Tadalafil + Chemotherapy for Stomach Cancer

Overseen By Rachel E Jarrett

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Arizona

Must not be taking: Nitrates, α-blockers

Disqualifiers: Metastatic disease, Cardiovascular disorders, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

10 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does exclude those using certain medications like nitrates, α-blockers, and some other interacting drugs. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

Is Tadalafil safe for use in humans?

Tadalafil, also known as Cialis, is generally considered safe for use in humans for conditions like erectile dysfunction and pulmonary arterial hypertension, but its safety in combination with chemotherapy for stomach cancer specifically has not been well-documented in the provided research articles. ^{1 2 3 4 5}

How does the drug Tadalafil combined with chemotherapy differ from other treatments for stomach cancer?

Tadalafil, typically used for erectile dysfunction, is being explored in combination with chemotherapy for stomach cancer, which is unique as it may enhance the effectiveness of chemotherapy by improving blood flow to tumors. This approach is novel compared to standard chemotherapy regimens that do not include Tadalafil. ^{5 6 7 8 9}

Research Team

Junaid Arshad, MD

Principal Investigator

University of Arizona

Eligibility Criteria

Adults with resectable gastric or gastroesophageal junction adenocarcinoma, who haven't had prior treatments for their cancer. They must have a certain level of albumin in the blood, measurable disease by scans, and adequate organ function. Participants should not be pregnant or breastfeeding and must agree to use contraception during the study and for six months after.

Inclusion Criteria

My cancer is in the early to mid stages and is located in my stomach or the junction connecting my stomach and esophagus.

My cancer can be measured on scans taken within the last 28 days.

I am fully active and can carry on all my pre-disease activities without restriction.

Exclusion Criteria

I have received treatment for stomach cancer before.

I haven't taken Tadalafil or similar drugs in the last 28 days.

My cancer has spread to other parts of my body.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Tadalafil Monotherapy

Participants receive Tadalafil alone to assess its effect on MDSCs

2 weeks

1 visit (in-person) for baseline assessments

Combination Treatment

Participants receive Tadalafil in combination with FLOT chemotherapy

8 weeks

Regular visits for chemotherapy administration and monitoring

Surgical Intervention

Surgical removal of the tumor following neoadjuvant treatment

1 week

1 visit (in-person) for surgery

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person) for follow-up assessments

Treatment Details

Interventions

• Tadalafil

Trial Overview The trial is testing Tadalafil's effect on immune cells in the tumor environment when given alone and alongside standard chemotherapy (FLOT) before surgery. Patients will take Tadalafil for two weeks then combine it with FLOT for eight weeks, aiming to reduce suppressor cells that can hinder anti-cancer responses.

Participant Groups

Group I: Tadalafil + chemotherapy Experimental Treatment 1 Intervention

Subjects will receive Tadalafil monotherapy for 2 weeks followed by Tadalafil in combination with neoadjuvant FLOT chemotherapy for 8 weeks in the window between their cancer diagnosis and surgical intervention.

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

Findings from Research

In a phase II study involving 58 patients with advanced gastric cancer, the combination of docetaxel, fluorouracil, and leucovorin (TFL) showed a moderate overall response rate of 26%, with 4 complete and 11 partial responses observed.

The TFL regimen was found to have manageable toxicity, with neutropenia being the most common severe side effect (30% of patients), and no toxic deaths reported, indicating a favorable safety profile for this chemotherapy combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination docetaxel (Taxotere), fluorouracil, and leucovorin (TFL), as first-line chemotherapy in advanced gastric cancer: a Hellenic Cooperative Oncology Group phase II study. Papakostas, P., Tsavdaridis, D., Kosmidis, P., et al.[2022]

A lower dose of docetaxel (50 mg/m2) combined with 5-FU and cisplatin showed a 40% response rate in patients with metastatic gastric cancer, indicating its efficacy in treating this condition.

While the treatment was associated with significant toxicities, including 68% of patients experiencing grade 3/4 neutropenia, the overall toxicity profile was considered tolerable, suggesting that this lower dose may reduce severe side effects compared to higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of low-dose docetaxel/fluorouracil/cisplatin in metastatic gastric carcinoma. Park, SR., Chun, JH., Kim, YW., et al.[2019]

In a phase I study involving 20 patients with upper gastrointestinal malignancies, the combination of docetaxel, cisplatin, and bolus 5-FU was found to have a maximally tolerated dose, with significant toxicities including neutropenia and sepsis leading to two treatment-related deaths.

The treatment regimen showed some efficacy, with three partial responses observed, indicating potential benefits for patients with esophagogastric and gastric cancers, but also highlighting the need for strategies to enhance tolerance to the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of docetaxel, Cisplatin, 5-Fluorouracil and leucovorin. Mulcahy, MF., Loehrer, PJ., Meropol, NJ., et al.[2018]

The recommended dose (RD) for the new DXO regimen, which combines docetaxel, capecitabine, and oxaliplatin, was established as 60 mg/m² of docetaxel, 1,000 mg/m² of capecitabine, and 100 mg/m² of oxaliplatin, showing promising efficacy in treating advanced gastric cancer (AGC) with 11 out of 14 patients achieving a partial response.

While the DXO regimen demonstrated substantial activity, it also presented significant toxicities, including neutropenia and diarrhea, which were manageable, indicating that this combination could be a viable alternative to the traditional DCF regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer. Sym, SJ., Ryu, MH., Kang, HJ., et al.[2018]

TS-1, an oral formulation of 5-fluorouracil, combined with low-dose cisplatinum (CDDP), showed promising efficacy in treating advanced gastric cancer, with three cases demonstrating significant improvement in symptoms and disease status.

The combination therapy was well tolerated, with only mild adverse reactions reported, suggesting it could be a safe treatment option for patients with advanced gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Three cases of advanced gastric cancer treated by TS-1 in combination with low-dose cisplatinum]. Gomi, T., Ohtoshi, M., Tamaki, N., et al.[2013]

A 68-year-old male with stage IIIb colon cancer showed a significant response to TS-1/CDDP combined chemotherapy, with a decrease in tumor marker CA19-9 and disappearance of metastatic lesions after three treatment courses.

The therapy not only proved effective for colon cancer but also highlighted the importance of individualizing chemotherapy based on tumor characteristics, such as high DPD activity, and it can be administered at home, improving the patient's quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A case report--TS-1/CDDP combined chemotherapy found effective for metastatic recurrence after operation for colon cancer]. Shimizu, T., Inaba, S., Nakata, M., et al.[2013]

In a phase II trial involving 158 untreated patients with advanced gastric cancer, the combination of docetaxel, cisplatin, and 5-fluorouracil (TCF) showed a significantly higher response rate and longer time to progression compared to docetaxel and cisplatin alone (TC).

While the TCF regimen had greater gastrointestinal toxicity and required more dose reductions, it was still manageable, and no deaths were reported in either treatment group, indicating a favorable safety profile for both regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel in combination for advanced gastric cancer. Ajani, JA.[2019]

A weekly formulation of the DCF chemotherapy regimen showed modest efficacy in treating locally advanced and metastatic gastric cancer, with a disease control rate of 57.8% among 64 patients studied.

The weekly DCF regimen resulted in minimal severe hematologic toxicity, making it a safer alternative for patients with lower performance status who cannot tolerate the standard every-three-weeks DCF treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of weekly docetaxel, cisplatin, and 5-fluorouracil for locally advanced or metastatic gastric cancer patients with ECOG performance scores of 1 and 2. Turkeli, M., Aldemir, MN., Cayir, K., et al.[2019]

Docetaxel-based chemotherapy shows significant promise in advanced gastric cancer, achieving response rates of 55% when combined with cisplatin and 5-fluorouracil, and a median survival of 9 months.

The combination of docetaxel with cisplatin and 5-fluorouracil (TCF) is well tolerated, with manageable hematotoxicity and less gastrointestinal toxicity compared to other regimens, indicating its potential as an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel-based chemotherapy in the treatment of gastric cancer. Roth, AD., Ajani, J.[2020]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Combination docetaxel (Taxotere), fluorouracil, and leucovorin (TFL), as first-line chemotherapy in advanced gastric cancer: a Hellenic Cooperative Oncology Group phase II study. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Phase II study of low-dose docetaxel/fluorouracil/cisplatin in metastatic gastric carcinoma. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

A phase I study of docetaxel, Cisplatin, 5-Fluorouracil and leucovorin. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer. [2018]

5. Japan pubmed.ncbi.nlm.nih.gov

[Three cases of advanced gastric cancer treated by TS-1 in combination with low-dose cisplatinum]. [2013]

6. Japan pubmed.ncbi.nlm.nih.gov

[A case report--TS-1/CDDP combined chemotherapy found effective for metastatic recurrence after operation for colon cancer]. [2013]

7. Japan pubmed.ncbi.nlm.nih.gov

Docetaxel in combination for advanced gastric cancer. [2019]

8. Thailand pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of weekly docetaxel, cisplatin, and 5-fluorouracil for locally advanced or metastatic gastric cancer patients with ECOG performance scores of 1 and 2. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Docetaxel-based chemotherapy in the treatment of gastric cancer. [2020]