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

D

Donald T. Weed, MD, FACS

Status and phase

Completed
Phase 1

Conditions

Head and Neck Cancer
Head and Neck Squamous Cell Carcinoma

Treatments

Other: Anti-Influenza Vaccine Placebo
Biological: Anti-Influenza Vaccine
Other: Standard of Care Treatment
Drug: Tadalafil
Other: Tadalafil Placebo
Other: Anti-MUC1 Vaccine Placebo
Biological: Anti-MUC1 Vaccine

Study type

Interventional

Funder types

Other

Identifiers

NCT02544880
20140960

Details and patient eligibility

About

The investigators hypothesize that Tadalafil treatment, by lowering Myeloid Derived Suppressor Cells (MDSCs) and regulatory T cells (Tregs), can prime an antitumor immune response and promote a permissive environment that should increase the efficacy of anti-tumor vaccine in a setting of minimal residual disease.

Full description

This study is halting accrual at the end of the phase 1 portion of the study as data from the phase I study suggest that an alternative approach for the phase 2 portion of the study be undertaken. A newly designed Phase II trial is being developed and will be submitted as a new study protocol.

Enrollment

16 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.]

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Double Blind

16 participants in 5 patient groups

Tadalafil plus Vaccine Group (Phase I)
Experimental group
Description:
The first 6 participants will be enrolled in the open label Phase I portion of the study and will receive Tadalafil, Anti-mucin 1 (MUC1) Vaccine and the Anti-Influenza Vaccine for 5 courses. A standard of care (SOC) tumor removal surgery will be completed after the completion of Course 1. Course 2 will resume 5-8 weeks after completion of SOC tumor removal surgery.
Treatment:
Biological: Anti-MUC1 Vaccine
Drug: Tadalafil
Biological: Anti-Influenza Vaccine
Tadalafil plus Vaccine Group (Phase II)
Experimental group
Description:
After completion of the Phase I portion of the study, new participants will be enrolled for the randomized, placebo-controlled Phase II. Participants randomized in this group will receive Tadalafil, Anti-MUC1 Vaccine and the Anti-Influenza Vaccine for 5 courses. A standard of care (SOC) tumor removal surgery will be completed after the completion of Course 1. Course 2 will resume 5-8 weeks after completion of SOC tumor removal surgery.
Treatment:
Biological: Anti-MUC1 Vaccine
Drug: Tadalafil
Biological: Anti-Influenza Vaccine
Tadalafil plus Vaccine Placebo Group (Phase II)
Experimental group
Description:
After completion of the Phase I portion of the study, new participants will be enrolled for the randomized, placebo-controlled Phase II. Participants randomized in this group will receive Tadalafil, placebo for the Anti-MUC1 Vaccine and placebo for the Anti-Influenza Vaccine for 5 courses. A standard of care (SOC) tumor removal surgery will be completed after the completion of Course 1. Course 2 will resume 5-8 weeks after completion of SOC tumor removal surgery.
Treatment:
Other: Anti-Influenza Vaccine Placebo
Drug: Tadalafil
Other: Anti-MUC1 Vaccine Placebo
Tadalafil Placebo plus Vaccine Group (Phase II)
Experimental group
Description:
After completion of the Phase I portion of the study, new participants will be enrolled for the randomized, placebo-controlled Phase II. Participants randomized in this group will receive placebo for Tadalafil, the Anti-MUC1 Vaccine and the Anti-Influenza Vaccine for 5 courses. A standard of care (SOC) tumor removal surgery will be completed after the completion of Course 1. Course 2 will resume 5-8 weeks after completion of SOC tumor removal surgery.
Treatment:
Biological: Anti-MUC1 Vaccine
Other: Tadalafil Placebo
Biological: Anti-Influenza Vaccine
Control Group
Other group
Description:
For eligible participants who opt out of receiving study intervention. Participants in this group will receive SOC treatment only.
Treatment:
Other: Standard of Care Treatment

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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