Four Doses of MAGE Vaccine for Patients With Squamous Cell Carcinoma of the Head and Neck

Squamous Cell Carcinoma of the Head and Neck (SCCHN) effects 43,000 individuals in the United States annually with an estimated overall survival of 50%. For some patients who develop local or distant metastases following primary therapy, surgery is not an option.

This study is being done to test the safety of experimental cancer vaccines made of MAGE-A3 and HPV-16 antigens. We also hope to learn what doses of the vaccine will best stimulate the immune system.

There will be 2 cohorts in this study, based on the results of tumor testing:

Cohort 1: Patients with tumor that is HPV 16 positive

Cohort 2: Patients with tumor that is MAGE-A3 positive

The doses of vaccine in both cohorts will be 500, 1000, or 1500 micrograms depending on when the patient is enrolled in the trial. Each vaccine treatment is every 2 weeks for 8 weeks, for a total of 4 vaccines doses.

Tests performed during this phase will assess the potential patients eligibility to participate in this study. The following will occur at this visit: 1. Review and completion of Health Insurance Portability and Accountability Act (HIPAA) consent and protocol informed consent documents Assessment of inclusion/ exclusion criteria Demographics and descriptive factors Physical examination Medical history Vital signs (blood pressure [BP], pulse rate, body temperature, body weight and heart rate.) Hematology Chemistry Thyroid-stimulating hormone (TSH) CT/PET Tumor biopsy to determine MAGE-A3 AND HPV 16 expression. Blood draw for HLA typing Concomitant medication recording Quality of Life (QOL) and Eastern Cooperative Toxicity Group (ECOG) status Serum pregnancy test Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan. Prior to study enrollment, patients are to be seen by the Medical Oncologist and Surgical Oncologist. A consensus will be reached that the patient is or is not a suitable candidate for this trial based upon the Inclusion and Exclusion criteria. If after the Screening of a potential study subject for eligibility the subject does not meet eligibility requirements, he or she will not be enrolled into the study, after consensus is made by the aforementioned physicians. The blood and tissue specimens obtained by the screened but ineligible subject will be stored for subsequent analysis. If during the Screening Process the patient is unable to continue with Screening due to an illness, a family matter or other personal matter beyond that individuals control, and falls out of the Screening timeframe of 30 days as stated in the protocol, that patient can be re-screened at a later date if the individual wishes. In this case, the patient will be re-consented and re-screened.

TREATMENT PHASE

Day 1, Treatment #1 The following will occur at this visit:

Assessment of Inclusion/ Exclusion Criteria (these will be reassessed prior to the first vaccination to ensure patient eligibility) Physical examination Hematology and chemistry (obtained 24 hours prior to visit) Concomitant medication recording Adverse event recording QOL and ECOG status Serum pregnancy test (obtained 24 hours prior to visit) Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan Review patient diary Administer vaccine treatment #1 Vital signs (BP, pulse rate, body temperature, body weight and heart rate.) evaluated pre dose and 0.5, 1, 2 and 4 hrs post-dose Evaluate injection site, evaluated immediately post-injection, 0.5, 1, 2 and 4 hrs post-dose

Day 15, Treatment #2 (+/-3 days) The following will occur at this visit:

Physical examination Adverse event recording QOL and ECOG status Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan Review patient diary Administer vaccine treatment #2 Vital signs (BP, pulse rate, body temperature, body weight and heart rate.) evaluated pre dose and 0.5, 1, 2 and 4 hrs post-dose Evaluate injection site, evaluated immediately post-injection, 0.5, 1, 2 and 4 hrs post-dose

Day 29, Treatment #3 (+/-3 days) The following will occur at this visit:

Physical examination Chemistry (obtained 24 hours prior to visit) Concomitant medication recording Adverse event recording QOL and ECOG status Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan Review patient diary Administer vaccine treatment #3 Vital signs (BP, pulse rate, body temperature, body weight and heart rate.) evaluated pre dose and 0.5, 1, 2 and 4 hrs post-dose Concomitant medication recording Evaluate injection site, evaluated immediately post-injection, 0.5, 1, 2 and 4 hrs post-dose

Day 43, Treatment #4 (+/-3 days) The following will occur at this visit:

Physical examination Adverse event recording QOL and ECOG status Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan Review patient diary Administer vaccine treatment #4 Vital signs (BP, pulse rate, body temperature, body weight and heart rate.) evaluated pre dose and 0.5, 1, 2 and 4 hrs post-dose Concomitant medication recording Evaluate injection site, evaluated immediately post-injection, 0.5, 1, 2 and 4 hrs post-dose

POST-TREATMENT PHASE

Post-Treatment Phase, Follow Up, Day 57 (+/- 3days) The following will occur at this visit:

Physical examination Vital signs Tumor biopsy (unless in the view of the PI no tumor site is safely amenable for biopsy) Concomitant medication recording Adverse event recording QOL and ECOG status Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan Review patient diary

Post- Treatment Phase, Month 3 through Month 24/ End of Study Follow Up (+/-7 days) The following will occur at these visits:

Physical examination Vital signs Hematology Chemistry Concomitant medication recording Adverse event recording QOL and ECOG status Physical tumor measurements. Immune response blood draw (ELISPOT, recall assays, restimulation assays, tetramers, sequencing of MAGE-A3 and HPV 16- specific DNA, antigenic profiling) Review contraceptive plan Review patient diary

• Squamous Cell Carcinoma
• Head and Neck Cancer

• Experimental: Cohort 1
  Patients with tumor that is HPV 16 positive
  Intervention: Biological: MAGE-A3 HPV-16 vaccine
• Experimental: Cohort 2
  Patients with tumor that is MAGE-A3 positive
  Intervention: Biological: MAGE-A3 HPV-16 vaccine

Inclusion Criteria:

1. Age 18 or older.
2. Biopsy proven progressive, recurrent (post-surgical, radiation therapy, chemotherapy, combination therapy), or metastatic SCC of the head and neck which, in the judgment of the attending physician, is incurable by standard treatment modalities, OR Biopsy proven SCC which the patient is unwilling to have treated with surgery, chemotherapy or radiation therapy.

3. One or more of the following:

   • MAGE-A3 positive tumor
   • HPV 16 positive tumor.

4. Laboratory values obtained ≤30days prior to registration:

   • Alkaline phosphatase ≤3 x upper normal limit (UNL)
   • AST ≤3 x UNL
   • Creatinine ≤1.5 x UNL
   • Hemoglobin ≥9.0 g/dL
   • Albumin ≥3 mg/dL
5. The subject must be capable of understanding the investigational nature, potential risks and benefits of the study and capable of providing valid informed consent.
6. The subject must be willing to return to the University of Maryland Medical center for treatment and study-related follow up procedures including blood and tumor collections and completion of imaging studies as required by the protocol.
7. Life expectancy 6 months or greater (in the judgment of the Medical Oncologist/Co-Investigator).
8. Tumor that is biopsy accessible and measurable. This includes, but is not limited to, open biopsy, endoscopic biopsy, image guided biopsy, core biopsy and fine needle aspiration.

Exclusion Criteria:

1. ECOG performance status 3 or 4.

2. Any of the following:

   • Known HIV infection,
   • Other circumstances (i.e. concurrent use of systemic immunosuppressants and immunocompromising condition) that in the opinion of the physician renders the patient a poor candidate for this trial.
   • Patients with ANY malignant or metastatic SCC mass or lesion within the Central Nervous System (CNS). (e.g. intraparenchymal - brain, intracordal / spinal canal, bony masses or lesions with extension into the CNS parenchyma)
   • Patients with ANY malignant or metastatic SCC mass or lesion or a volume of a mass or lesion in a location that in the judgment of the investigator may significantly impair the health of or threaten the patient's life, should an Inflammatory Response occur.

3. Any of the following prior therapies:

   • Chemotherapy < 4 weeks from the date of first vaccination
   • Immunotherapy < 4 weeks from the date of first vaccination
   • Biologic therapy < 4 weeks from the date of first vaccination
   • Radiation therapy < 4 weeks from the date of first vaccination

4. Any of the following:

   • Pregnant women
   • Nursing women unwilling to stop breastfeeding
   • Men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], or abstinence, etc.).

   NOTE: This study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown.

5. Other concurrent chemotherapy, immunotherapy, radiotherapy, device, or any ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation).

6. Either of the following:

   • Other active cancer requiring therapy to control the disease
   • History of other malignancy (i.e. excluding disease under study) ≤3 years. Exceptions to the above include: adequately treated basal cell or squamous cell skin cancer, prostate cancer.