Clinical trial NCT03148275: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Locally Advanced Epithelioid Hemangioendothelioma
Metastatic Epithelioid Hemangioendothelioma
Unresectable Epithelioid Hemangioendothelioma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2017-05-10
Enrollment: 44
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: PRIMARY OBJECTIVE:

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.

EXPLORATORY 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. Treatment repeats every 28 days for up to 52 cycles 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 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), and tumor tissue (paraffin-embedded tissue block or tumor tissue on unstained glass slides) available for fusion fluorescence in situ hybridization (FISH) analysis at Cleveland Clinic; patient tumor tissue stored in pathology archives may be used for fusion FISH; a new biopsy is not mandatory
* 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
* Because there is no established standard or approved drug therapy for treatment of epithelioid hemangioendothelioma (EHE), patients previously untreated or treated with drug therapy for 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 5.0 (CTCAE v5) grade =\< 1 (except alopecia) at the time of enrollment
* Absolute neutrophil count (ANC) \>= 1 x 10\^9/L (within 2 weeks of patient registration)
* Hemoglobin \>= 9 g/dL, patients may receive transfusion to meet criterion (within 2 weeks of patient registration)
* Platelets \>= 75 x 10\^9/L (within 2 weeks of patient registration)
* Albumin \>= 2.5 g/dL (within 2 weeks of patient registration)
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (within 2 weeks of patient registration); 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 (within 2 weeks of patient registration)
* 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 (within 2 weeks of patient registration)
* Left ventricular ejection fraction (LVEF) \>= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) (within 30 days of registration)
* Trametinib can cause fetal harm when administered to a pregnant woman; 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
  * Because the composition, pharmacokinetics (PK), and metabolism of many herbal supplements are unknown, 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:

  * 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
* Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. Therefore, 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

Primary outcomes:
measure: Objective Response Rate
timeFrame: 6 months
Secondary outcomes:
measure: 6 Month Progression-free Survival
timeFrame: 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
measure: Overall Survival
timeFrame: From the time of first dose of study drug to occurrence of death from any cause, assessed at 2 years
measure: Incidence of Adverse Events
timeFrame: at 6 months
measure: Change in Patient Reported Symptoms
timeFrame: Baseline and at 6 months
measure: Median Progression-free Survival
timeFrame: 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
Other outcomes:
measure: Change in Epithelioid Hemangioendothelioma Growth Rate
timeFrame: Baseline up to 6 months
measure: Change in CRP Level
timeFrame: Baseline up to 6 months
measure: Change in ESR Level
timeFrame: Baseline up to 6 months
measure: Change in Plasma CTGF Level
timeFrame: Baseline up to 6 months
measure: Change in Tumor Volume
timeFrame: Baseline up to 6 months
measure: Number of TAZ-CAMTA1 Gene Fusion
timeFrame: Up to 6 months
measure: Percent of TAZ-CAMTA1 Gene Fusion
timeFrame: Up to 6 months
measure: MAP Kinase Activation
timeFrame: Up to 6 months
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital in Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Palo Alto
country: United States
facility: Stanford Cancer Institute Palo Alto
state: California
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Center/Yale-New Haven Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bellevue
country: United States
facility: Nebraska Medicine-Bellevue
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Medicine-Village Pointe
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler Hospital
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Breast Center at One Hundred Oaks
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
Study officials:
affiliation: University of Michigan Comprehensive Cancer Center EDDOP
name: Scott M Schuetze
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ma S, Kanai R, Pobbati AV, Li S, Che K, Seavey CN, Hallett A, Burtscher A, Lamar JM, Rubin BP. The TAZ-CAMTA1 Fusion Protein Promotes Tumorigenesis via Connective Tissue Growth Factor and Ras-MAPK Signaling in Epithelioid Hemangioendothelioma. Clin Cancer Res. 2022 Jul 15;28(14):3116-3126. doi: 10.1158/1078-0432.CCR-22-0421.