PDE5 Inhibition Via Tadalafil (Cialis®) to Enhance Anti-Tumor MUC1 Vaccine Efficacy in Patients With Resectable, and Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma (HNSCC): A Phase I/II Clinical Trial
Overview
- Phase
- Phase 1
- Intervention
- Tadalafil
- Conditions
- Head and Neck Squamous Cell Carcinoma
- Sponsor
- Donald T. Weed, MD, FACS
- Enrollment
- 16
- Locations
- 1
- Primary Endpoint
- Phase 2 - Rate of tumor-specific immune response to protocol therapy.
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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.
Detailed 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.
Investigators
Donald T. Weed, MD, FACS
Professor
University of Miami
Eligibility Criteria
Inclusion Criteria
- •Biopsy-proven recurrent or second primary HNSCC of the oral cavity, oropharynx, hypopharynx or larynx (second primary includes unknown primary)
- •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.)
- •Surgically resectable, recurrent or second primary HNSCC
- •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
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 or equivalent scale score. See Appendix D for equivalent scale criteria.
- •Acceptable organ function as defined by all of the following:
- •Alkaline phosphatase \< 4.0 x upper limit of normal (ULN)
Exclusion Criteria
- •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
- •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).
- •Distant metastatic disease
- •Recurrent or second primary HNSCC of the nasopharynx, paranasal sinuses, or cervical esophagus
- •Use of Phosphodiesterase Type 5 (PDE5) inhibitors such as vardenafil (Levitra®), Tadalafil (Cialis®), and sildenafil citrate (Viagra®) ≤15-days prior to (intended) enrollment
- •Patients who have the intention to receive non-study PDE5 inhibitors and flu vaccination(s) anytime during the study will be excluded.
- •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
- •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
Arms & Interventions
Tadalafil plus Vaccine Group (Phase I)
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.
Intervention: Tadalafil
Tadalafil plus Vaccine Group (Phase I)
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.
Intervention: Anti-MUC1 Vaccine
Tadalafil plus Vaccine Group (Phase I)
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.
Intervention: Anti-Influenza Vaccine
Tadalafil plus Vaccine Group (Phase II)
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.
Intervention: Tadalafil
Tadalafil plus Vaccine Group (Phase II)
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.
Intervention: Anti-MUC1 Vaccine
Tadalafil plus Vaccine Group (Phase II)
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.
Intervention: Anti-Influenza Vaccine
Tadalafil plus Vaccine Placebo Group (Phase II)
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.
Intervention: Tadalafil
Tadalafil plus Vaccine Placebo Group (Phase II)
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.
Intervention: Anti-MUC1 Vaccine Placebo
Tadalafil plus Vaccine Placebo Group (Phase II)
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.
Intervention: Anti-Influenza Vaccine Placebo
Tadalafil Placebo plus Vaccine Group (Phase II)
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.
Intervention: Anti-MUC1 Vaccine
Tadalafil Placebo plus Vaccine Group (Phase II)
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.
Intervention: Anti-Influenza Vaccine
Tadalafil Placebo plus Vaccine Group (Phase II)
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.
Intervention: Tadalafil Placebo
Control Group
For eligible participants who opt out of receiving study intervention. Participants in this group will receive SOC treatment only.
Intervention: Standard of Care Treatment
Outcomes
Primary Outcomes
Phase 2 - Rate of tumor-specific immune response to protocol therapy.
Time Frame: Up to 3.5 years
The primary objective of phase II is to evaluate immune response (tumor-specific immune response of the anti- MUC1 and anti-influenza vaccines when combined with Tadalafil. Immune response will be evaluated by determining patients' immunological profile (e.g. peripheral blood mononuclear cells (PBMCs), leukocyte subsets, and serum cytokine levels) and immunological reactivity (e.g. through DTH skin test, T cell proliferation, by Enzyme-Linked ImmunoSpot (ELISPOT), specific Immunoglobulin G (IgG) concentration, and immune response by peripheral blood sera) before and after surgery, and during treatment with Tadalafil and the anti-MUC1 and anti-Influenza vaccines.
Phase 1 - Number of participants experiencing adverse events and/or treatment limiting-toxicities after receiving protocol therapy.
Time Frame: Up to 2 Years
The primary objective of the lead-in, open-label, single-arm, phase I part of study will evaluate the safety of Tadalafil in combination with anti-MUC1/anti-influenza vaccines (TV) in terms of adverse events (AEs), serious adverse events (SAEs) and treatment-limiting toxicities (TLTs).
Secondary Outcomes
- Phase 1 - Rate of tumor-specific immune response to protocol therapy.(Up to 2 years)
- Phase 1/2 - Rate of recurrence-free survival (RFS) in participants(Up to 3.5 years)