A Phase II Trial of Tadalafil in Patients With Squamous Cell Carcinoma of the Upper Aero Digestive Tract

Phase 2

Completed

Conditions: Head and Neck Squamous Cell Carcinoma

Interventions: Drug: Placebo
Drug: Tadalafil

Registration Number: NCT01697800

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary: Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year survival estimates of approximately 50%, and is associated with a high rate of systemic immune impairment as well as evasion of a tumor specific immune response. Preclinical and clinical data have shown that phosphodiesterase 5 (PDE5) inhibitors (tadalafil) can be used to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid derived suppressor cells (MDSCs).

A multi site phase II, randomized, prospective, biomarker endpoint trial to determine optimum timing and design of PDE5 antitumor immunotherapy (tadalafil) in conjunction with conventional therapy for HNSCC.

40 patients with biopsy proven HNSCC will be randomized to receive tadalafil (n=25) or placebo (n=15) for at least 10-14 days before starting conventional therapy and continuing until 90 days after completion of conventional therapy. Tumor-specific T cell responses will be assessed using HNSCC cell lines, in blood collected before initiation of tadalafil/placebo and at 60 and 90 days after completion of conventional therapy. Number and function of MDSC and Treg cells will be assessed before and at 60 and 90 days after completion of conventional therapy. Prevnar 13® vaccine will be administered 10-14 days after commencing tadalafil/placebo (before conventional therapy begins) and again at 60 days after completion of conventional therapy. Vaccine-specific responses assessed at 60 and 90 days post-conventional therapy will be used to measure the ability of tadalafil to augment immune response to vaccine.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Age ≥21 years
Histologically confirmed, previously untreated invasive head and neck squamous cell carcinoma OR histologically confirmed not yet treated recurrent head and neck squamous cell carcinoma (must be at least 3 months after diagnosis and completion of treatment for primary disease or last recurrence). Patients may have local Stage I or II, or locoregionally advanced HNSCC Stage III or IV of the oral cavity, oropharynx, larynx, hypopharynx, or unknown primary, but no metastatic disease; Intent to treat with primary radiotherapy +/-chemotherapy
Disease location amenable to biopsy in outpatient clinical setting or operative biopsy within routine accepted schedule and practice of clinical care
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Required laboratory data (to be obtained within 2 weeks of initiation):
- Platelets > 75,000/mm³
- Calculated Creatinine Clearance (CRCL)> 60 mL/min
- Total serum bilirubin < 1.5 mg/dL
Willingness and ability to give signed written informed consent.

Exclusion Criteria

Medical contraindication to biopsy of target lesion
Intercurrent illness likely to prevent protocol therapy or conventional planned therapy
Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or greater
Known severe hypersensitivity to tadalafil or any of the excipients of this product
Current treatment with nitrates
Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such as ketoconazole or ritonavir
History of hypotension and/or blindness during prior treatment with tadalafil or other PDE5 inhibitors
Prior history of non-arterial ischemic optic retinopathy
Prior adverse reaction to diphtheria vaccine
Pregnant or breastfeeding; a negative pregnancy test is required within 14 days of randomization for all women of childbearing potential.
Concurrent malignancy or a history of previous malignancy treated with curative therapy within the last 3 months (other than squamous/basal cell cancer of the skin or cervical cancer), for which the survival prognosis is < 5 years
Treatment with a non-approved or investigational drug within 30 days before visit 1
Incomplete healing from previous oncologic or other major surgery
As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)
Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the trial
History of significant hypotensive episode requiring hospitalization
History of acute myocardial infarction within prior 3 months, uncontrolled angina, uncontrolled arrhythmia, or uncontrolled congestive heart failure
History of any of the following cardiac conditions:

I. Angina requiring treatment with long-acting nitrates II. Angina requiring treatment with short-acting nitrates within 90 days of planned tadalafil administration III. Unstable angina within 90 days of visit 1 (Braunwald 1989) IV. Positive cardiac stress test without documented evidence of subsequent, effective cardiac intervention
History of any of the following coronary conditions within 90 days of planned tadalafil administration:

I. Myocardial Infarction II. Coronary artery bypass graft surgery III. Percutaneous coronary intervention (for example, angioplasty or stent placement) IV. Any evidence of heart disease (NYHA≥Class III as defined in Protocol Attachment LVHG.3) within 6 months of planned tadalafil administration
Prior chronic immune suppressive state (AIDS, immunosuppressive therapy)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment
Tadalafil	Tadalafil	Patients received 20 mg tadalafil capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment

Primary Outcome Measures