Photo by Artem Podrez from Pexels
(Photo : Artem Podrez from Pexels)

Recently CEL-SCI Corporation, a company we have been watching since we first discussed Multikine in August of 2021, announced that results from the company's historic 10-year IT-MATTERS Phase 3 clinical trial for head and neck cancer patients with the investigational immunotherapy Multikine®* (Leukocyte Interleukin, Injection) have been officially submitted, reviewed and now posted on the largest clinical trial database in the world.

ClinicalTrials.gov is run by the U.S. National Library of Medicine at the National Institutes of Health and all final trial data must be posted on clinicaltrials.gov per U.S. government requirements before any drug can submit an FDA BLA application in the process of seeking regulatory approval.

Additionally, elements of the data were previously presented in two peer-reviewed abstracts and a poster presentation at this year's ASCO 2022 Conference held in June of 2022. ASCO is the largest professional oncology conference in the world with over 40,000 attendees this year. It is the hub for the latest up-to-date clinical cancer advances in every area of cancer research offering oncologists real-time insights from world-renown faculty with one of the largest, most diverse audiences in global oncology. CEL-SCI predicts additional results will be published in scientific journals and presented in scientific forums in the future.

The "Proposed Indication" for Multikine that will be submitted to the FDA in a license application eligibility criteria would require patients who are deemed by NCCN Guidelines as having a lower risk for tumor recurrence. This Proposed Indication for Multikine covers an estimated 210,000 patients globally each year. The current standard of care for patients with lower-risk advanced primary head and neck cancer is surgery followed by radiotherapy, but not chemotherapy.

To CEL-SCI's knowledge, the last medical development that had a significant impact on overall survival for these patients was when Methotrexate was authorized over 60 years ago. The FDA gave Multikine orphan drug status for "neoadjuvant therapy in squamous cell carcinoma of the head and neck (SCCHN) patients." There is thus an unmet medical need for improved therapies for these individuals.

About The IT-MATTERS Phase 3 Trial

The 928-patient IT-MATTERS study was designed to determine if Multikine provided survival and other clinical benefits to patients suffering from locally advanced primary squamous cell carcinoma of the head and neck (SCCHN), oral cavity, and soft palate. Multikine is a mixture of naturally occurring cytokines that help regulate the immune system.

Multikine is the cancer immunotherapy being developed as a potential neo-adjuvant treatment to be given to patients before they start standard of care (SOC) for previously untreated, locally advanced primary squamous cell carcinoma of the head and neck (SCCHN).

The global IT-MATTERS trial was conducted across 23 countries worldwide and met standards set by Good Clinical Practices, the International Counsel for Harmonization, as well as all other country-specific regulatory requirements.

Following diagnosis, subjects were randomized into one of three treatment arms.

Multikine Phase 3 Primary Treatment Arm

In the primary treatment arm (3/7) subjects received three consecutive weeks of treatment with supraphysiologic doses of Multikine injected 5x/wk peritumorally and perilymphatically plus "CIZ" before receiving the SOC.

CIZ comprised a non-chemotherapeutic dose of cyclophosphamide (administered one-time only IV-bolus, 3 days before the 1st dose of Multikine), and indomethacin and zinc-multivitamins daily from day 1 of Multikine administration to one day before surgery to enhance Multikine activity.

Multikine Phase 3 Second Treatment Arm

In the second arm (1/7), subjects received the three-week Multikine regimen without CIZ before receiving the SOC.

Multikine Phase 3 Study Control Arm

In the third arm (3/7), which was the study control arm, subjects received only the SOC (with no Multikine or CIZ).

The study was made up of three groups, who all received the standard of care (SOC). Some subjects additionally received Multikine before SOC (study treatment arms), while others did not receiveMultikine and only received SOC(study control arm). The two main comparator groups in the study were the primary arm receiving both treatments and those in the control group who just received SOC.

To determine which treatment option a patient should pursue, after surgery, the treating physicians relied on pathology and medical judgment as guided by the National Comprehensive Cancer Network (NCCN) Guidelines to decide whether the patient was at a higher risk for tumor recurrence.

Patients in the high-risk group would receive chemoradiotherapy concurrently. All other patients, who were classified as lower risk for recurrence, would only receive radiotherapy after surgery.

For lower-risk squamous cell carcinoma of the head and neck (SCCHN) patients, the results speak for themselves regarding SOC + Multikine when chemotherapy is not introduced.

It's also worth noting that the bifurcated treatment path outlined above was not developed for CEL-SCI's research, but it is, and still is, according to NCCN Guidelines for advanced primary SCCHN patients.

To adhere to ethical practices, the only way the study could be conducted was by using the bifurcated SOC model following surgery-it would have been unethical to study Multikine with only one treatment arm at a time (lower-risk or higher-risk).

CEL-SCI CEO Geert Kersten touched on this in a September 2021 interview noting "The analysis for the treatment arm getting surgery and radiation is pre-specified in the protocol and the data analysis was conducted before we became unblinded to the study results. Since we planned and met all of the requirements, we can now go for FDA approval. We always plan. That is the only way a small company can be successful."

When the research was planned CEL-SCI was aware that Multikine might only provide a benefit in one of the two SOC risk categories, so the company specified in its original study plan that analyses of trial results should be conducted for all participants as well as for each of these groups.

Separate analyses of the lower-risk-for-recurrence and higher-risk-for-recurrence treatment arms were also pre-specified in the study's statistical analysis plan, which was completed before data lock and the conclusion was assessed.

Multikine Phase 3 Clinical Trial Results

Data collected during the Phase 3 trial that will be submitted to the FDA in support of the Proposed Indication are:

  • Partial and complete tumor responses within 3 weeks and before surgery (objective responses per RECIST):

  • 8.1% (32/395) objective response rate (ORR) for Multikine+CIZ patients in the intent-to-treat (ITT) population versus zero in the SOC group (n=394).

  • 15.2% (24/158) ORR for Multikine+CIZ patients in the lower-risk-for-recurrence arm versus zero in the SOC group (n=168).

  • Two-sided Fisher Exact p-values <0.0000001 for ORR.

  • Complete responses before surgery were seen in 5 Multikine+CIZ patients.

  • Objective response before surgery was prognostic/predictive of improved overall survival (OS) and significant for reduced death rate:

  • In the ITT population, 22.2% death rate versus 54.1% death rate (Multikine objective responders versus Multikine non-responders; two-sided Fisher Exact p-value <0.0001; HR=0.301 [95% CI 0.16, 0.566]).

  • In the lower-risk-for-recurrence arm, 12.5% death rate versus 41.0% death rate (Multikine+CIZ objective responders versus Multikine+CIZ non-responders; two-sided Fisher Exact p-value=0.0101; HR=0.246 [95% CI 0.077, 0.787]).

Data that will be provided to FDA to confirm efficacy in the Proposed Indication:

  • Analysis of the lower-risk-for-recurrence arm was pre-specified in the original study protocol and the statistical analysis plan. This arm comprised about 40% of all study participants.

  • 14.1% absolute OS advantage at 5-years in the lower-risk-for-recurrence arm (62.7% vs 48.6%) for Multikine+CIZ patients versus SOC patients. OS benefit was also shown at 1, 2, 3, and 4 years.

  • Nearly 4-year increase in median overall survival in the lower-risk-for-recurrence arm (101.7 months for Multikine+CIZ versus 55.2 months for the SOC).

  • Histopathological analysis confirmed the effect of Multikine, as 61 markers, ratios, and combinations showed a statistically significant effect in the lower-risk-for-recurrence arm (two-sided p<0.05) favoring Multikine+CIZ versus the SOC for OS, progression-free survival, and loco-regional control outcomes.

  • Additional (confirmatory) progression-free survival benefit in the lower-risk-for-recurrence arm was observed for Multikine+CIZ versus the SOC.

  • No excess safety issues: The overall incidence of adverse events and serious adverse events in the Multikine arms was not substantially different from the SOC.

Importance of CEL-SCI's IT-MATTERS Trial Results

Annually, 890,000 people worldwide are diagnosed with head and neck carcinomas. In the United States alone, there are 68,000 new cases annually. Of those cases, 90% are squamous cell carcinomas--and two-thirds of these patients have never received treatment for their primary disease by the time they're first seen.

The median 3-year survival rate with the current standard of care is approximately 55%. The 5-year OS is about 43%. There are many locally advanced primary SCCHN patients for whom available treatment modalities are not effective.

The IT-MATTERS trial confirms that a 3-week treatment with Multikine provides objective responses before surgery. 

The study showed a five-year OS benefit for the Proposed Indication, involving patients who are considered at lower risk of recurrence by NCCN Guidelines and thus would receive radiotherapy without chemotherapy following surgery.

The Multikine group had an 8.5% objective complete and partial response rate in the Intent-to-Treat population and a 16% overall response rate among all patients treated with Multikine (+/- CIZ) in the lower risk for recurrence arm of the study before surgery was performed.

A partial response indicates that the tumor has been reduced by at least 30%, and a complete response indicates that the tumor has vanished completely. 

These objective tumor responses were observed within three weeks of beginning Multikine therapy through surgery, providing indisputable evidence of its anti-cancer effects.

Although objective responses to cancer treatments do not always result in improved survival, Multikine's objective responses resulted in a significant decrease in mortality. 

In the Proposed Indication, the death rate for Multikine+CIZ patients fell from 41% for non-responders to 12.5 percent for objective responders. Objective responders also saw a similar reduction in overall mortality rates in the ITT.

In the lower-risk-for-recurrence treatment arm, these reduced death rates yielded an absolute OS advantage of 14.1% at 5 years versus the SOC alone, with a proportional hazard p-value of 0.0236, a hazard ratio of 0.68 (representing 47% prolongation of survival), confirmatory PFS benefit, and median overall survival that is nearly 4 years longer than from the SOC alone as well as histopathological data showing a direct effect of Multikine on tumor and tumor microenvironment.

Multikine Plans for FDA Approval

The majority of the objective responders were observed in the arm of the study where 40 percent of study subjects (n=380) were classified and met NCCN criteria for a reduced risk of tumor recurrence. Multikine+CIZ-treated non-responders in this arm also experienced an OS benefit, as was seen in the other arm.

Therefore, when the data for the lower-risk-for-recurrence arm is reviewed as a whole (responders and non-responders together), CEL-SCI identified that there was a significant increase in overall survival time for those who were given Multikine. The median survival time was nearly four years longer than the control group.

CEL-SCI used data from the study to develop eligibility criteria that would select patients who, before surgery, would be at lower risk for recurrence. This distinction can only currently be determined after surgery has been completed.

CEL-SCI plans to seek FDA approval for the treatment of those with locally advanced primary disease SCCHN who would receive Multikine first, followed by surgery and then only radiotherapy according to NCCN Guidelines.

About CEL-SCI Corporation

CEL-SCI believes that the best chance for survival lies in boosting a patient's immune system while it is still intact. Therefore, in the Phase 3 study, CEL-SCI treated newly diagnosed subjects with advanced primary squamous cell carcinoma of the head and neck before they received surgery and radiotherapy (the current standard of care for these patients) with Multikine.

CEL-SCI's technique is one-of-a-kind. Most other cancer immunotherapies are only used after standard treatments have failed. Multikine (Leukocyte Interleukin, Injection) was granted Orphan Drug status by the FDA for neoadjuvant therapy in squamous cell carcinoma of the head and neck patients. CEL-SCI thinks that this research, which involved over 500 participants, is the world's largest Phase 3 study for treating advanced primary head and neck cancer.

Multikine is designed to help the immune system "see" tumors at a time when the immune system is still relatively intact, which then allows for a better chance of attacking and destroying the tumor. 

The Phase 3 study began in early 2011 and was completed with 928 subjects enrolled by September 2016. To prove an overall survival benefit from using Multikine, CEL-SCI needed to wait until 298 people had died among the two main comparator groups. CEL-SCI has operations located in Vienna, Virginia as well as Baltimore, Maryland.

Final Take

According to the statistics, after Multikine is approved and followed by surgery and radiotherapy, there will be 14 more people living at 5 years compared to existing SOC.

In this study, it was seen that the Multikine+CIZ treatment regimen followed by surgery and radiotherapy had an OS advantage. If all 210,000 advanced primary SCCHN patients globally who would be eligible for this treatment received this care plan, then 5 years post-therapy 29,000 more people would be alive in comparison to the SOC (standard of care).

CEL-SCI plans to utilize the Phase 3 trial results are intended to support a Biologics Licensing Application to FDA which is the only U.S. entity authorized to determine safety and efficacy.