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

The Phase III Clinical Trial: 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.

On September 26, 2016, CEL-SCI received verbal notice from FDA that the Phase 3 clinical trial in advanced primary head and neck cancer has been placed on partial clinical hold. At such time, enrollment in the Phase 3 study was 928 patients. Pursuant to this communication from FDA, patients currently receiving study treatments can continue to receive treatment, and patients already enrolled in the study will continue to be followed. On October 21, 2016, CEL-SCI received a partial clinical hold letter from FDA and, on November 18, 2016, CEL-SCI submitted a response to FDA's partial clinical hold letter.

In its partial clinical hold letter, FDA identified the following deficiencies: a) FDA stated that there is an unreasonable and significant risk of illness or injury to human subjects and cited among other things the absence of prompt reports by us to the FDA of Independent Data Monitoring Committee (IDMC) recommendations to close the study entirely (made in spring of 2014) or at least to close it to accrual of new patients (made in spring of 2016); b) FDA stated that the investigator brochure is misleading, erroneous, and materially incomplete; and c) FDA stated that the plan or protocol is deficient in design to meet its stated objectives. In its partial clinical hold letter, FDA also identified the information needed to resolve these deficiencies. In addition, FDA's partial clinical hold letter included two requests relating to quality information regarding our investigational final drug product, which were noted by FDA as non-hold issues. We believe that our response submitted to FDA on November 18, 2016, addressed each of the deficiencies identified by FDA including detailing our belief that, under the applicable FDA guidance, there was no obligation to report the cited IDMC recommendations to the FDA at the time they were issued, and it also requested a face-to-face meeting with FDA, and outlined our commitment to diligently work with FDA in an effort to have the partial clinical hold for the study lifted.

On December 8, 2016, FDA advised CEL-SCI that the Agency was denying CEL-SCI's request for a meeting at that time because FDA's review of our November 18, 2016 response was ongoing. CEL-SCI also was advised that it would be receiving a letter addressing its November 18, 2016 response by December 18, 2016.

On December 16, 2016, FDA issued an Incomplete Response To Hold letter to CEL-SCI indicating that based on the Agency's preliminary review of our November 18, 2016 submission, FDA has determined that it is not a complete response to all of the issues listed in FDA's clinical hold letter. In its letter, FDA identified the following deficiencies: a) FDA stated that we did not provide the information identified as necessary to address FDA's statement that patients enrolled in the study are exposed to unreasonable and significant risk of illness or injury to human subjects; b) FDA stated that we did not provide the information identified as necessary to address FDA's statement that continued enrollment of patients in the study exposes the patients to unreasonable risks and the FDA furthermore stated that the study is unlikely to demonstrate that the addition of our investigational drug Multikine to the standard of care is superior to standard of care and thus should be terminated for futility; (c) FDA stated that we did not provide the information identified as necessary to address FDA's statement that the investigator brochure is misleading, erroneous, and materially incomplete; (d) FDA stated that we did not provide the information identified as necessary to address FDA's statement that the proposed revised clinical protocol is inadequate in design to meet its stated objectives and FDA furthermore stated that this deficiency cannot be addressed by further revisions to the protocol. In its incomplete response to hold letter, FDA also identified the steps we must take to address these deficiencies. In addition, FDA's Incomplete Response to Hold letter noted with respect to FDA's two requests relating to quality information regarding our investigational final drug product, which we had been instructed by FDA to submit separately from the response to the partial clinical hold, which again were noted by FDA as non-hold issues, that our November 18, 2016, submission had not included the information addressing these two requests.

In early January 2017, in preparation for the request for a Type A meeting with FDA and resolution of the partial clinical hold issues, CEL-SCI prepared a comprehensive submission to FDA detailing our belief, accompanied by what CEL-SCI believe to be appropriate supporting data, records, and information reflecting that we have taken the steps necessary to address the specific deficiencies identified by FDA, including: a) demonstrating that patients enrolled in the study are not exposed to unreasonable and significant risk of illness or injury; b) demonstrating that continued enrollment of patients in the study does not expose the patients to unreasonable risks and that the study should not be terminated for futility; (c) demonstrating that a supplemented investigator brochure is not misleading, erroneous, or materially incomplete; (d) demonstrating that the proposed revised clinical protocol is adequate in design to meet its stated objectives and that this deficiency can be addressed by the proposed revisions to the protocol.

On February 8, 2017, CEL-SCI met with the FDA to allow an open and frank discussion of the clinical hold issues raised by the FDA and to secure the FDA's input and clarification on how to address the partial hold issues. On March 1, 2017 CEL-SCI received the written minutes of this meeting from FDA. The Action Items for CEL-SCI to pursue per the minutes from the FDA were the following: 1) provide an updated Investigator's Brochure and current procedures for compliance with requirements under 21 CFR 312 Subpart D to address the partial clinical hold, and 2) provide a list of major protocol deviations, which CEL-SCI believes will affect study results, and provide a plan to identify major protocol deviations across all patients enrolled in the Phase 3 protocol.

CEL-SCI is diligently continuing to work with the FDA to have the partial clinical hold lifted. CEL-SCI has been in a continuing dialogue with the FDA to try to resolve their questions and to supply them with supplemental information. CEL-SCI has supplied its response to those Action Items to the FDA. In accordance with the partial clinical hold, CEL-SCI is continuing to follow the 928 patients enrolled in the study, and this includes following patients until the targeted 298 deaths between the 2 comparison groups is observed. This number of deaths is required to evaluate if the study's primary endpoint is achieved.

Currently CEL-SCI is not looking to enroll any more patients. CEL-SCI will not be able to enroll any additional patients in the Phase 3 study unless FDA lifts the partial clinical hold. In addition, in the spring of 2016, the IDMC recommended to us that new patient enrollment should stop in the Phase 3 study, but patients already on study should continue to be treated and followed. Although CEL-SCI had expected to work through the concerns raised by the IDMC while we worked through the partial clinical hold with FDA, the IDMC informed CEL-SCI on December 13, 2016, that because the study is on partial clinical hold imposed by FDA, the IDMC has no formal recommendation regarding continuation of the trial at that time. Another IDMC meeting was held on February 6, 2017. Due to the fact that the study is still on partial clinical hold imposed by the FDA, the IDMC had no formal recommendation regarding continuation of the trial at that time. If the partial clinical hold is not lifted by FDA or if it is determined by FDA that the study has been compromised, the study may be terminated, or if the partial clinical hold is lifted by FDA but the IDMC continues to recommend that enrollment not be allowed to continue, the study may be terminated by CEL-SCI.

In August 2016, CEL-SCI announced that the data available at that time from the Phase 3 clinical study reflected that the accumulation of deaths in the study was lower than that which was anticipated based on reported literature at the Phase 3 study's inception. If the number of deaths continued to be accumulated at the rate at that time, it had been determined that it would take longer than originally planned to complete the study. To minimize this eventuality, CEL-SCI decided it would be necessary to enroll additional patients. As required by law and in order to be able to implement the plan, CEL-SCI submitted an amendment to the existing Phase 3 protocol for our head and neck cancer study to the FDA and multiple regulatory agencies in the countries abroad where the Phase 3 study is being conducted to allow for this expansion in patient enrollment.

In April 2017, CEL-SCI announced that in light of new information CEL-SCI has decided to withdraw the study protocol amendment for additional patients that was submitted to the FDA and other regulatory agencies in the summer of 2016. It is now possible that CEL-SCI may not need to add more patients to the study or that only a smaller number of patients need to be added to the study to complete it in a reasonable period of time. Should additional patients be needed, CEL-SCI will submit a future study amendment to the FDA and other regulatory agencies to seek their clearance to proceed.

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.

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 that is on Partial Clinical Hold by the US FDA 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.

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. Below is a general overview of the current 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 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. Enrolled: 928

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

 

* 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 on Partial Clinical Hold by the US FDA.