Gemcitabine, Nab-Paclitaxel, and Bosentan for the Treatment of Unresectable Pancreatic Cancer

Phase 1

Recruiting

• Conditions: Unresectable Pancreatic Carcinoma; Stage IV Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8
• Interventions: Drug: Bosentan; Drug: Gemcitabine; Drug: Nab-paclitaxel; Other: Quality-of-Life Assessment; Other: Questionnaire Administration

• Registration Number: NCT04158635
• Lead Sponsor: City of Hope Medical Center

Brief Summary

This phase I trial studies the side effects and best dose of bosentan and how well it works when given together with gemcitabine and nab-paclitaxel for the treatment of pancreatic cancer that cannot be removed by surgery (unresectable). Bosentan may block the hormone endothelin and prevent the growth and spread of pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bosentan with chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

Detailed Description

PRIMARY OBJECTIVE:

I. To assess the safety, toxicity and feasibility of administering bosentan with nab-paclitaxel and gemcitabine.

SECONDARY OBJECTIVES:

I. To assess the response rate associated with this combination therapy in first line pancreatic cancer patients.

II. To assess the progression-free survival and overall survival of all patients who start protocol therapy, and describe the outcomes based on measures of compliance during the lead-in week, and compliance with supplement during chemotherapy.

EXPLORATORY OBJECTIVES:

I. To determine the impact of bosentan on the mass transport in the tumor (surrogate of alterations in tumor stroma and blood flow). (Pharmacodynamic Investigations) II. To describe the pharmacokinetic profile of nab-paclitaxel and bosentan and compare to historic single-agent profile. (Pharmacokinetic Investigations) III. To explore the association between hepatotoxicity to study agents and organic anion-transporting polypeptide (OATP) polymorphisms. (Pharmacogenomic Investigations) IV. To explore biomarkers on pre-treatment biopsy samples and peripheral blood samples for correlations of predictive of response.

V. To describe quality of life utilizing the Functional Assessment of Cancer Therapy: General (FACT-G) questionnaire.

OUTLINE:

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

After completion of study treatment, patients are followed up at 30 days. Patients who complete study treatment without disease progression are followed up every 2 months until disease progression and then biannually thereafter. Patients who complete study treatment with disease progression are followed up biannually.

Study Timeline

• Study First Submitted: 2019-11-07
• Study First Submitted QC: 2019-11-07
• Study First Posted: 2019-11-12
• Study Start: 2021-09-01
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-08
• Last Update Posted: 2024-08-09
• Primary Completion: 2026-01-27
• Study Completion: 2026-01-27

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12	Nab-paclitaxel	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12	Quality-of-Life Assessment	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21	Nab-paclitaxel	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9	Nab-paclitaxel	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9	Quality-of-Life Assessment	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9	Questionnaire Administration	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12	Questionnaire Administration	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21	Quality-of-Life Assessment	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21	Questionnaire Administration	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9	Bosentan	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9	Gemcitabine	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12	Bosentan	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12	Gemcitabine	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21	Bosentan	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.
Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21	Gemcitabine	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.

Primary Outcome Measures

Name	Time	Method
Incidence of adverse events	Up to 30 days after last dose of protocol therapy	Will be recorded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0.
Dose limiting toxicities (DLTs)	Up to 21 days (Cycle 1)	Toxicities will be graded according to NCI CTCAE v 4.0. DLT's apply only to bosentan-only single stage AND cycle 1 and should be attributable to the treatment.
Compliance	During the first week	Number of bosentan tablets and bottles returned will be reconciled with the patient diary.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	Time to death as a result of any cause, assessed up to 2 years	Will be evaluated using the Kaplan-Meier methods, both as a single group and by disease classification (metastatic vs. advanced unresectable). Response will also be examined by disease classification as part of a secondary analysis.
Progression-free survival (PFS)	Time to disease progression/ relapse or death as a result of any cause, assessed up to 2 years	Will be evaluated using the Kaplan-Meier methods, both as a single group and by disease classification (metastatic versus \[vs.\] advanced unresectable). Response will also be examined by disease classification as part of a secondary analysis.
Time to treatment failure (TTF)	Time to treatment termination for any reason (progression, toxicity, death, patient preference), assessed up to 2 years	Will be evaluated using the Kaplan-Meier methods, both as a single group and by disease classification (metastatic vs. advanced unresectable). Response will also be examined by disease classification as part of a secondary analysis.

Trial Locations

Locations (1)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States