Combination Chemotherapy for Pancreatic Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Warfarin, Cyclosporine A, Rifampicin, Glyburide

Disqualifiers: Other cancers, Peripheral neuropathy, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

21 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for pancreatic cancer that cannot be removed by surgery. The researchers aim to determine the best dose of bosentan (a medication typically used to treat high blood pressure in the lungs) and assess its effectiveness with two chemotherapy drugs, gemcitabine and nab-paclitaxel, in stopping the cancer from growing or spreading. People with pancreatic cancer who cannot undergo surgery and are already receiving certain types of chemotherapy might be suitable candidates for this trial. The goal is to determine if adding bosentan can improve treatment outcomes compared to chemotherapy alone. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including Warfarin, Cyclosporine A, Rifampicin, Glyburide, and any drugs that strongly affect specific liver enzymes (CYP2C9 and CYP3A). Other diabetic medications are allowed.

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

Research has shown that combining bosentan with chemotherapy drugs like gemcitabine and nab-paclitaxel might improve treatment for pancreatic cancer. Bosentan blocks a hormone that aids cancer growth, while gemcitabine and nab-paclitaxel directly attack cancer cells.

Regarding safety, bosentan is still under study in this context, so its complete safety profile with these chemotherapy drugs remains unknown. The FDA has already approved nab-paclitaxel and gemcitabine for other uses, so doctors are familiar with their side effects. Common side effects of gemcitabine and nab-paclitaxel include tiredness, nausea, and low blood cell counts.

This combination of treatments is currently being tested in a phase 1 trial. This phase assesses the safety and tolerability of the treatment in people, involving careful observation of patient responses and side effects. As this is a phase 1 trial, detailed safety information specific to this combination is still being collected. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for pancreatic cancer because it includes bosentan, which is not traditionally used in this context. Bosentan is known for treating pulmonary hypertension, but here it may help enhance the effectiveness of chemotherapy. The treatment also combines nab-paclitaxel and gemcitabine, two established drugs for pancreatic cancer, potentially increasing their impact. This unique combination aims to tackle cancer more effectively and might improve patient outcomes compared to the standard treatments like gemcitabine alone or in combination with other drugs like FOLFIRINOX.

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

Research has shown that adding bosentan to chemotherapy might improve treatment for pancreatic cancer. In this trial, participants will receive a combination of bosentan, gemcitabine, and nab-paclitaxel. Bosentan blocks a hormone that aids cancer growth and spread. Studies indicate that bosentan can enhance the effectiveness of gemcitabine, a chemotherapy drug, by inhibiting tumor growth and killing cancer cells. Gemcitabine and nab-paclitaxel, another chemotherapy drug, are already known to extend the lives of pancreatic cancer patients. Combining these treatments could potentially be more effective than using chemotherapy alone. ^{1 2 4 6 7}

Who Is on the Research Team?

Ravi Salgia

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with pancreatic cancer that can't be surgically removed. They must not have had prior chemotherapy, except certain types in the adjuvant setting if recurrence occurred after 6 months. Participants need functioning major organs, no severe allergies to study drugs or their components, and agree to use effective birth control methods.

Inclusion Criteria

Agreement by females and males of childbearing potential to use an adequate method of birth control (hormonal contraception is inadequate) or abstain from heterosexual activity for the course of the study through 30 days after the last dose of study medication

My condition cannot be treated with surgery.

You are expected to live for more than 3 months.

Exclusion Criteria

I am not taking strong CYP3A inhibitors or inducers.

I am not taking Cyclosporine A or rifampicin.

Women who are or are planning to become pregnant or breastfeed

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive bosentan orally twice daily and nab-paclitaxel and gemcitabine intravenously on days 1, 8, and 15 of each 28-day cycle

Up to 2 years

Visits on days 1, 8, and 15 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days after last dose, then every 2 months until disease progression, then biannually

What Are the Treatments Tested in This Trial?

Interventions

• Bosentan
• Gemcitabine
• Nab-paclitaxel

Trial Overview The trial tests bosentan combined with gemcitabine and nab-paclitaxel chemotherapy to see if it's more effective for treating unresectable pancreatic cancer than chemotherapy alone. It also aims to determine the best dose of bosentan and assess its side effects when used with these chemotherapies.

How Is the Trial Designed?

Group I: Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21 Experimental Treatment 5 Interventions

Patients receive bosentan PO BID on days 1-21 of cycle 1 and days 1-21 of subsequent cycles. Patients also receive nab-paclitaxel IV over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12 Experimental Treatment 5 Interventions

Patients receive bosentan PO BID on days -7 to 21 and days 1-21 of subsequent cycles. Patients also receive nab-paclitaxel IV over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9 Experimental Treatment 5 Interventions

Patients receive bosentan PO BID on days 8-21 of cycle 1 and days 1-21 of subsequent cycles. Patients also receive nab-paclitaxel IV over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Bosentan is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:

Approved in European Union as Tracleer for:

• Pulmonary arterial hypertension

Approved in United States as Tracleer for:

• Pulmonary arterial hypertension

Approved in Canada as Tracleer for:

• Pulmonary arterial hypertension

Approved in Switzerland as Tracleer for:

• Pulmonary arterial hypertension

Approved in Japan as Tracleer for:

• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a retrospective study of 29 patients with advanced pancreatic carcinoma and elevated bilirubin levels, treatment with nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) was found to be safe, showing no unexpected toxicities.

The median overall survival for patients treated with nab-P/G was 11.7 months, with no significant differences in survival based on bilirubin levels, indicating that nab-P/G is a feasible treatment option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis. Pelzer, U., Wislocka, L., Jühling, A., et al.[2022]

The combination of nab-paclitaxel, gemcitabine, and capecitabine was found to be well tolerated in a phase I study with 15 patients, establishing a maximum-tolerated dose (MTD) but showing only modest antitumor activity in metastatic pancreatic cancer.

Despite the regimen being generally safe, with a low incidence of severe hematologic toxicities, only 14.3% of patients had a partial response, indicating that optimizing dose intensity may be crucial for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer. Ko, AH., Truong, TG., Kantoff, E., et al.[2022]

In a phase II trial involving 61 patients with borderline resectable pancreatic cancer, the neoadjuvant therapy of nab-paclitaxel plus gemcitabine resulted in a median overall survival of 25.2 months and a median recurrence-free survival of 12.3 months, indicating promising efficacy.

The treatment had a high resection rate of 73.8% and an R0 resection rate of 63.9%, but it also presented significant safety concerns, with 73.8% of patients experiencing grade 3/4 adverse events, highlighting the need for careful patient selection, especially for those with prior lung issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of neoadjuvant nab-paclitaxel plus gemcitabine therapy in patients with borderline resectable pancreatic cancer: A multicenter single-arm phase II study (NAC-GA trial). Okada, KI., Kimura, K., Yamashita, YI., et al.[2023]

In a study involving 17 patients with malignant solid tumors, nab-paclitaxel (Abraxane) showed a significantly higher exposure to unbound paclitaxel compared to solvent-based paclitaxel, which may enhance its effectiveness against tumors.

The pharmacokinetics of nab-paclitaxel remained consistent across treatment cycles, indicating stable drug behavior and suggesting improved tolerability and efficacy due to its unique formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Gardner, ER., Dahut, WL., Scripture, CD., et al.[2022]

In a study of 27 elderly Japanese patients (aged ≥ 75) with non-curatively resectable pancreatic cancer, the combination of nanoparticle albumin-bound paclitaxel (nab-PTX) and gemcitabine (GEM) showed a high disease control rate of 92.6%, indicating strong efficacy in managing the disease.

Despite its effectiveness, the treatment was associated with significant adverse effects, including a 51.9% incidence of grade 3 or higher hemotoxicity and a 22% rate of grade ≥ 3 peripheral nerve disorders, highlighting the need for careful monitoring and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical trial to assess the feasibility and efficacy of nab-paclitaxel plus gemcitabine for elderly patients with unresectable advanced pancreatic cancer. Hasegawa, R., Okuwaki, K., Kida, M., et al.[2022]

In a study involving 221 patients with metastatic pancreatic ductal adenocarcinoma and poor performance status, the combination of NAB-paclitaxel and gemcitabine was found to be well tolerated, with manageable side effects such as anemia and neutropenia.

Both dosing regimens of NAB-paclitaxel (100 mg/m2 and 125 mg/m2) showed similar efficacy, with comparable response rates and median progression-free survival, indicating that this treatment is effective for fragile patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2. Macarulla, T., Pazo-Cid, R., Guillén-Ponce, C., et al.[2022]

In a phase 3 trial involving 861 patients with metastatic pancreatic cancer, the combination of nab-paclitaxel and gemcitabine significantly improved overall survival (8.5 months) compared to gemcitabine alone (6.7 months), with a hazard ratio for death of 0.72, indicating a 28% reduction in the risk of death.

The combination therapy also resulted in better progression-free survival (5.5 months vs. 3.7 months) and a higher overall response rate (23% vs. 7%), although it was associated with increased rates of adverse events like neutropenia and neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. Von Hoff, DD., Ervin, T., Arena, FP., et al.[2022]

In a small study of 6 women with heavily pretreated HER2-negative metastatic breast cancer, the combination of nab-paclitaxel (nab-P) and bevacizumab (B), with or without gemcitabine (G), showed promising safety and preliminary efficacy, with only one patient experiencing significant toxicity.

Out of the 6 patients, 2 achieved partial responses and 4 had stable disease, indicating that this combination therapy may be effective, warranting further investigation in a formal phase II trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel albumin-bound particles (abraxane) in combination with bevacizumab with or without gemcitabine: early experience at the University of Miami/Braman Family Breast Cancer Institute. Lobo, C., Lopes, G., Silva, O., et al.[2022]

In a study using 10 patient-derived pancreatic cancer xenograft mouse models, the combination of S-1 and nab-paclitaxel showed significantly greater tumor growth inhibition (103.56%) compared to either treatment alone, indicating enhanced antitumor activity.

Biomarkers such as thymidylate synthase, OPRT, and DPD were identified as potential predictors of S-1 efficacy, while HER2 was linked to improved efficacy of nab-paclitaxel, suggesting that these markers could help tailor treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models. Li, JA., Xu, XF., Han, X., et al.[2017]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04158635

NCT04158635 | Gemcitabine, Nab-Paclitaxel, and ... Giving bosentan with chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-06609

Bosentan with Nab-Paclitaxel and Gemcitabine for the ... Giving bosentan with chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4631139/

Increased Survival in Pancreatic Cancer with nab-Paclitaxel ... Among patients with metastatic disease, the 5-year survival rate is only 2%, and 1-year survival rates of 17 to 23% have been reported with gemcitabine.

4. letswinpc.org letswinpc.org/research/hypertension-drug-treatment-for-unresectable-pancreatic-cancer/

Hypertension Drug as Part of First-Line Treatment for ... This phase I trial studies the side effects and best tolerable dose of bosentan and how well it works when given together with gemcitabine and ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006291X20308585

Blockade of endothelin receptor A enhances the ... Furthermore, our results revealed that bosentan, an ETAR antagonist, enhanced the growth-inhibiting and proapoptotic effects of gemcitabine on pancreatic cancer ...

6. reporter.nih.gov reporter.nih.gov/project-details/10773010

Modulation of Tumor Microenvironment for ... - NIH RePORTER Further, we propose to evaluate the safety of ET-axis antagonist bosentan in combination with FDA approved combination of chemotherapeutic agents (Abraxane and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03636308

Study Details | NCT03636308 | Nab-paclitaxel Plus S-1(AS ... Nab-paclitaxel added to gemcitabine has showed improving survival and overall response rate vs gemcitabine alone in metastatic PDAC first-line treatment in the ...