Trial Title:
Tadalafil Effect + Chemotherapy in Resectable Gastric/GEJ Cancer
NCT ID:
NCT05709574
Condition:
Gastric Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Tadalafil
Conditions: Keywords:
PDE5,6i inhibitor
chemotherapeutic cell death
resectable Gastric/GEJ cancer
tadalafil
FLOT chemotherapy
Myeloid Derived Suppressor Cells (MDSCs)
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Tadalafil 20 MG
Description:
Tadalafil 20 mg tablets will be taken daily for 2 weeks alone and then for 8 weeks in
combination with neoadjuvant chemotherapy in the window between gastric/GEJ
adenocarcinoma diagnosis and interventional surgery.
Arm group label:
Tadalafil + chemotherapy
Other name:
Cialis
Summary:
The goal of this clinical trial is to assess the ability of Tadalafil alone and in
combination with neoadjuvant FLOT (5-Fluorouracil, Oxaliplatin, and Docetaxel)
chemotherapy to suppress myeloid derived suppressor cells (MDSCs) in patients with
resectable gastric or gastroesophageal junction adenocarcinoma. Resectable means the
tumor may be removed through surgical intervention. Neoadjuvant chemotherapy is
chemotherapy received before the primary course of treatment i.e.surgical intervention.
The main questions it aims to answer are:
- Is Tadalafil treatment with FLOT feasible and safe?
- How does tadalafil treatment with FLOT affect the tumor microenvironment (TME)?
- Will 8 weeks of neoadjuvant exposure to tadalafil with chemotherapy reduce MDSCs in
the TME?
Participants will receive Tadalafil for 14 days followed by combination of Tadalafil +
FLOT for approximately 8 weeks as a part of standard of care neoadjuvant treatment in the
window between cancer diagnosis and surgical intervention to remove their tumor. Tumor
tissue, blood, and urine will be collected at the start of the study, after 2 weeks of
treatment with Tadalafil alone, and around the time of surgical intervention. Saliva will
also be collected at the start of the study.
Detailed description:
Despite the availability of multimodality approaches for localized gastric cancer, the
survival rates remain dismal for resectable disease. There is a large unmet need to
identify new therapeutic options, to be used in combination with chemotherapy and to
improve survival outcomes. Emerging data have shown the implication of myeloid derived
suppressor cells (MDSCs) in the alteration of tumor microenvironment. The MDSCs are
involved in tumor progression by promoting immune suppression, tumor angiogenesis, drug
resistance, tumor metastasis and limiting the effects of cancer immunotherapy. In vitro
and animal studies have demonstrated that phosphodiesterase 5 inhibitors (PDE5i) such as
Sildenafil or Tadalafil inhibit MDSCs, augment the endogenous antitumor immunity and
improve the effectiveness of chemotherapy. There have been similar reports of enhanced
chemotherapeutic efficacy with PDE5i in murine models of melanoma, multiple myeloma,
lung, breast, head and neck, colorectal and brain cancer. PDE5 inhibitors suppress nitric
oxide synthetase (Nos)-expressing myeloid derived stem cells (MDSCs). There have been no
prior clinical studies using a PDE5,6 inhibitor to enhance chemotherapeutic cell death in
the upper gastrointestinal cancers. Therefore, the investigators propose this trial to
study the effect of the long-acting PDE5,6i Tadalafil in combination with chemotherapy
(FLOT) in resectable Gastric/GEJ cancers.
This is a single arm, phase II, window trial to assess the ability of Tadalafil to
suppress MDSCs as monotherapy and in combination with neoadjuvant FLOT chemotherapy in
patients with resectable gastric or gastroesophageal junction adenocarcinoma.
The study will enroll 10 patients. Patients will receive Tadalafil for 14 days followed
by combination of Tadalafil + FLOT for approximately 8 weeks as a part of standard of
care neoadjuvant treatment. Tumor specimens, blood, and urine will be collected at
baseline, after 2 weeks of monotherapy treatment with Tadalafil, and around the time of
surgical intervention to analyze the tumor microenvironment (TME) and to determine
whether PDE5, 6 inhibition reduces the immune suppressive microenvironment. Saliva will
also be collected at baseline.
Hypothesis: The investigators hypothesize that daily dosing of Tadalafil with
chemotherapy will significantly reduce myeloid-derived suppressor cells (MDSCs) in the
TME.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Stage I-III (T1-3Nx) Gastric or GEJ (Siewert 3) adenocarcinoma, confirmed by
histology or cytology.
2. Radiographically measurable disease by Response Evaluation Criteria in Solid Tumors
version 1.1 (RECIST 1.1). Images (MRI or CT scan) must be completed within 28 days
prior to treatment start.
3. Age ≥ 18 years.
4. Adequate organ and marrow function, based upon meeting all of the following
laboratory criteria within 14 days before first dose of study treatment:
1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte
colony-stimulating factor support within 2 weeks.
2. White blood cell count ≥ 2500/µL including Lymphocyte count ≥ to 500/µL.
3. Platelets ≥ 100,000/µL without transfusion.
4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN) with the following
exceptions: Patients with documented liver metastases: AST and ALT ≤ 5 x ULN.
Patients with documented liver or bone metastases: ALP ≤ 5 x ULN.
6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).
7. Serum albumin ≥ 2.8 g/dl.
8. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN.
9. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min
using the Cockcroft- Gault equation:
- Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)
- Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] ×
0.85
5. ECOG performance status ≤ 1.
6. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 6 months after the last dose of study treatment.
7. Female subjects of childbearing potential must not be pregnant at screening. Female
subjects are considered to be of childbearing potential unless one of the following
criteria are met: documented permanent sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or documented postmenopausal status
(defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of
other biological or physiological causes. Note: Documentation may include review of
medical records, medical examinations, or medical history interview by study site.
8. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
1. Prior treatment for gastric cancer.
2. Prior treatment with Tadalafil or other PDE inhibitors within 28 days.
3. Known metastatic disease.
4. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
a) Cardiovascular disorders: i. Congestive heart failure New York Heart Association
Class II-IV, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. iii.
Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or
other ischemic event, or thromboembolic event (e.g., deep venous thrombosis,
pulmonary embolism) within 6 months before first dose of study treatment. iv.
Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are
allowed if stable, asymptomatic, and treated with a stable dose of permitted
anticoagulation (see exclusion criterion #6) for at least 1 week before first dose
of study treatment. v. Ventricular tachyarrhythmia requiring ongoing treatment vi.
Unstable angina pectoris vii. Sinus bradycardia b) Gastrointestinal (GI) disorders
including those associated with a high risk of perforation or fistula formation: i.
The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute
obstruction of the pancreatic duct or common bile duct, or gastric outlet
obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or
intra-abdominal abscess within 6 months before first dose of study treatment. iii.
Note: Complete healing of an intra-abdominal abscess must be confirmed before first
dose of study treatment.
5. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis (see Appendix III for a more comprehensive list of
autoimmune diseases and immune deficiencies), with the following exceptions:
1. Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met: i. Rash must cover < 10% of body surface area. ii. Disease is well
controlled at baseline and requires only low-potency topical corticosteroids.
iii. No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the
previous 12 months.
6. Active infection requiring systemic treatment with the following exceptions:
1. Urinary tract infections.
2. HCV on active treatment.
7. Patients with SARS-COV-2 infections with the following exceptions:
a) Recovery from active symptoms 30 days prior to treatment start.
8. Known history of infection with human immunodeficiency virus (HIV) or acquired
immunodeficiency syndrome (AIDS)-related illness, or a known positive test for
tuberculosis due to tuberculosis infection.
9. Concomitant medication uses of nitrates, α-blockers and other interacting
medications (CYP3A4 inhibitors and CYP3A4 inductors).
10. Other clinically significant disorders as deemed by the investigator, that would
preclude safe study participation.
1. Serious non-healing wound/ulcer/bone fracture.
2. Uncompensated/symptomatic hypothyroidism.
3. Moderate to severe hepatic impairment.
11. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of
brain metastasis) within 2 weeks before first dose of study treatment. Subjects must
have complete wound healing from major surgery or minor surgery before first dose of
study treatment. Subjects with clinically relevant ongoing complications from prior
surgery are not eligible.
12. Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study
treatment, with the following exceptions:
1. Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are eligible for the study after
Principal Investigator confirmation has been obtained.
2. Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study.
13. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
of within 6 months after the final dose of study treatment. Women of childbearing
potential must have a negative serum pregnancy test result within screening. Test
will need to be repeated if last completed >3 days prior to initiation of study
treatment.
14. Inability to swallow tablets.
15. Previously identified allergy or hypersensitivity to components of the study
treatment formulations.
16. Previous episode of Non-arteritic anterior ischemic optic neuropathy (NAION)
17. Any other active malignancy at time of first dose of study treatment or diagnosis of
another malignancy within 3 years prior to first dose of study treatment that
requires active treatment, except for locally curable cancers that have been
apparently cured, such as basal or squamous cell skin cancer, superficial bladder
cancer, or carcinoma in situ of the prostate, cervix, or breast.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Arizona Cancer Center at UMC North/University Medical Center
Address:
City:
Tucson
Zip:
85719
Country:
United States
Status:
Recruiting
Contact:
Last name:
Junaid Arshad, MD
Phone:
520-694-2873
Email:
junaidarshad@arizona.edu
Contact backup:
Last name:
Prisca Zimmerman
Phone:
520-626-8286
Email:
priscaz@arizona.edu
Investigator:
Last name:
Junaid Arshad, MD
Email:
Principal Investigator
Start date:
April 20, 2023
Completion date:
May 2025
Lead sponsor:
Agency:
University of Arizona
Agency class:
Other
Source:
University of Arizona
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05709574
