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

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT01697800
• Collaborator: National Institute of Dental and Craniofacial Research (NIDCR) (NIH)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 22.4
• Patients Per Site Per Month: 1.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Squamous Cell Carcinoma	Drug: Tadalafil; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Tadalafil in Patients With Squamous Cell Carcinoma of the Upper Aero Digestive Tract
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jul 14, 2014
• Actual Study Completion Date: Jul 14, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment	Drug: Placebo
Active Comparator: 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	Drug: Tadalafil; Other Names: Cialis

Outcome Measures

Primary Outcome Measures

1. Change in Immune Response After Tadalafil Administration [Baseline and 120-150 Days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. Eastern Cooperative Oncology Group (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

1. 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 PDE5 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:

1. 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

1. History of any of the following coronary conditions within 90 days of planned tadalafil administration:

1. 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21231

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Institute of Dental and Craniofacial Research (NIDCR)

Investigators

• Principal Investigator: Zubair Khan, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01697800
• Other Study ID Numbers: J1247; 2P50DE019032; NA_00073880
• First Posted: Oct 2, 2012
• Last Update Posted: Feb 28, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Tadalafil

Study Results

Participant Flow

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment	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
Period Title: Overall Study
STARTED	15	25
COMPLETED	15	24
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo	Tadalafil	Total
Arm/Group Description	Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment	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	Total of all reporting groups
Overall Participants	15	25	40
Age, Customized (Count of Participants)
18-99 years	15 100%	25 100%	40 100%
Sex: Female, Male (Count of Participants)
Female	1 6.7%	2 8%	3 7.5%
Male	14 93.3%	23 92%	37 92.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 13.3%	4 16%	6 15%
White	13 86.7%	21 84%	34 85%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	15 100%	25 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Change in Immune Response After Tadalafil Administration
Time Frame	Baseline and 120-150 Days

Outcome Measure Data

Analysis Population Description

Blood samples were collected. However, the samples were not analyzed and hence no data were generated.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment	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
Measure Participants	0	0

Adverse Events

Arm/Group Title	Placebo		Tadalafil
Arm/Group Description	Patients received placebo capsules for 2 weeks prior to standard of care treatment and continued for 3 months post standard of care treatment		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
All Cause Mortality
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		1/25 (4%)
Serious Adverse Events
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.