Clinical Trials /

Trametinib in Treating Patients With Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery

NCT03148275

Description:

This phase II trial studies how well trametinib works in treating patients with epithelioid hemangioendothelioma that has spread to other places in the body, nearby tissue or lymph nodes, or cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Epithelioid Hemangioendothelioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trametinib in Treating Patients With Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery
  • Official Title: A Non-randomized, Open-Label, Phase 2 Study of Trametinib in Patients With Unresectable or Metastatic Epithelioid Hemangioendothelioma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00712
  • SECONDARY ID: NCI-2017-00712
  • SECONDARY ID: SARC033
  • SECONDARY ID: 10015
  • SECONDARY ID: 10015
  • SECONDARY ID: P30CA046592
  • NCT ID: NCT03148275

Conditions

  • Epithelioid Hemangioendothelioma

Interventions

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

Purpose

This phase II trial studies how well trametinib works in treating patients with epithelioid hemangioendothelioma that has spread to other places in the body, nearby tissue or lymph nodes, or cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Estimate the objective response rate (ORR) using Response Evaluation Criteria in Solid
      Tumors version 1.1 (RECIST 1.1).

      SECONDARY OBJECTIVES:

      I. Estimate the 6-month and median progression free survival (PFS) rates. II. Estimate the
      2-year and median overall survival (OS) rates. III. Evaluate the safety of trametinib in
      patients with epithelioid hemangioendothelioma.

      IV. Evaluate patient-reported symptoms using National Institutes of Health Patient Reported
      Outcomes Measurement Information System (NIH PROMIS) global health; pain intensity,
      interference and behavior short form inventories prior to, after 4 weeks and after 6 months
      (if stable or better disease) of treatment, and on evidence of disease progression.

      TERTIARY OBJECTIVES:

      I. Compare the rates of epithelioid hemangioendothelioma progression prior to starting
      trametinib to rates on treatment by central review of radiology images.

      II. Evaluate the effect of trametinib on change in tumor volume and compare to RECIST 1.1
      response through central imaging review.

      III. Evaluate the effect of trametinib on markers of inflammation including c-reactive
      protein (CRP), erythrocyte sedimentation rate (ESR) and plasma connective tissue growth
      factor (CTGF).

      OUTLINE:

      Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
      days for up to 52 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 6 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib)ExperimentalPatients receive trametinib PO QD on days 1-28. Courses repeat every 28 days for up to 52 courses in the absence of disease progression or unacceptable toxicity.
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
             conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam; baseline imaging
             must be obtained within 30 days of day 1 of study

          -  Patients must have histologically confirmed epithelioid hemangioendothelioma which is
             metastatic or locally advanced (unresectable)

          -  Patients must have evidence of disease progression per RECIST 1.1 prior to enrollment
             or have evidence of cancer-related pain requiring symptom management with narcotic
             analgesics

          -  Patients previously untreated or treated with drug therapy for epithelioid
             hemangioendothelioma (EHE) are eligible; there is no limit on the number of prior
             regimens used to be eligible

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 6 months

          -  Able to swallow orally-administered medication and does not have any clinically
             significant gastrointestinal abnormalities that may alter absorption such as
             malabsorption syndrome or major resection of the stomach or small bowel

          -  All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
             Events version 4 (CTCAE v4) grade =< 1 (except alopecia) at the time of enrollment

          -  Absolute neutrophil count (ANC) >= 1 x 10^9/L

          -  Hemoglobin >= 9 g/dL, patients may receive transfusion to meet criterion

          -  Platelets >= 75 x 10^9/L

          -  Albumin >= 2.5 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); NOTE: patients
             with elevated bilirubin secondary to Gilbert's disease are eligible to participate in
             the study

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
             institutional ULN

          -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
             formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

          -  Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN)
             by echocardiogram (ECHO) or multigated acquisition scan (MUGA)

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, during
             the study participation, and for four months after the last dose of the drug; women of
             child-bearing potential must have a negative serum pregnancy test within 14 days prior
             to enrollment and agree to use effective contraception throughout the treatment period
             and for 4 months after the last dose of study treatment; should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately

          -  Human immunodeficiency virus (HIV)-patients positive for human immunodeficiency virus
             (HIV) are NOT excluded from this study, however HIV-positive patients must meet the
             following criteria:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based test

        Exclusion Criteria:

          -  Prior systemic therapy with a MEK inhibitor

          -  History of another malignancy

               -  Exception: patients who have been disease-free for 3 years or patients with a
                  history of completely resected non-melanoma skin cancer and/or patients with
                  indolent secondary malignancies, are eligible; consult the Cancer Therapy
                  Evaluation Program (CTEP) medical monitor if unsure whether second malignancies
                  meet the requirements specified above

          -  History of interstitial lung disease or pneumonitis requiring supplemental oxygen or
             treatment with oral or intravenously administered corticosteroids

          -  Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity (e.g.
             doxorubicin), biologic therapy, or immunotherapy within 21 days prior to enrollment
             and/or daily or weekly chemotherapy (e.g. sunitinib, sorafenib and pazopanib) without
             the potential for delayed toxicity within 14 days prior to enrollment

          -  Use of other investigational drugs within 28 days (or five half-lives, whichever is
             shorter; with a minimum of 14 days from the last dose) preceding the first dose of
             trametinib and during the study

          -  Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression

          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO)

          -  Current use of a prohibited medication; the following medications or non-drug
             therapies are prohibited:

               -  Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if
                  used as an appetite stimulant is allowed)

               -  Concurrent treatment with bisphosphonates is permitted; however, treatment must
                  be initiated prior to the first dose of study therapy; prophylactic use of
                  bisphosphonates in patients without bone disease is not permitted, except for the
                  treatment of osteoporosis

               -  The concurrent use of all herbal supplements is prohibited during the study
                  (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo
                  biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

          -  History or current evidence/risk of retinal vein occlusion (RVO)

          -  History or evidence of cardiovascular risk including any of the following:

               -  LVEF < LLN (lower limit of normal range)

               -  A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480
                  msec

               -  History or evidence of current clinically significant uncontrolled arrhythmias
                  (exception: patients with controlled atrial fibrillation for > 30 days prior to
                  randomization are eligible)

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to randomization

               -  History or evidence of current >= class II congestive heart failure as defined by
                  the New York Heart Association (NYHA) functional classification system

               -  Treatment-refractory hypertension defined as a blood pressure of systolic >140
                  mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
                  therapy

               -  Patients with intra-cardiac defibrillators

               -  Known cardiac metastases

          -  Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with
             chronic or cleared HBV and HCV infection are eligible)

          -  Any serious and/or unstable pre-existing medical disorder (aside from malignancy
             exception above), psychiatric disorder, or other conditions that could interfere with
             subject's safety, obtaining informed consent or compliance to the study procedures

          -  The study drug must not be administered to pregnant women or nursing mothers; women of
             childbearing potential should be advised to avoid pregnancy and use effective methods
             of contraception; men with a female partner of childbearing potential must have either
             had a prior vasectomy or agree to use effective contraception; if a female patient or
             a female partner of a patient becomes pregnant while the patient receives trametinib,
             the potential hazard to the fetus should be explained to the patient and partner (as
             applicable)

          -  Inability to comply with protocol-required procedures
      
Maximum Eligible Age:N/A
Minimum Eligible Age:15 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate as assessed by Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 6 months
Safety Issue:
Description:A Simon minimax sampling two-stage design will be used to estimate the objective response rate. Will be calculated along with 95% confidence intervals.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:From time of first dose of study medication to occurrence of radiologic tumor progression per Response Evaluation Criteria in Solid Tumors 1.1, clinical progression based on treating physician assessment or death from any cause, assessed at 6 months
Safety Issue:
Description:Will be calculated along with 95% confidence intervals and estimated by the Kaplan-Meier method.
Measure:Median progression-free survival
Time Frame:From time of first dose of study medication to occurrence of radiologic tumor progression per Response Evaluation Criteria in Solid Tumors 1.1, clinical progression based on treating physician assessment or death from any cause, assessed up to 6 months
Safety Issue:
Description:Will be calculated along with 95% confidence intervals and estimated by the Kaplan-Meier method.
Measure:Overall survival
Time Frame:From the time of first dose of study drug to occurrence of death from any cause, assessed at 2 years
Safety Issue:
Description:Will be calculated along with 95% confidence intervals and estimated by the Kaplan-Meier method.
Measure:Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events version 4.0
Time Frame:Up to 6 months
Safety Issue:
Description:The rates of adverse events occurring in at least 5% of subjects and rates of grade 3-5 adverse events will be tabulated by system and term.
Measure:Change in patient reported symptoms as assessed by National Institutes of Health Patient Reported Outcomes Measurement Information System questionnaire
Time Frame:Baseline up to 6 months
Safety Issue:
Description:Patient Reported Outcomes Measurement Information System questionnaires will be scored according to recommended standardized system and t-scores generated. A mixed model will be used to analyze change in t-scores over time.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 7, 2018