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 13 Regulatory Agencies including the U.S. FDA, 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 (since about 50% of the patients diagnosed with the disease will die within three years following treatment) with minimal progress over the last 50 years.

The Multikine global pivotal Phase III study will enroll approximately 880 subjects (in order to have approximately 784 evaluable subjects) with advanced primary (not yet treated) head and neck cancer worldwide. The Phase III open-label, randomized, controlled, multi-center study will be conducted in about 100 centers in 20 countries and 3 continents.

A major challenge facing CEL-SCI in 2013 was when CEL-SCI was 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 therefore anticipates full enrollment in the Phase III study by the end of 2015.

The Phase III trial is designed to compare the Multikine investigational therapy combined with the current standard of care therapy (SOC) for head and neck cancer patients (as currently defined by the NCCN Guidelines) vs. the SOC for these patients alone. The current SOC for head and neck cancer - as recommended by the NCCN Clinical Practice Guidelines in Oncology issued by the National Comprehensive Cancer Network - is surgery, followed by radiation, or surgery followed by radiation and concurrent chemotherapy.

Subject to completion of CEL-SCI's global Phase III clinical trial and FDA's review of our entire data set on this investigational therapy, if FDA were to conclude that the safety and efficacy of this investigational therapy is established, the early-phase clinical data is encouraging in suggesting the potential that 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, i.e. prior to receiving any conventional treatment for cancer, including surgery, radiation and/or chemotherapy.  This could be shown to be important because conventional therapy may weaken the immune system, and may compromise the potential effect of immunotherapy. Because Multikine is given before conventional cancer therapy when the immune system may be more intact, CEL-SCI believes the possibility exists for it to have a greater potential likelihood of activating an anti-tumor immune response. This potential is one of the clinical aspects being evaluated in the ongoing global Phase III clinical trial.

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 Standard of Care (SOC) (as currently defined by the NCCN Guidelines). 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 a very large number, particularly 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 Multikine Phase III study is the same as the Phase II study; no changes were made. Consequently, we reasonably anticipate the potential that the Phase II results could 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 sterile injectable products (such as 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.