Clinical Trials /

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

NCT04158635

Description:

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.

Related Conditions:
  • Pancreatic Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Gemcitabine, Nab-Paclitaxel, and Bosentan for the Treatment of Unresectable Pancreatic Cancer
  • Official Title: A Phase 1 Study of Gemcitabine, Nab-Paclitaxel, and Bosentan in Patients With Unresectable Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19312
  • SECONDARY ID: NCI-2019-07206
  • SECONDARY ID: 19312
  • NCT ID: NCT04158635

Conditions

  • Stage III Pancreatic Cancer AJCC v8
  • Stage IV Pancreatic Cancer AJCC v8
  • Unresectable Pancreatic Carcinoma

Interventions

DrugSynonymsArms
BosentanBosentan Monohydrate, Ro 47-0203, TracleerTreatment (bosentan, nab-paclitaxel, gemcitabine)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineTreatment (bosentan, nab-paclitaxel, gemcitabine)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, Paclitaxel Albumin, paclitaxel albumin-stabilized nanoparticle formulation, protein-bound paclitaxelTreatment (bosentan, nab-paclitaxel, gemcitabine)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (bosentan, nab-paclitaxel, gemcitabine)ExperimentalPatients receive bosentan PO BID on days -7 to 21 or 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 21 days in the absence of disease progression or unacceptable toxicity.
  • Bosentan
  • Gemcitabine
  • Nab-paclitaxel

Eligibility Criteria

        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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after last dose of protocol therapy
Safety Issue:
Description:Will be recorded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Time to disease progression/ relapse or death as a result of any cause, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Time to death as a result of any cause, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Time to treatment failure (TTF)
Time Frame:Time to treatment termination for any reason (progression, toxicity, death, patient preference), assessed up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

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