PDE5 Inhibition Via Tadalafil to Enhance Anti-Tumor Mucin 1 (MUC1) Vaccine Efficacy in Patients With HNSCC

The investigators will perform a phase I/II placebo-controlled clinical trial in patients
with HNSCC whose tumor has recurred, or secondary primary tumor is detected, post
conventional radiotherapy with or without prior surgery or chemotherapy. For these patients,
salvage surgery is the only standard curative therapeutic option, post-surgical recurrence
rate is high, and life expectancy is poor. Patients will be given Tadalafil (or Placebo) in
combination with vaccination (anti-MUC1 + anti-Influenza vaccines or placebos) prior to
surgery, and in 3 additional courses after surgery in combination with
anti-MUC1/anti-Influenza vaccines (or placebo vaccines). A final booster vaccination (with
anti-MUC1/anti-Influenza vaccines or placebo vaccines alone) will be administered
approximately one-year post salvage surgery. Response to treatment will include
antigen-specific immune response and characterization of the leukocytes subset. As a
secondary endpoint, tumor recurrence at 2 years will be evaluated to determine whether a
trend toward a beneficial prognosis might be observed in treated patients.

Eligible patients who are unwilling to receive study treatment but who undergo standard
curative resection and consent to be followed for recurrence-free survival (RFS) and/or to
donate specimens for correlative research studies (blood and/or tumor) will also be included
in all analyses as an additional non-randomized control group. These analyses may include all
blood tests obtained as for non-control patients at specified study intervals and DTH testing
as for non-control patients at specified intervals. Control group patients may elect to not
undergo blood tests and or DTH testing at any specified time interval at their discretion but
will continue to be followed for recurrence free survival.

Inclusion Criteria:

1. Biopsy-proven recurrent or second primary HNSCC of the oral cavity, oropharynx,
hypopharynx or larynx (second primary includes unknown primary)

2. Stage III or IV (AJCC, 7th ed., 2010) recurrent or second primary HNSCC (For recurrent
tumors, staging is determined by the recurrent stage, not by the original pretreatment
stage.)

3. Surgically resectable, recurrent or second primary HNSCC

4. Prior radiation, with or without prior surgery and/or chemotherapy, to the head and
neck for definitive treatment of HNSCC of the oral cavity, oropharynx, hypopharynx or
larynx with previously documented complete clinical or radiographic response to
initial treatment

- a. Prior radiation and any chemotherapy, must have been completed >4 months prior
to biopsy-proven recurrence or second primary site disease

- b. Recurrent or second primary HNSCC arises within the previously irradiated
field

5. Age ≥ 18 years

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 or
equivalent scale score. See Appendix D for equivalent scale criteria.

7. Acceptable organ function as defined by all of the following:

- Alkaline phosphatase < 4.0 x upper limit of normal (ULN)

- Aspartate transaminase (AST) ≤ 2.5 x ULN

- Alanine transaminase (ALT) ≤ 2.5 x ULN

- calculated Creatinine Clearance ≥ 51ml/min as determined by the Cockcroft-Gault
Equation:

- [(140-age) * (Weight in kg) * (0.85, if female)] / (72 * Cr)

8. Suitable venous access to allow for all study related blood sampling (safety and
research)

9. Ability to understand and willingness to sign the written informed consent and Health
Insurance Portability and Accountability Act (HIPAA) document/s.

Inclusion Criteria (non-randomized control)

1. Biopsy-proven recurrent or second primary HNSCC of the oral cavity, oropharynx,
hypopharynx or larynx (second primary includes unknown primary)

2. Stage III or IV (AJCC, 7th ed., 2010) recurrent or second primary HNSCC (For recurrent
tumors, staging is determined by the recurrent stage, not by the original pretreatment
stage.)

3. Surgically resectable, recurrent or second primary HNSCC

4. Prior radiation with or without prior surgery and/or chemotherapy, to the head and
neck for definitive treatment of HNSCC of the oral cavity, oropharynx, hypopharynx or
larynx with previously documented complete clinical or radiographic response to
initial treatment

- a. Prior radiation and any chemotherapy, must have been completed >4 months prior
to biopsy-proven recurrence or second primary site disease

- b. Recurrent or second primary HNSCC arises within the previously irradiated
field

5. Age ≥18 years

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 or
equivalent scale score.

7. Suitable venous access to allow for all study related blood sampling (safety and
research)

8. Ability to understand and willingness to sign the written informed consent and HIPAA
document/s.

Exclusion Criteria:

1. Salvage surgery is not recommended as per National Comprehensive Cancer Network (NCCN)
guidelines, or after multidisciplinary treatment evaluation, including those with
surgically unresectable disease at primary site or regional lymph nodes

2. Recurrent or second primary AJCC Stage I or II HNSCC (for recurrent tumors, staging is
determined by the recurrent stage, not by the original pretreatment stage).

3. Distant metastatic disease

4. Recurrent or second primary HNSCC of the nasopharynx, paranasal sinuses, or cervical
esophagus

5. Use of Phosphodiesterase Type 5 (PDE5) inhibitors such as vardenafil (Levitra®),
Tadalafil (Cialis®), and sildenafil citrate (Viagra®) ≤15-days prior to (intended)
enrollment

6. Patients who have the intention to receive non-study PDE5 inhibitors and flu
vaccination(s) anytime during the study will be excluded.

7. Prior or known adverse reactions to PDE5 inhibitors, poly-ICLC (Hiltonol®), and prior
dose(s) of Influenza vaccine including but not limited to their components

8. History of severe or unstable cardiac or cerebrovascular disease:

- a. Myocardial infarction within the last 90 days

- b. Unstable angina or angina occurring during sexual intercourse

- c. New York Heart Association (NYHA) Class 2 or greater heart failure in the last
3 months.

- d. Uncontrolled arrhythmias

- e. Sustained hypotension (<90/50 mmHg) or uncontrolled Hypertension (>170/100
mmHg)

- f. Stroke within the last 6 months

9. Therapy with nitrates, alpha-blockers, or cytochrome P450 (CYP3A4) inhibitors within
7-days prior to study treatment initiation and for whom stopping is unsafe and/or a
safe substitute is not medically recommended. Some examples are provided in Appendix
A.

10. Positive Antinuclear Antibody Test (ANA)

11. Immunosuppression or immunocompromised for reasons not directly related to patient's
malignancy (e.g. HIV or kidney transplant)

12. History of severe or life threatening autoimmune diseases [Exceptions: Mild autoimmune
diseases determined at the discretion of the Investigator(s), e.g. psoriasis.]

13. Unilateral blindness, hereditary retinal disorders, or at an increased risk of
blindness

14. Unilateral deafness, or severe hearing loss dependent upon hearing aid(s) for
serviceable communication

15. Female patients who are pregnant or breastfeeding. (Females of childbearing potential
are required to have a negative urine β-human chorionic gonadotropin (β-hCG) pregnancy
test result obtained during screening; pregnancy testing is not required for
post-menopausal or surgically sterilized women.)

16. Females of childbearing potential who refuse to practice effective methods of
contraception or abstain from heterosexual intercourse from the time of signing the
informed consent through 30-days after the last vaccination.

17. Serious medical or psychiatric illness/condition, including alcohol or drug abuse
likely in the judgment of the Investigator(s) to interfere with compliance to protocol
treatment/research.

18. Patients of vulnerable populations such as children less than 18 years of age,
prisoners, institutionalized individuals or others likely to be vulnerable are not
eligible for participation in this study.

Exclusion Criteria (non-randomized control)

1. Salvage surgery is not recommended as per NCCN guidelines, or after multidisciplinary
treatment evaluation, including those with surgically unresectable disease at primary
site or regional lymph nodes

2. Recurrent or second primary AJCC Stage I or II HNSCC (for recurrent tumors, staging is
determined by the recurrent stage, not by the original pretreatment stage).

3. Distant metastatic disease

4. Recurrent or second primary HNSCC of the nasopharynx, paranasal sinuses, or cervical
esophagus

5. Use of PDE5 inhibitors such as vardenafil (Levitra®), Tadalafil (Cialis®), and
sildenafil citrate (Viagra®) ≤15-days prior to (intended) enrollment

6. Patients who have the intention to receive non-study PDE5 inhibitors and flu
vaccination(s) anytime during the study will be excluded.

7. Positive Antinuclear Antibody Test (ANA)

8. Immunosuppression or immunocompromised for reasons not directly related to patient's
malignancy (e.g. HIV or kidney transplant)

9. History of severe or life threatening autoimmune diseases [Exceptions: Mild autoimmune
diseases determined at the discretion of the Investigator(s), e.g. psoriasis.]