RECRUITING

Tadalafil Effect + Chemotherapy in Resectable Gastric/GEJ Cancer

Conditions

Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma PDE5,6i inhibitor chemotherapeutic cell death resectable Gastric/GEJ cancer tadalafil FLOT chemotherapy Myeloid Derived Suppressor Cells (MDSCs)

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

An Open-Label, Phase II Single-Arm, Window Trial of Tadalafil Effect + Chemotherapy in Patients With Resectable Gastric/GEJ Adenocarcinoma

Quick Facts

Study Start:2023-04-20

Study Completion:2025-05

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05709574

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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.	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: 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. 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: 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.

Inclusion Criteria

Exclusion 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.

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:
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.
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:
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.

Contacts and Locations

Study Contact

Prisca Zimmerman

CONTACT

520-626-8286

priscaz@arizona.edu

Rachel E Jarrett

CONTACT

520-626-0375

rjarrett@arizona.edu

Principal Investigator

Junaid Arshad, MD

PRINCIPAL_INVESTIGATOR

University of Arizona

Study Locations (Sites)

Arizona Cancer Center at UMC North/University Medical Center

Tucson, Arizona, 85719

United States

Collaborators and Investigators

Sponsor: University of Arizona

Junaid Arshad, MD, PRINCIPAL_INVESTIGATOR, University of Arizona

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-04-20

Study Completion Date2025-05

Study Record Updates

Study Start Date2023-04-20

Study Completion Date2025-05

Terms related to this study

Keywords Provided by Researchers

PDE5,6i inhibitor
chemotherapeutic cell death
resectable Gastric/GEJ cancer
tadalafil
FLOT chemotherapy
Myeloid Derived Suppressor Cells (MDSCs)

Additional Relevant MeSH Terms

Gastric Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma