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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2021-06609 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| 19312 | Other Identifier | City of Hope Medical Center |
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Accrual Goal met
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9 | Experimental | 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 | Experimental | 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. |
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| Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21 | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bosentan | Drug | Given PO |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of adverse events | Will be recorded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. | Up to 30 days after last dose of protocol therapy |
| Dose limiting toxicities (DLTs) | 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. | Up to 21 days (Cycle 1) |
| Compliance | Number of bosentan tablets and bottles returned will be reconciled with the patient diary. | During the first week |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-free survival (PFS) | 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 disease progression/ relapse or death as a result of any cause, assessed up to 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Temporal impact of bosentan therapy on tumor vs. normal pancreatic tissue perfusion profile (tumor stroma and blood flow) | Up to 2 years | |
| Levels of nab-paclitaxel, bosentan and active plasma metabolite Ro 48-5033 | Will be quantitated in the peripheral blood. |
Main Inclusion Criteria
Arm A2: gemcitabine plus nab-paclitaxel given every 2 weeks (arm A1 is closed per this amendment)
Arm B: mFOLFIRINOX given every 2 weeks
Main Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Ravi Salgia | City of Hope Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| City of Hope Medical Center | Duarte | California | 91010 | United States |
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| Gemcitabine | Drug | Given IV |
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| Nab-paclitaxel | Drug | Given IV |
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| Quality-of-Life Assessment | Other | Ancillary studies |
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| Questionnaire Administration | Other | Ancillary studies |
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| Overall survival (OS) | 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. | Time to death as a result of any cause, assessed up to 2 years |
| Time to treatment failure (TTF) | 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. | Time to treatment termination for any reason (progression, toxicity, death, patient preference), assessed up to 2 years |
| Up to 2 years |
| Analysis of loci that encode organic anion transporting polypeptides (OATP) in participants who experience severe hepatotoxicity, increased during protocol therapy | Up to 2 years |
| Quantification of the number of circulating tumor cells and temporal proteomic/micro ribonucleic acid (miRNA) profile will assess response to therapy | Up to 2 years |
| Histopathology/ structural assessment and quantification of the miRNA profile | Will allow the identification of prognostic biomarkers. | Up to 2 years |
| Quality of life assessment | Assesses using Functional Assessment of Cancer Therapy: General (FACT-G) questionnaire. | Up to 2 years |
| ID | Term |
|---|---|
| D010190 | Pancreatic Neoplasms |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004701 | Endocrine Gland Neoplasms |
| D004066 | Digestive System Diseases |
| D010182 | Pancreatic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000077300 | Bosentan |
| D000093542 | Gemcitabine |
| C520255 | 130-nm albumin-bound paclitaxel |
| D000068196 | Albumin-Bound Paclitaxel |
| D013660 | Taxes |
| ID | Term |
|---|---|
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D017239 | Paclitaxel |
| D043823 | Taxoids |
| D043822 | Cyclodecanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D004224 | Diterpenes |
| D013729 | Terpenes |
| D000418 | Albumins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D004467 | Economics |
| D004472 | Health Care Economics and Organizations |
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