| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Advanced Primary Sqamous Cell Carcinoma of the oral Cavity/Soft Palate |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to determine the efficacy of peri-tumoral and peri-lymphatic injection of Multikine plus CIZ given prior to Standard of Care (SOC) as measured by overall survival. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effects of Multikine plus CIZ treatment on the cumulative incidence of locoregional control, progression-free survival, tumor histopathology, and quality of life,
while confirming Multikine safety. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Genomic Microarray – A Stand Alone collaborative study (with the US NIH/NCI) that derives its samples from the subjects of this Phase III study to allow analysis of gene expression in the tumor samples. |
|
| E.3 | Principal inclusion criteria |
1. Previously untreated primary squamous cell carcinoma of the oral cavity inclusive of the tongue (but not the base of the tongue), floor of the mouth, cheek (buccal mucosa) and soft palate only, confirmed by biopsy, with or without regional lymph nodal metastases, deemed curable by and scheduled for definitive treatment by surgical resection and postoperative radiation therapy or surgical resection and postoperative concurrent chemoradiotherapy (standard of care).
Tumors in other locations (and those in other locations of the head and neck) are excluded.
- The primary tumor class must be T1, T2 or T3 and must NOT measure more than 6 cm in greatest dimension. T4 is allowed if invasion of the mandible is minimal (defined as <0.5cm as confirmed by CT, and/or MRI with the use of CT imaging being mandatory) and can be salvaged by marginal mandiblectomy (retention of function and having intact mandible post surgery).
- The class of clinically positive lymph node(s) must be N1 or N2 and must not measure more than 6 cm in greatest dimension.
- Clinical tumor stage must be III or IV. For stage IV, only subjects treatable by surgical resection or surgical resection followed by postoperative radiation/ radiochemotherapy are eligible:
Eligible TNM Categories:
T1 N1-2 M0
T2 N1-2 M0
T3 N0-2 M0
T4* N0-2, M0
* T4 is allowed if invasion of the mandible is minimal (defined as <0.5cm as confirmed by CT, and or MRI with CT imaging mandatory) and can be salvaged by marginal mandiblectomy (retention of function and having intact mandible post surgery).
2. Primary tumor and, if present, clinically positive lymph node(s) with at least one measurable lesion as defined by the RECIST criteria (Appendix 10) and measurable in two dimensions by physical examination.
3. ≥18 years of age.
4. If female, is neither pregnant nor lactating.
5. If subject is of reproductive potential they must be willing and able to utilize effective methods of contraception (e.g. barrier methods with spermicide).
6. Hemoglobin: >9gm/dL; WBC: > 3000/mm3; platelets: > 100,000/mm3, bilirubin < 1.0 mg/dL; creatinine < 1.2 mg/dL.
7. No prior therapy with IL-2, IL-1 or any other biological response modifier in past one year.
8. Negative reaction to intradermal test with ciprofloxacin (a fluoroquinolone antibiotic).
9. No immune depressive drugs, e.g., corticosteroids, cyclosporine, methotrexate, or anticancer agents, in past one year. Subjects on topical corticosteroids to treat dermatological conditions covering not more than 5% of body surface area are considered eligible.
10. Life expectancy greater than six months.
11. Karnofsky score 70 or greater.
12. Able to take oral medication.
13. Able to provide informed consent.
14. Must have normal immune function, i.e., must not be known to be HIV infected or have any other disease or condition causing significant immunodeficiency. |
|
| E.4 | Principal exclusion criteria |
1. Subjects other than those to be treated by surgery, followed by radiation therapy +/- chemotherapy.
2. Tumor invasion of bone as detected by a suitable imaging technique MRI and/or CT or by physical examination, except for mandibular invasion (as described above for T4 Tumor).
3. Any T1N0 or T2N0 stage tumors and all tumors classified as T4, N3 and/or any TN classification with M1 or greater (Note: only M0 is allowed in this study), or in locations other than those specified in Inclusion Criteria #1 (Section 4.1).
4. Active peptic ulcer disease despite ongoing adequate medical therapy.
5. Prior surgical resection of the jugular lymph nodes on the ipsilateral neck that the injection is to be administered.
6. Any acute or chronic viral, bacterial, immune or other disease in a stage usually associated with abnormal cellular immunity (e.g., HIV infection, hepatitis, nephritis, lung disease, rheumatoid arthritis or other autoimmune disease).
7. Subjects on hemodialysis or peritoneal dialysis.
8. Prior history of asthma.
9. Prior completion of one or more courses of therapeutic irradiation, excluding such treatment of the extremities.
10. History of allergic reaction to fluoroquinolone antibiotics (e.g., ciprofloxacin, ofloxacin).
11. History of any other malignancy, excluding basal cell carcinoma of the skin and in-situ carcinoma of the cervix.
12. History of congestive heart failure (CHF) and other heart conditions that in the opinion of the investigator would cause the subject to likely be unable to participate in the study or tolerate the study’s protocol regimen (including the surgical procedure).
13. The opinion of the investigator that the subject may be unable to tolerate the protocol regimen or that participation in the trial may compromise the subject’s preparation for tumor treatment .
14. Failure to meet the Inclusion Criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is Overall Survival. After Multikine injection (with or without Cyclophosphamide, Indomethacin and Zinc ) followed by Standard of Care treatment, subjects will be monitored on a regular basis by clinical and radiographic criteria and will be followed for 30-36 months after completion of study drug + Standard of Care until the required number of deaths are observed. The SOC group will also be followed. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
After Multikine injection (with or without CIZ) followed by SOC treatment, subjects will be monitored on a regular basis by clinical and radiographic criteria and will be followed for 30-36 months after
completion of study drug + SOC until the required number of deaths are observed. |
|
| E.5.2 | Secondary end point(s) |
1.Progression-free survival (defined as survival without tumor recurrence, new disease or distant metastases) and on the rate and distribution of distant metastases.
2.Disease progression defined as loco-regional failure, i.e. the reappearance (recurrence) of disease, progressive disease (but not distant metastases), or any new disease above the clavicle not present
at baseline.
3.Quality of life assessments on subjects receiving Multikine treatment and standard of care.
4.Histopathological nature of cellular tumor infiltration stimulated by Multikine injection. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study and until 3 years after the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of care + Cyclophosphamide, Indomethacin and Zinc (CIZ) |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belarus |
| Bosnia and Herzegovina |
| Canada |
| Croatia |
| France |
| Germany |
| Hungary |
| India |
| Israel |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient - last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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