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



Status:Active, not recruiting
Conditions:Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:21 - 99
Updated:1/16/2019
Start Date:September 2012
End Date:December 2019

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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 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.


Inclusion Criteria:

1. Age ≥21 years

2. 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

3. Disease location amenable to biopsy in outpatient clinical setting or operative biopsy
within routine accepted schedule and practice of clinical care

4. ECOG performance status 0-1

5. 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

6. Willingness and ability to give signed written informed consent.

Exclusion Criteria:

1. Medical contraindication to biopsy of target lesion

2. Intercurrent illness likely to prevent protocol therapy or conventional planned
therapy

3. Prior daily use of tadalafil or other long-acting PDE5 inhibitors for one month or
greater

4. Known severe hypersensitivity to tadalafil or any of the excipients of this product

5. Current treatment with nitrates

6. Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor such
as ketoconazole or ritonavir

7. History of hypotension and/or blindness during prior treatment with tadalafil or other
PDE-5 inhibitors

8. Prior history of non-arterial ischemic optic retinopathy

9. Prior adverse reaction to diphtheria vaccine

10. Pregnant or breastfeeding; a negative pregnancy test is required within 14 days of
randomization for all women of childbearing potential.

11. 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

12. Treatment with a non-approved or investigational drug within 30 days before visit 1

13. Incomplete healing from previous oncologic or other major surgery

14. As judged by the investigator, any evidence of severe or uncontrolled systemic disease
(e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)

15. Evidence of any other significant clinical disorder or laboratory finding that makes
it undesirable for the subject to participate in the trial

16. History of significant hypotensive episode requiring hospitalization

17. History of acute myocardial infarction within prior 3 months, uncontrolled angina,
uncontrolled arrhythmia, or uncontrolled congestive heart failure

18. 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

19. 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

20. Prior chronic immune suppressive state (AIDS, immunosuppressive therapy)
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