Chemotherapy Switch + Losartan for Pancreatic Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: OHSU Knight Cancer Institute

Must not be taking: Other anti-cancer therapy

Disqualifiers: Metastasis, Active malignancy, Cardiovascular, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating pancreatic cancer, whether or not it can be removed by surgery. Researchers aim to determine if switching chemotherapy combinations before surgery fights the cancer more effectively. The trial also tests losartan, a drug typically used for high blood pressure, with these treatments to see if it improves outcomes. People with pancreatic cancer that hasn't spread to distant organs and who haven't received previous chemotherapy might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are currently taking an ACE inhibitor or ARB, you can continue with it, but you won't receive losartan as part of the study. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking an ACE inhibitor or ARB, you will continue with it instead of receiving losartan as part of the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the mFOLFIRINOX chemotherapy treatment is generally well-tolerated by people with pancreatic cancer. Studies have found it to be safe, with manageable side effects. Patients have experienced better outcomes and lived longer compared to some other treatments. However, like most chemotherapy, it can still cause side effects such as nausea and tiredness.

Adding losartan, a medication usually used for high blood pressure, does not significantly alter the safety of the chemotherapy treatment. Studies have not reported any major safety issues that would make it harder to tolerate.

Overall, research indicates that both mFOLFIRINOX and losartan are safe for treating pancreatic cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for pancreatic cancer, which often rely on traditional chemotherapy regimens, this approach explores a unique combination of chemotherapy switch and the addition of losartan. Researchers are excited about this treatment because losartan, typically used to treat high blood pressure, might improve the effectiveness of chemotherapy and radiation therapy by affecting the tumor's microenvironment. Additionally, the possibility of switching to a different regimen if initial treatments aren't effective offers a tailored approach, potentially improving outcomes for patients who don't respond to standard options.

What evidence suggests that this trial's treatments could be effective for pancreatic cancer?

Research has shown that the mFOLFIRINOX treatment, which participants in this trial may receive, holds promise for pancreatic cancer. Patients using mFOLFIRINOX have responded better and experienced longer periods without disease progression compared to other treatments. One study found that patients on this treatment lived for a median of 11.1 months. In this trial, some participants will also receive losartan, a medication for high blood pressure, alongside chemotherapy. Early research suggests that adding losartan might improve results when combined with chemotherapy for pancreatic cancer. Although the evidence is still developing, losartan could potentially enhance the effectiveness of current treatments. ^{1 4 5 6 7}

Who Is on the Research Team?

Charles D. Lopez

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

Adults with pancreatic cancer that is resectable, borderline resectable, or locally-advanced unresectable. They must have proper liver function, no history of other cancers with less than a 90% cure rate, not be pregnant or breastfeeding, and agree to use contraception. Participants should not have had previous chemotherapy for pancreatic cancer (except possibly one cycle), and must be physically fit enough for surgery.

Inclusion Criteria

I have never had chemotherapy for pancreatic cancer.

Ability to understand and the willingness to sign a written informed consent document

I haven't had a laparoscopy to diagnose my condition.

Exclusion Criteria

My cancer has spread to distant parts of my body.

I have had fainting spells, irregular heartbeats, or sudden cardiac arrest due to heart issues.

I have another cancer with less than a 90% chance of being cured.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mFOLFIRINOX or switch to GA regimen, with additional losartan and potential radiation therapy

Up to 4 months

Bi-weekly visits for chemotherapy administration

Surgery

Participants undergo surgery if eligible after chemotherapy and radiation therapy

1-4 weeks post-RT

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months for 6 months, then every 6 months for up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Fluorouracil
• Irinotecan Hydrochloride
• Leucovorin Calcium
• Oxaliplatin
• Radiation Therapy
• Resection

Trial Overview

The trial tests if switching from mFOLFIRINOX to gemcitabine/nab-paclitaxel before surgery improves outcomes in patients with certain types of pancreatic cancer. It also examines the effects of adding losartan to these treatments. The study involves chemotherapy drugs designed to kill or stop the spread of tumor cells.

How Is the Trial Designed?

Group I: Treatment (mFOLFIRINOX, chemotherapy) Experimental Treatment 12 Interventions

mFOLFIRINOX REGIMEN: Oxaliplatin intravenously (IV) over 2 hrs, leucovorin calcium IV over 2 hrs, and irinotecan hydrochloride IV over 90 minutes on day 1. Also receive fluorouracil IV over 46 hrs starting on day 1. Repeats every 14 days for up to 4 cycles. Those with response and no disease progression may receive an additional 2 months. GA REGIMEN: Those with disease progression or toxicity to mFOLFIRINOX switch to GA regimen comprising gemcitabine hydrochloride IV over 30-60 mins and nab-paclitaxel IV over 30-40 mins on days 1, 8, and 15. Repeats every 28 days for 2 cycles. LOSARTAN: Cycle 1 day 1, start losartan potassium orally once daily until end of RT. RT/SURGERY: Short-course RT for 10 fractions over 5 days weekly or long-course RT with 15-25 fractions over 5 days weekly along with oral capecitabine twice daily on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks following RT

Fluorouracil is already approved in United States, European Union, Canada for the following indications:

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Published Research Related to This Trial

In a study of 198 patients with advanced pancreatic cancer, the SOXIRI chemotherapy regimen showed similar overall survival (12.1 months) and progression-free survival (6.5 months) compared to the standard mFOLFIRINOX regimen (11.2 months and 6.8 months, respectively), indicating comparable efficacy.

While both regimens had similar safety profiles, SOXIRI was associated with a higher incidence of anemia (41.4% vs. 24%), suggesting that while effective, it may have specific side effects that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of SOXIRI versus mFOLFIRINOX in advanced pancreatic cancer. Li, X., Huang, J., Wang, F., et al.[2023]

The modified FOLFIRINOX (mFOLFIRINOX) regimen showed a tolerable safety profile with lower hematological toxicity compared to the full-dose FOLFIRINOX, while still maintaining comparable efficacy in treating advanced pancreatic ductal adenocarcinoma (PDAC).

In a study of 18 patients, 80% achieved at least stable disease, with a median overall survival of 9.3 months and progression-free survival of 7.2 months, indicating that mFOLFIRINOX can be an effective treatment option for fit patients with advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. Ghorani, E., Wong, HH., Hewitt, C., et al.[2023]

In a study of 114 patients with metastatic pancreatic ductal adenocarcinoma, the use of losartan during chemotherapy did not show significant differences in overall survival (OS) or progression-free survival (PFS) compared to patients not using losartan.

While there was a trend towards longer PFS in patients treated with losartan and FOLFIRINOX, this did not reach statistical significance, suggesting that further research is needed to explore the potential benefits of losartan in metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy. Kasi, A., Allen, J., Mehta, K., et al.[2022]

The modified FOLFIRI regimen, which includes irinotecan, 5-fluorouracil, and a low dose of leucovorin, demonstrated a 47.8% overall response rate in 44 patients with recurrent or metastatic colorectal cancer, indicating its efficacy as a first-line treatment.

The treatment was well-tolerated, with mild and manageable toxicities; only a few patients experienced severe side effects, such as Grade 3/4 leukopenia and diarrhea, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, continuous 5-fluorouracil, and low dose of leucovorin (modified FOLFIRI) as first line of therapy in recurrent or metastatic colorectal cancer. Lee, MA., Byun, JH., Shim, BY., et al.[2019]

In a study of 19 patient-derived pancreatic cancer cell lines, FOLFIRINOX showed optimal sensitivity in six cell lines, while three cell lines responded better to gemcitabine plus nab-paclitaxel (Gem-Pac), indicating that different regimens may work better for different patients.

The findings suggest that understanding the specific sensitivity of cancer cells to these treatments could help identify biomarkers, which may guide personalized chemotherapy choices for patients with pancreatic ductal adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRINOX Versus Gemcitabine-based Therapy for Pancreatic Ductal Adenocarcinoma: Lessons from Patient-derived Cell Lines. Begg, SKS., Birnbaum, DJ., Clark, JW., et al.[2023]

In a study using a rat model of pancreatic cancer, the combination of gemcitabine and losartan significantly improved survival rates, extending life expectancy to 102.6 days compared to 59.6 days in the control group.

Both gemcitabine and losartan reduced cancer cell proliferation and inhibited the expression of vascular endothelial growth factor, suggesting that targeting the AT1 receptor with losartan enhances the effectiveness of gemcitabine in treating advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effect of angiotensin II type 1 receptor blocker losartan for orthotopic rat pancreatic adenocarcinoma. Kim, S., Toyokawa, H., Yamao, J., et al.[2022]

Irinotecan hydrochloride, approved in 1996 for second-line treatment of metastatic colorectal cancer, is generally well tolerated and can be safely administered on an outpatient basis, demonstrating clinically relevant activity against the disease.

Both irinotecan and gemcitabine, which will be discussed in a subsequent article, have manageable side effects that can be addressed with proper monitoring and dose adjustments, highlighting the importance of oncology nurses in patient education and symptom management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New agents in gastrointestinal malignancies: Part 1: Irinotecan in clinical practice. Stucky-Marshall, L.[2019]

In a study of 137 patients with unresectable pancreatic cancer, the modified FOLFIRINOX (mFFX) regimen showed a trend towards longer overall survival (11.8 months) compared to liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI/5-FU/LV) (7.4 months) and FOLFIRI (8.4 months).

The FOLFIRI group exhibited a lower incidence of grade ≥3 treatment-related adverse events compared to the other regimens, suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nal-IRI/5-FU/LV versus modified FOLFIRINOX and FOLFIRI as second-line chemotherapy for unresectable pancreatic cancer: A single center retrospective study. Tezuka, S., Ueno, M., Kobayashi, S., et al.[2023]

In a study of modified FOLFIRINOX (mFOLFIRINOX) for advanced gastrointestinal cancers, including pancreatic and biliary tract cancers, the tolerability based on UGT1A1 genotype-guided dosing was not established, as dose-limiting toxicities (DLTs) exceeded acceptable limits in some patient groups.

Despite the toxicity concerns, the mFOLFIRINOX regimen showed promising efficacy, with response rates of 38% in pancreatic cancer and 21% in biliary tract cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX in previously untreated patients with advanced gastrointestinal malignancies. Sharma, MR., Joshi, SS., Karrison, TG., et al.[2020]

In a study of 18 patients with locally advanced pancreatic cancer (LAPC), neoadjuvant therapy using FOLFIRINOX resulted in a promising R0 resection rate of 44%, indicating that a significant portion of patients became eligible for surgical removal of their tumors after treatment.

The treatment showed high efficacy with a 1-year overall survival rate of 100% and a progression-free survival rate of 83%, although it was associated with notable chemotherapy-related toxicities, including neutropenia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. Hosein, PJ., Macintyre, J., Kawamura, C., et al.[2022]

In a phase II trial, adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy and chemoradiation (CRT) led to a 61% rate of R0 surgical resection in patients with locally advanced pancreatic cancer, indicating improved surgical outcomes.

LOS treatment was associated with reduced immunosuppression and pro-invasion gene expression, as well as changes in immune cell populations, suggesting that LOS enhances the effectiveness of FFX+CRT by modifying the tumor microenvironment favorably.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer. Boucher, Y., Posada, JM., Subudhi, S., et al.[2023]

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