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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1 Study of Gemcitabine, Nab-Paclitaxel, and Bosentan in Patients With Unresectable Pancreatic Cancer

Conditions
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Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8, Unresectable Pancreatic Carcinoma

Intervention / Treatment
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* Drug: Bosentan
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent by the participant Willingness to permit study team to obtain and use archival tissue, if already existing Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Life expectancy of > 3 months Histologic diagnosis of pancreatic carcinoma Unresectable disease Patients must not have received prior chemotherapy for disease with the following exceptions: Gemcitabine with or without capecitabine or fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) in the adjuvant setting if the recurrence is greater than 6 months from the completion of chemotherapy Radiation sensitizing doses of 5-fluorouracil or capecitabine are allowed as part of adjuvant treatment and recurrence must be documented >= 6 months from the completion of chemotherapy 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 Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Absolute neutrophil count (ANC) >= 1,500/mm^3 (performed within 14 days prior to day 1 of bosentan) Platelets >= 100,000/mm^3 (performed within 14 days prior to day 1 of bosentan) Total serum bilirubin =< 1.5 x upper limit of normal (ULN) (performed within 14 days prior to day 1 of bosentan) Aspartate aminotransferase (AST) =< 1.5 x ULN or =< 3 x ULN with liver metastases (performed within 14 days prior to day 1 of bosentan) Alanine aminotransferase (ALT) =< 1.5 x ULN or =< 3 x ULN with liver metastases (performed within 14 days prior to day 1 of bosentan) Creatinine clearance of >= 60 mL/min per 24 hour urine or the Cockcroft-Gault (performed within 14 days prior to day 1 of bosentan) Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Exclusion Criteria: Dietary/herbal supplements Other investigational products Warfarin Cyclosporine A or rifampicin Glyburide; other hypoglycemic agents may be permitted Current or planned use of agents contraindicated for use with strong CYP3A4 inducers Strong inhibitors or inducers of CYP2C9 Strong inhibitors or inducers of CYP3A Agent or agents that moderately inhibit both CYP2C9 and CYP3A (via a single concomitant agent, or co-administration of concomitant agents) Current or history of >= grade 2 peripheral neuropathy Issues with tolerating oral medication (e.g. inability to swallow pills, malabsorption issues, ongoing nausea or vomiting) Women who are or are planning to become pregnant or breastfeed Known allergy to eggs or any of the components within the study agents and/or their excipients No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years Intercurrent or historic medical condition that increases subject risk in the opinion of the investigator. Eligibility may be revisited for intercurrent medical conditions once resolution/recovery is deemed adequate by the investigator (e.g. recovery from major surgery, completion of treatment for severe infection) Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 1-9<br>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. | Drug: Bosentan<br>* Given PO<br>* Other names: Tracleer;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: protein-bound paclitaxel;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 10-12<br>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. | Drug: Bosentan<br>* Given PO<br>* Other names: Tracleer;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: protein-bound paclitaxel;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Treatment (bosentan, nab-paclitaxel, gemcitabine) - Participant 13-21<br>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. | Drug: Bosentan<br>* Given PO<br>* Other names: Tracleer;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: protein-bound paclitaxel;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 |