Clinical Trials /

Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer

NCT03825289

Description:

This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxychloroquine, 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 trametinib together with hydroxychloroquine may work better in treating patients with pancreatic cancer.

Related Conditions:
  • Pancreatic Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer
  • Official Title: THREAD: A Phase I Trial of Trametinib and Hydroxychloroquine in Patients With Advanced Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: HCI116898
  • NCT ID: NCT03825289

Conditions

  • Metastatic Pancreatic Carcinoma
  • Stage II Pancreatic Cancer
  • Stage IIA Pancreatic Cancer
  • Stage IIB Pancreatic Cancer
  • Stage III Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Unresectable Pancreatic Carcinoma

Interventions

DrugSynonymsArms
HydroxychloroquineTreatment (trametinib, hydroxychloroquine)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (trametinib, hydroxychloroquine)

Purpose

This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxychloroquine, 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 trametinib together with hydroxychloroquine may work better in treating patients with pancreatic cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose of hydroxychloroquine in combination with
      trametinib as assessed by the occurrence of dose-limiting toxicities (DLTs).
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib, hydroxychloroquine)ExperimentalPatients receive trametinib PO QD on days 1-28 and hydroxychloroquine PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Hydroxychloroquine
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Subject with histologically confirmed metastatic or locally advanced, unresectable
             pancreatic carcinoma

          -  Subject must have sufficient available archival tissue OR be willing to provide a
             baseline biopsy

          -  Subject must have progressed during or after first line treatment with either
             gemcitabine/ nab-paclitaxel or FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin)

          -  Subject must have computed tomography (CT) measurable disease by Response Evaluation
             Criteria in Solid Tumors (RECIST) 1.1 criteria

          -  Subject must be able and willing to undergo disease assessment while on study and
             afterwards, if removed for reason other than progression

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Platelet count >= 100 x 10^9/L

          -  Hemoglobin >= 9 g/dL

          -  Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 3 x ULN.
             Patients with liver metastases will be allowed to enroll with AST and ALT levels =< 5
             x ULN

          -  Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula
             (or local institutional standard method)

          -  Negative serum or urine pregnancy test at screening for women of childbearing
             potential

          -  Highly effective contraception for both male and female subjects throughout the study
             and for at least 4 months after last study treatment administration

          -  Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events
             (CTCAE) version (v)5.0 from toxicities related to any prior treatments, unless adverse
             event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy

          -  Able to provide informed consent and willing to sign an approved consent form that
             conforms to federal and institutional guidelines

        Exclusion Criteria:

          -  Subject who have received systemic antineoplastic therapy (including unconjugated
             therapeutic antibodies and toxin immunoconjugates) or any investigational therapy
             within 2 weeks or within 5 half-lives of the investigational therapy prior to starting
             study treatment, whichever is shorter.

          -  Subject who have received radiotherapy within 2 weeks prior to the first dose of study
             treatment. Localized radiation therapy for the treatment of symptomatic bone
             metastasis is allowed during that timeframe

          -  Subjects who have undergone major surgery =< 3 weeks prior to starting study drug or
             who have not recovered from side effects of such procedure

          -  Patients with multiple primary malignancies may be enrolled if non-pancreatic ductal
             adenocarcinoma (PDAC) tumor(s) does not have the potential to interfere with the
             safety or efficacy assessment of the investigational regimen as determined by treating
             investigator and do not require active treatment

          -  Known brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
             before first dose of study treatment. Eligible subjects must be neurologically
             asymptomatic and without corticosteroid treatment at the time of first dose of study
             treatment

          -  History or current evidence of retinal vein occlusion (RVO) or current risk factors
             for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
             or hypercoagulability syndromes)

          -  History of active major bleeding.

          -  Patients whom thromboembolic prophylaxis is medically contraindicated per the treating
             investigator's assessment.

          -  Current evidence of uncontrolled, significant intercurrent illness including, but not
             limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  Congestive heart failure New York Heart Association class 3 or 4, unstable
                       angina pectoris, serious cardiac arrhythmias.

                    -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
                       (MI), or other ischemic event, or thromboembolic event (eg, deep venous
                       thrombosis, pulmonary embolism) within 3 months before first dose

               -  History of glucose-6-phosphate dehydrogenase (G6PD) deficiency

               -  History of seizures

               -  Patients who are planning on embarking on a new strenuous exercise regimen after
                  first dose of study treatment. Muscular activities, such as strenuous exercise,
                  that can result in significant increases in plasma creatine kinase (CK) levels
                  should be avoided while on study treatment

               -  Patients who have neuromuscular disorders that are associated with elevated CK
                  (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
                  sclerosis, spinal muscular atrophy)

               -  Impairment of gastrointestinal function or gastrointestinal disease (e.g.,
                  ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption
                  syndrome, or small bowel resection that under the judgment of the principal
                  investigator [PI] may impair absorption of study drugs)

               -  Any other condition that would, in the Investigator?s judgment, contraindicate
                  the patient?s participation in the clinical study due to safety concerns or
                  compliance with clinical study procedures, e.g., infection/inflammation,
                  intestinal obstruction, unable to swallow medication.(patients may not receive
                  drug through a feeding tube), social/ psychological issues, etc

          -  Screening corrected QT interval by Fridericia (QTcF) > 500 msec

          -  Known human immunodeficiency virus (HIV), unless patient is on effective
             anti-retroviral therapy with undetectable viral load within 6 months are eligible for
             this trial

          -  Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load is
             undetectable

          -  Known history of hepatitis C virus (HCV) infection, unless treated and cured; for
             patients with HCV infection who are currently on treatment, they are eligible if they
             have an undetectable HCV viral load

          -  Medical, psychiatric, cognitive or other conditions that may compromise the patient's
             ability to understand the patient information, give informed consent, comply with the
             study protocol or complete the study

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive human chorionic gonadotropin (hCG) laboratory test

          -  Sexually active males who are not willing to use a condom during intercourse while
             taking the drug and for 4 months after stopping treatment. A condom is also required
             to be used by vasectomized men in order to prevent delivery of the drug via seminal
             fluid

          -  Known prior severe hypersensitivity to investigational product or any component in its
             formulations, including known severe hypersensitivity reactions to monoclonal
             antibodies (National Cancer institute [NCI] CTCAE v5.0 grade >= 3)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of dose-limiting toxicities during the DLT assessment window.
Time Frame:At 28 days
Safety Issue:
Description:To determine the recommended phase II dose (RP2D) hydroxychloroquine in combination with trametinib.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs) for the duration of study treatment
Time Frame:30 days after last dose
Safety Issue:
Description:To assess the safety of the combination of trametinib and hydroxychloroquine
Measure:Response Rate
Time Frame:5 years
Safety Issue:
Description:To assess the efficacy of the combination of trametinib and hydroxychloroquine

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Utah

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