NCT05709574

Tadalafil Effect + Chemotherapy in Resectable Gastric/GEJ Cancer

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

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 10 (estimated)
• Sponsor: University of Arizona · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Gastric Adenocarcinoma
• Gastroesophageal Junction Adenocarcinoma

Interventions

Type	Name	Description
DRUG	Tadalafil 20 MG	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.

Timeline

• Start date: 2023-04-20
• Primary completion: 2026-03-30
• Completion: 2026-05-31
• First posted: 2023-02-02
• Last updated: 2025-10-16

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study