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

NCT02544880 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 20140960
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Head and Neck Squamous Cell Carcinoma; Head and Neck Cancer

Keywords

HNSCC; Tadalafil; PDE5 Inhibition; Anti-MUC1 Vaccine; Recurrent Head and Neck Squamous Cell Carcinoma; Recurrent HNSCC; Second primary site disease stage III; Second primary site disease stage IV; Anti-Influenza Vaccine

Outcome Measures

Primary Outcomes (2)

• Phase 1 - Number of participants experiencing adverse events and/or treatment limiting-toxicities after receiving protocol therapy.

  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).

  Up to 2 Years

• Phase 2 - Rate of tumor-specific immune response to protocol therapy.

  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.

  Up to 3.5 years

Secondary Outcomes (2)

• 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

Study Arms (5)

Tadalafil plus Vaccine Group (Phase I)

EXPERIMENTAL

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.

Drug: Tadalafil; Biological: Anti-MUC1 Vaccine; Biological: Anti-Influenza Vaccine

Tadalafil plus Vaccine Group (Phase II)

EXPERIMENTAL

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.

Drug: Tadalafil; Biological: Anti-MUC1 Vaccine; Biological: Anti-Influenza Vaccine

Tadalafil plus Vaccine Placebo Group (Phase II)

EXPERIMENTAL

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.

Drug: Tadalafil; Other: Anti-MUC1 Vaccine Placebo; Other: Anti-Influenza Vaccine Placebo

Tadalafil Placebo plus Vaccine Group (Phase II)

EXPERIMENTAL

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.

Biological: Anti-MUC1 Vaccine; Biological: Anti-Influenza Vaccine; Other: Tadalafil Placebo

Control Group

OTHER

For eligible participants who opt out of receiving study intervention. Participants in this group will receive SOC treatment only.

Other: Standard of Care Treatment

Interventions

Tadalafil DRUG

Tadalafil tablets administered by mouth. Dose will be between 10 to 20 mg adjusted depending on patient's body weight. On course 1, Tadalafil will be administered daily for 19 consecutive days. On Course 2 through 4, Tadalafil will be administered daily for 14 consecutive days. No Tadalafil will be provided on Course 5.

Also known as: Cialis

Tadalafil plus Vaccine Group (Phase I); Tadalafil plus Vaccine Group (Phase II); Tadalafil plus Vaccine Placebo Group (Phase II)

Anti-MUC1 Vaccine BIOLOGICAL

300 uL Anti-MUC1 vaccine will be administered intramuscularly in the right upper limb. Anti-MUC1 vaccine will be administer on Day 7 on course 1, on Day 10 for courses 2 through 4 and on Day 1 on course 5.

Also known as: Hiltonol

Tadalafil Placebo plus Vaccine Group (Phase II); Tadalafil plus Vaccine Group (Phase I); Tadalafil plus Vaccine Group (Phase II)

Anti-Influenza Vaccine BIOLOGICAL

300 uL Anti-Influenza vaccine will be administered intramuscularly in the left upper limb. Anti-Influenza vaccine will be administer on Day 7 on course 1, on Day 10 for courses 2 through 4 and on Day 1 on course 5.

Also known as: Flublok

Tadalafil Placebo plus Vaccine Group (Phase II); Tadalafil plus Vaccine Group (Phase I); Tadalafil plus Vaccine Group (Phase II)

Tadalafil Placebo OTHER

Placebo tablets mimicking Tadalafil administered by mouth. On course 1, Tadalafil Placebo will be administered daily for 19 consecutive days. On Course 2 through 4, Tadalafil placebo will be administered daily for 14 consecutive days. No Tadalafil Placebo will be provided on Course 5.

Tadalafil Placebo plus Vaccine Group (Phase II)

Anti-MUC1 Vaccine Placebo OTHER

Placebo for Anti-MUC1 vaccine will be administered intramuscularly in the right upper limb. Placebo for Anti-MUC1 vaccine will be administer on Day 7 on course 1, on Day 10 for courses 2 through 4 and on Day 1 on course 5..

Tadalafil plus Vaccine Placebo Group (Phase II)

Standard of Care Treatment OTHER

Treatment according to prescribed standard of care regimen.

Control Group

Anti-Influenza Vaccine Placebo OTHER

Placebo for Anti-Influenza vaccine will be administered intramuscularly in the left upper limb. Placebo for Anti-Influenza vaccine will be administer on Day 7 on course 1, on Day 10 for courses 2 through 4 and on Day 1 on course 5.

Tadalafil plus Vaccine Placebo Group (Phase II)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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
• 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
• 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.

Sponsors & Collaborators

• Donald T. Weed, MD, FACS: lead

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

Location

Related Publications (1)

• Weed DT, Zilio S, Reis IM, Sargi Z, Abouyared M, Gomez-Fernandez CR, Civantos FJ, Rodriguez CP, Serafini P. The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial. Front Immunol. 2019 May 31;10:1206. doi: 10.3389/fimmu.2019.01206. eCollection 2019.

  PMID: 31214178 RESULT

Related Links

• The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms

Interventions

Tadalafil; poly ICLC; FluBlok

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Study Officials

• Donald T Weed, MD, FACS

  University of Miami

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 4, 2015
• First Posted: September 9, 2015
• Study Start: April 25, 2016
• Primary Completion: June 2, 2019
• Study Completion: June 8, 2021
• Last Updated: June 15, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)