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

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT03148275
First Posted: May 10, 2017
Last Update Posted: November 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  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.

Condition Intervention Phase
Epithelioid Hemangioendothelioma Other: Laboratory Biomarker Analysis Other: Questionnaire Administration Drug: Trametinib Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Non-randomized, Open-Label, Phase 2 Study of Trametinib in Patients With Unresectable or Metastatic Epithelioid Hemangioendothelioma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective response rate as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Up to 6 months ]
    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:
  • 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 ]
    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.

  • 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 ]
    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.

  • 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 ]
    Will be calculated along with 95% confidence intervals and estimated by the Kaplan-Meier method.

  • Overall survival [ Time Frame: From the time of first dose of study drug to occurrence of death from any cause, assessed at 2 years ]
    Will be calculated along with 95% confidence intervals and estimated by the Kaplan-Meier method.

  • 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 ]
    Will be calculated along with 95% confidence intervals and estimated by the Kaplan-Meier method.


Other Outcome Measures:
  • Change in CRP level [ Time Frame: Baseline up to 6 months ]
    Will be used as time-dependent variables in a Cox model to determine the association with epithelioid hemangioendothelioma survival.

  • Change in epithelioid hemangioendothelioma growth rate [ Time Frame: Baseline up to 6 months ]
    McNemar test will be used to compare the number of patients with epithelioid hemangioendothelioma progression prior to starting trametinib to the number of patients with epithelioid hemangioendothelioma progression during treatment.

  • Change in ESR level [ Time Frame: Baseline up to 6 months ]
    Will be used as time-dependent variables in a Cox model to determine the association with epithelioid hemangioendothelioma survival.

  • Change in plasma CTGF level as analyzed by enzyme-linked immunosorbent assay [ Time Frame: Baseline up to 6 months ]
    Will be used as time-dependent variables in a Cox model to determine the association with epithelioid hemangioendothelioma survival.

  • Change in tumor volume as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Baseline up to 6 months ]
    Will be summarized with a scatterplot. The Pearson correlation coefficient (or Spearman, if more appropriate) will be assessed to determine the strength of the agreement. Agreement of the tumor classifications (response versus no response) will be summarized as the raw agreement and with a Kappa Statistic. The association of the change in tumor volume with survival will be evaluated in two ways. The first will be to use the change in tumor volume as a time dependent variable in a Cox model. The second will be a landmark analysis (done at either the first radiographic assessment or at the secon

  • MAP kinase activation as analyzed by immunohistochemistry [ Time Frame: Up to 6 months ]
    Descriptive statistics will be generated, and estimates for the proportion of samples with demonstrated inhibition of MAPK signaling post-treatment compared to pre-treatment will be generated along with 95% confidence intervals. Likewise, the proportion of patients with demonstrated MAPK signaling inhibition at time of disease progression will be determined with the corresponding 95% confidence interval.

  • Number of TAZ-CAMTA1 gene fusion [ Time Frame: Up to 6 months ]
    Will be evaluated by fluorescence in situ hybridization.

  • Percent of TAZ-CAMTA1 gene fusion [ Time Frame: Up to 6 months ]
    Will be evaluated by fluorescence in situ hybridization.


Estimated Enrollment: 27
Actual Study Start Date: April 19, 2017
Estimated Study Completion Date: December 31, 2023
Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (trametinib)
Patients 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Questionnaire Administration
Ancillary studies
Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   15 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03148275


Locations
United States, California
Stanford Cancer Institute Palo Alto Recruiting
Palo Alto, California, United States, 94304
Contact: Kristen N. Ganjoo    650-498-7061    ccto-office@stanford.edu   
Principal Investigator: Kristen N. Ganjoo         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Victor M. Villalobos    720-848-0650      
Principal Investigator: Victor M. Villalobos         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Christian F. Meyer    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Christian F. Meyer         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Edwin Choy    877-726-5130      
Principal Investigator: Edwin Choy         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Edwin Choy    877-726-5130      
Principal Investigator: Edwin Choy         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Edwin Choy    877-726-5130      
Principal Investigator: Edwin Choy         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Edwin Choy    877-726-5130      
Principal Investigator: Edwin Choy         
United States, Michigan
University of Michigan Comprehensive Cancer Center EDDOP Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Scott M. Schuetze    800-865-1125      
Principal Investigator: Scott M. Schuetze         
University of Michigan Comprehensive Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Scott M. Schuetze    800-865-1125      
Principal Investigator: Scott M. Schuetze         
United States, Missouri
Siteman Cancer Center at West County Hospital Recruiting
Creve Coeur, Missouri, United States, 63141
Contact: Brian A. Van Tine    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Brian A. Van Tine         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Brian A. Van Tine    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Brian A. Van Tine         
United States, New York
Montefiore Medical Center-Einstein Campus Recruiting
Bronx, New York, United States, 10461
Contact: Joseph A. Sparano    718-904-2730    aecc@aecom.yu.edu   
Principal Investigator: Joseph A. Sparano         
Montefiore Medical Center-Weiler Hospital Recruiting
Bronx, New York, United States, 10461
Contact: Joseph A. Sparano    718-904-2730    aecc@aecom.yu.edu   
Principal Investigator: Joseph A. Sparano         
Montefiore Medical Center - Moses Campus Recruiting
Bronx, New York, United States, 10467-2490
Contact: Joseph A. Sparano    718-904-2730    aecc@aecom.yu.edu   
Principal Investigator: Joseph A. Sparano         
Columbia University/Herbert Irving Cancer Center Recruiting
New York, New York, United States, 10032
Contact: Gary K. Schwartz    212-639-7202      
Principal Investigator: Gary K. Schwartz         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: James L. Abbruzzese    888-275-3853      
Principal Investigator: James L. Abbruzzese         
United States, Ohio
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Aaron T. Gerds    866-223-8100      
Principal Investigator: Aaron T. Gerds         
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Gabriel R. Tinoco Suarez    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Gabriel R. Tinoco Suarez         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Melissa A. Burgess    412-692-2001      
Principal Investigator: Melissa A. Burgess         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Elizabeth J. Davis    800-811-8480      
Principal Investigator: Elizabeth J. Davis         
United States, Utah
Huntsman Cancer Institute/University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Jonathan Whisenant    801-581-4477    clinical.trials@hci.utah.edu   
Principal Investigator: Jonathan Whisenant         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Scott Schuetze University of Michigan Comprehensive Cancer Center EDDOP
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03148275     History of Changes
Other Study ID Numbers: NCI-2017-00712
NCI-2017-00712 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
SARC033
10015 ( Other Identifier: University of Michigan Comprehensive Cancer Center EDDOP )
10015 ( Other Identifier: CTEP )
P30CA046592 ( U.S. NIH Grant/Contract )
First Submitted: May 1, 2017
First Posted: May 10, 2017
Last Update Posted: November 17, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Hemangioendothelioma
Hemangioendothelioma, Epithelioid
Hemangioma
Neoplasms, Vascular Tissue
Neoplasms by Histologic Type
Neoplasms
Trametinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action