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

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of three drugs for patients with pancreatic cancer that cannot be surgically removed. One drug blocks a hormone to stop cancer growth, while the other two drugs kill cancer cells or prevent them from multiplying. One of these drugs has been widely used in pancreatic cancer treatment, often in combination with other drugs to improve effectiveness.

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.

What data supports the effectiveness of the drug combination of Bosentan, Tracleer, Gemcitabine, Gemzar, Nab-paclitaxel, ABI-007, nanoparticle albumin-bound paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, protein-bound paclitaxel, Abraxane, Pazenir for pancreatic cancer?

Research shows that combining nanoparticle albumin-bound paclitaxel with gemcitabine significantly improves survival in patients with advanced pancreatic cancer compared to using gemcitabine alone. This combination has demonstrated substantial antitumor activity and is considered an evidence-based treatment for advanced pancreatic cancer. ^{1 2 3 4 5}

Is the combination chemotherapy of nab-paclitaxel and gemcitabine safe for humans?

The combination of nab-paclitaxel (Abraxane) and gemcitabine has been studied for safety in patients with advanced pancreatic cancer, including those with specific conditions like hyperbilirubinaemia (a liver condition causing high bilirubin levels). These studies suggest that the treatment is generally safe, but individual tolerability can vary, especially in elderly patients. ^{2 3 4 6 7}

What makes the combination chemotherapy with Bosentan, Gemcitabine, and Nab-paclitaxel unique for treating pancreatic cancer?

This treatment is unique because it combines Bosentan, a drug not typically used for pancreatic cancer, with Gemcitabine and Nab-paclitaxel, which are known to improve survival in advanced cases. The combination may offer a novel approach by potentially enhancing the effectiveness of standard chemotherapy regimens. ^{1 2 3 8 9}

Research Team

Ravi Salgia

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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]

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 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 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 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]

References

1. United States 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. [2022]

2. England 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. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer. [2022]

4. Japan 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. [2022]

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

Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models. [2017]

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

Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. [2022]

7. France 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. [2022]

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

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. [2022]

9. Japan 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). [2023]