the rate of disease progression in patients with squamous cell carcinoma of the head and neck, or SCCHN. SCCHN is the most common type of head and neck cancer.

The primary clinical endpoint in our ongoing Phase 3 clinical trial is the achievement of a 10% improvement in overall survival in the Multikine plus SOC treatment arm over that which is achieved in the SOC treatment arm alone. All patients in the Phase 3 study will receive SOC. Based on what is presently known about the current survival statistics for this population, we believe that achievement of this endpoint should enable us, subject to further consultations with the FDA, to move forward, prepare and submit a Biologic License Application, or BLA, to the FDA for Multikine as neoadjuvant therapy in patients with SCCHN. Approximately 60-66% (2/3) of head and neck cancer patients who present with advanced primary disease could be candidates for this investigational therapy if it were to be approved by FDA.

This study is also thought to be the first Phase III study in the world in which immunotherapy is given to patients first meaning it is given after diagnosis and before any conventional treatment for cancer. It seems logical to us that boosting an intact immune system should be more helpful to patients than trying to boost a significantly weakened immune system after radiation and chemotherapy.

Study Summary: A Pivotal Phase III, Open-label, Randomized, Controlled Multi-center Global Study of the Effects of Multikine Plus Standard of Care (Surgery + Radiotherapy or Surgery + Concurrent Chemoradiotherapy) in Subjects with Advanced Primary Squamous Cell Carcinoma of the Oral Cavity and Soft Palate Versus Standard of Care Only.

Objectives: As set forth in the study protocol, the primary objective of this Phase III trial is to evaluate the efficacy of peri-tumoral and peri-lymphatic injection of the investigational Multikine therapy given prior to SOC. This will be evaluated based upon measurements of overall survival. The secondary objectives are to evaluate the effects of the investigational Multikine therapy on the cumulative incidence of local-regional control, progression-free survival, tumor histopathology, and quality of life, while also seeking to confirm Multikine safety. Tumor response is a tertiary outcome in this immunotherapy study.

Number of Subjects: 880

Clinical Centers: approximately 100 globally distributed; North America, Europe, Asia

Statistics: 80% Power; 95% confidence - to show a 10% Overall Survival advantage

Steps taken to reduce the risk of failure of the Multikine Phase III trial:

The most common reasons for Phase III study failures or the failure to receive approval to sell a drug, other than the drug not working, are:

1. Phase III study that is not reviewed by the FDA and not acceptable to the FDA:

Multikine Phase III study was reviewed in detail and changes were made to the Phase III protocol based on FDA's comments.
   
2. A study that is too small:

The Multikine study will enroll 880 patients, which is the largest study conducted in this population, and one that enables the study to be appropriately powered to evaluate achievement of the study endpoints.
   
3. The clinical endpoints are not relevant:

The Multikine study follows the overall survival of the patients, which is considered to be the "gold standard" of endpoints in clinical trials. The clinical endpoint cannot be more relevant.
   
4. A change in treatment protocol between Phase II and Phase III without additional studies:

The Phase III study Multikine treatment is the same as the treatment that was used in the final Phase II study; no changes were made. Consequently, we reasonably anticipate that the Phase II results should be representative of the results that we hope to achieve in the Phase III trial.
   
5. Insufficient attention to manufacturing issues:

The Multikine manufacturing process is validated and CEL-SCI has built a dedicated manufacturing facility for Multikine. The manufacturing facility is designed and built to meet US FDA and EU regulations and requirements for the manufacture of Multikine.

The general schema and comparator arms of the Phase III trial are depicted in the Trial design cartoon (below, click image to enlarge).

Trial Design

 

* 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 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). Further research is required, and early-phase clinical trial results must be confirmed in the well-controlled, Phase III clinical trial of this investigational therapy that is currently in progress.