CEL-SCI Corporation Announces Phase 3 Multikine® Head and Neck Cancer Results
CEL-SCI Corporation announced that the results of its 10-year IT-MATTERS pivotal Phase 3 clinical trial in head and neck cancer with its investigational immunotherapy Multikine® (Leukocyte Interleukin, Injection) have been posted on clinicaltrials.gov per U.S. government requirements. Design of 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 regulate the immune system. Multikine is the first investigational cancer immunotherapy being developed as a first-line neo-adjuvant treatment to be provided to previously untreated locally advanced primary disease SCCHN patients before they receive the SOC. The global IT-MATTERS trial was conducted in 23 countries in accordance with Good Clinical Practices, International Counsel for Harmonization standards, and all other country-specific regulatory requirements. Following diagnosis, subjects were randomized into one of three treatment arms. 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” prior to receiving the SOC. (CIZ comprised a non-chemotherapeutic dose of cyclophosphamide (administered one-time only IV-bolus, 3 days prior to 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.) In the second arm (1/7), subjects received the three-week Multikine regimen without CIZ prior to receiving the SOC. In the third arm (3/7), which was study control arm, subjects received only the SOC (with no Multikine or CIZ). Thus, all subjecsummarizes the results recently posted on clinicaltrials.gov for the overall ITT population as well as the subjects constituting the Proposed Indication representing 41.2% of the study overall ITT population. Objective Responses Before Surgery (partial and complete tumor response per RECIST, confirmed at surgery by pathology): In the overall ITT population, objective responses before surgery (sometimes also called “early responses”) were observed in 45 subjects who received Multikine for 3 weeks; no such responses were observed in the SOC alone (control) (p<0.00000001). Five subjects who received Multikine+CIZ had complete tumor responses confirmed at surgery. In the overall ITT population (n=923), objective responses were seen in: 8.5% of Multikine-treated subjects (45/529); 8.1% of the Multikine+CIZ treatment arm (32/395); 9.7% of the Multikine without CIZ treatment arm (13/134); 0% of the SOC alone (control) treatment arm (0/394). In the Proposed Indication (n=380), objective responses were seen in: 16.0% of Multikine-treated subjects (34/212);15.2% of the Multikine+CIZ treatment arm (24/158);18.5% of the Multikine without CIZ treatment arm (10/54); and 0% of the SOC alone (control) treatment arm (0/168). Objective Responses Before Surgery Were Prognostic For Survivalwith a Significant Decrease in Death Rate: In the overall ITT population (n=923), the 22.2% death rate among Multikine objective responders before surgery (n=45) was significantly lower (two-sided Fisher Exact test p<0.0001; HR=0.301) than the 54.1% death rate for the remaining Multikine non-responders (n=484); In the Proposed Indication (n=380): the 17.6% death rate among all Multikine objective responders before surgery (n=34) was significantly lower (two-sided Fisher Exact test p=0.0067; HR=0.348) than the 42.7% death rate for the remaining Multikine non-responders (n=178). the 12.5% death rate among Multikine+CIZ objective responders before surgery (n=24) was significantly lower (two-sided Fisher Exact test p=0.0101; HR=0.246) than the 41.0% death rate for the remaining Multikine non-responders (n=134). Significant OS advantage in the Proposed Indication for the Multikine+CIZ treatment arm versus the SOC control: 5-year absolute OS advantage of 14.1% (62.7% vs 48.6%); proportional hazards two-sided p=0.0236; 0.68 hazard ratio equating to a 47% OS prolongation; and 3-year and 4-year absolute OS advantage of 4.9% and 9.5%, respectively, are supportive. In the overall ITT population, no statistically significant OS difference was seen between the two main comparator groups (proportional hazards two-sided p=0.4128). It is believed that the higher-risk-for-recurrence patients in the overall ITT were too sick to tolerate the extra three-weeks before surgery for the Multikine treatment and also that chemotherapy may impair Multikine’s immunological mechanism of action. Nearly Four-Year Median OS Benefit: In the Proposed Indication, the median OS for those receiving Multikine+CIZ was 101.7 months versus 55.2 months for the control, a survival improvement of almost four years. The Multikine treatment arm without CIZ in the Proposed Indication also had better median OS than control (68.2 months vs. 55.2 months). Progression-Free Survival (PFS): In the Proposed Indication, there was confirmatory PFS difference between the two main comparator groups (HR=0.76; proportional hazards two-sided p=0.0896). In the overall ITT population, there was no statistically significant PFS difference between the two main comparator groups (proportional hazards two-sided p=0.3728). Locoregional Control (LRC): In the Proposed Indication, there was no statistically significant LRC difference between the two main study groups (proportional hazards two-sided p=0.4082). In the overall ITT population, there was no statistically significant LRC difference between the two main comparator groups (proportional hazards two-sided p=0.8020). Significant Histopathological Results: OS, PFS, and LRC were examined using a proportional hazards model to assess the interactions between histopathology (HP) cellular marker expression levels, risk group (lower and higher), and treatment in the two main comparator groups. Twenty HP markers were classified as low, medium, and high. Two HP ratios were classified as low, medium, and high. Fourteen HP combinations were classified as low and high. These resulted in 94 possible comparisons for each of OS, PFS, and LRC. Significance favoring Multikine+CIZ vs. control (two-sided p<0.05) was observed in the Proposed Indication as follows: OS: 14 markers, 2 ratios, and 9 combinations; PFS: 11 markers, 1 ratio, and 5 combinations; LRC: 9 markers, 1 ratio, and 6 combinations; Combined (summed across endpoints), significance was reached for 21.6% (61/282) of the total possible comparisons, and the one-sided 97.5% confidence bound on the fraction significance was 16.3% which exceeds 5% chance alone.