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*.

  o 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 is currently on Partial Clinical Hold by the US FDA. SCCHN is a type of head and neck cancer, and CEL-SCI believes that, in the aggregate, there is 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 over 50 years ago. In the aggregate, head and neck cancer represents about 6% of the world's cancer cases, with approximately over 650,000 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.

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 o 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.

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 1 and 2 studies, and in the current global pivotal Phase 3 clinical trial, Multikine investigational therapy was/is being 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.

Clinical and histopathology data collected during Phase 2 clinical trials of Multikine indicate that Multikine appears to have reduced the number of recurrences of tumors in the treated head and neck cancer patients beyond that which would otherwise normally would be expected in this same patient population based on literature reports. However, no definitive conclusions can be drawn from these preliminary data about the potential efficacy and/or safety profile of this investigational therapy. Moreover, further research is required, and these results must be confirmed in the well-controlled Phase 3 clinical trial of this investigational therapy that is currently in progress.

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 ongoing Phase 3 clinical study in advanced primary head and neck cancer that is on Partial Clinical Hold by the US FDA 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 chemotherapy and radiation. The potential for the possible enhancement of chemotherapy and radiation is a particularly important field to investigate because it may open the potential to reduce the amounts of radiation and possibly chemotherapy given to patients.

 
       
  o Summary of results from our last Phase 2 clinical trials of the investigational therapy Multikine in head and neck cancer patients with advanced primary disease**:  
   
       
  o In a follow-up analysis of the Phase 2 clinical study population, which used the same dosage and treatment regimen as is being used in the Phase 3 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, or 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 2 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 2 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. Moreover, further research is required, and these results must be confirmed in the Phase 3 clinical trial of this investigational therapy that is currently in progress. Subject to completion of that Phase 3 trial, and the FDA's review and acceptance of CEL-SCI's entire data set on this investigational therapy, CEL-SCI believes that these early-stage clinical trial results indicate the potential for our Multikine product candidate to become a treatment for advanced primary head and neck cancer, if approved.

The primary clinical endpoint in CEL-SCI's ongoing Phase 3 clinical trial specify that a 10% improvement in overall survival in the Multikine treatment arm plus the current standard of care (SOC - consisting of surgery + radiotherapy or surgery + radiochemotherapy) over that which can be achieved in the SOC arm alone (in the well-controlled Phase 3 clinical trial currently ongoing) must be achieved in order to meet the primary endpoint of the Phase 3 study. Based on what is presently known about the current survival statistics for this population, CEL-SCI believes that achievement of this endpoint should enable CEL-SCI, subject to further consultations with FDA, to move forward, prepare and submit a Biologic License Application to FDA for Multikine.
 
       
 o Data from the Final Phase 2 study has also shown the following:  
       
  o Reported average of 50% reduction in tumor cells in Phase 2 trials (based on 19 patients evaluable by pathology, having OSCC): The clinical investigators who administered the three-week Multikine treatment regimen used in the Phase 2 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).  
       
  o Reported 10.5% complete response in the Phase 2 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 2 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 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 clinical significance of these and other data, to date, from the multiple Multikine clinical trials is not yet known. These preliminary clinical data do suggest the potential to demonstrate a possible improvement in the clinical outcome for patients treated with Multikine.  
 
     

* 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). 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.