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Erdheim-Chester DiseasePhase 2NCT03794297

Dabrafenib and Trametinib in Treating Patients With Erdheim Chester Disease With BRAF V600 Mutations

A Phase 2 study testing Dabrafenib Mesylate, Quality-of-Life Assessment and Questionnaire Administration in people with Erdheim-Chester Disease, run by National Cancer Institute (NCI) at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This phase II trial studies the side effects and how well dabrafenib and trametinib work in treating patients with Erdheim Chester disease that have BRAF V600 gene mutations. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Erdheim-Chester Disease
What is being tested?
Dabrafenib Mesylate, Quality-of-Life Assessment and Questionnaire Administration
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteUnited States
Study dates
4 Jan 2019to 18 Feb 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients can be previously or simultaneously enrolled in the natural history ECD protocol #11-HG-0207, "Clinical and Basic Investigations into Erdheim Chester disease". Eligible patients must have been diagnosed with Erdheim Chester disease, confirmed by pathological evaluation of the affected tissue with adequate staining. Affected tissue must harbor the BRAF V600 mutation
  • Patients must have measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors 1.1
  • Prior treatment, involving interferon, anakinra, imatinib, steroids, chemotherapy with, but not limited to cladribine, vinblastine, 6-mercaptopurine and etoposide, or other medications used empirically for the treatment of ECD, will be acceptable. These therapies should have been completed and discontinued 4 weeks or for biologic agents 4 weeks or 5 half-lives (whichever comes shorter) prior to enrollment in this study
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Exception will be made for patients with ECOG performance status =< 3 and Karnofsky performance scale >= 50%, who require the use of wheelchairs, walkers or canes as well as assistance with daily routines secondary to disabilities caused by ECD cerebellar or brain disease that has been stable for >= 3 months
  • Life expectancy of greater than 3 months
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  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • Patients must have BRAF V600 mutation in the tumor tissue and/or cell-free deoxyribonucleic acid (DNA), identified by a Clinical Laboratory Improvement Act (CLIA)-certified lab
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • Hemoglobin >= 8 g/dL
  • Platelets >= 75 x 10^9/L
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional ULN
  • Serum creatinine =< 1.5 x institutional ULN
  • Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO)
  • Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration or randomization
  • Pregnancy and breast feeding. The effects of dabrafenib and trametinib on the developing human fetus are unknown. For this reason women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed due to drug-drug interactions which can render hormonal contraceptives ineffective) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Based on studies in animals, it is also known that dabrafenib may cause damage to the tissue that makes sperm. This may cause sperm to be abnormal in shape and size and could lead to infertility, which may be irreversible. Safety and efficacy of the combination of dabrafenib and trametinib in pediatric populations have not been investigated. Dabrafenib or trametinib-dabrafenib combination should not be administered to pediatric populations outside clinical trials
  • Therapeutic level dosing of warfarin can be used with close monitoring of prothrombin time (PT)/international normalized ratio (INR) by the site. Exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR. Consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate. Prophylactic low dose warfarin may be given to maintain central catheter patency
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • Inability to provide informed consent
  • Patients treated with prior BRAF and/or MEK inhibitors
  • Current use of a prohibited medication. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible. Current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded
  • Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) grade 2 or higher from previous anti-cancer therapy, except alopecia, at the time of randomization
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib
  • A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed)
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  • Presence of active malignancy other than the study indication
  • Patients with known RAS in ECD, or history of other malignancies with RAS mutations
  • Leptomeningeal or brain metastases are allowed. Subjects on a stable dose of corticosteroids can be enrolled with approval of the principal investigator (PI) and Cancer Therapy Evaluation Program (CTEP) medical monitor. Subjects must not receive enzyme-inducing anticonvulsants
  • History or evidence of cardiovascular risks, except stable ECD cardiac lesion, including any of the following:
  • QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480 msec
  • History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization
  • History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  • Intra-cardiac defibrillators
  • Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study
  • History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible
  • Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
  • Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures
  • Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dabrafenib/trametinib, breastfeeding should be discontinued prior to treatment with dabrafenib/trametinib. These potential risks may also apply to other agents used in this study
  • History of retinal vein occlusion (RVO)
  • Interstitial lung disease or pneumonitis not secondary to ECD
  • Central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or visible pathology (e.g., evidence of optic disc cupping, evidence of new visual field defects on automated perimetry, or intraocular pressure > 21 mmHg as measured by tonography) as assessed by ophthalmic examination
  • Inability to travel to the treating center
  • Patients with confirmed diagnosis of ECD that are asymptomatic and with no visceral involvement are not eligible for this trial (patients with no target lesions as per RECIST 1.1 criteria)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Lesions in Erdheim Chester Disease

This phase II trial studies the side effects and how well dabrafenib and trametinib work in treating patients with Erdheim Chester disease that have BRAF V600 gene mutations. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To study the efficacy and safety of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) as combination therapy in patients with BRAF V600E positive Erdheim Chester disease.

II. To determine the clinical response rate to dabrafenib and trametinib combination therapy in patients with BRAF V600E positive Erdheim Chester disease.

SECONDARY OBJECTIVES:

  1. To determine time response, progression free survival and overall survival. II. To assess disease resistance to this combination therapy.

EXPLORATORY OBJECTIVES:

  1. To monitor the degree of histiocytic infiltration-fibrosis progression, stability and regression under combination therapy using fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scan, magnetic resonance imaging (MRI) scans, computed tomography (CT) scans and technetium (T)-99m bone scans.

II. To monitor serum C-reactive protein (CRP), estrogen receptor (ESR), and cytokine levels as inflammatory markers prior to and during combination therapy.

III. To monitor renal function prior to and during combination therapy in order to assess for functional improvement.

IV. To evaluate the level of functioning, fatigue, motor skills and ability to perform routine daily activities prior to and during therapy in order to assess for improvements in these areas as well as quality of life improvement.

  1. To establish duration of treatment-endpoints in patients with BRAF V600E positive Erdheim-Chester disease (ECD) lesions.

OUTLINE:

Patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 48 weeks.

Being tested
Dabrafenib Mesylate, Quality-of-Life Assessment, Questionnaire Administration, Trametinib Dimethyl Sulfoxide
Medical subject headings
Erdheim-Chester Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Dabrafenib MesylateDrug

    Also called Dabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, Tafinlar

    Given PO

  • Quality-of-Life AssessmentOther

    Also called Quality of Life Assessment

    Ancillary studies

  • Questionnaire AdministrationOther

    Ancillary studies

  • Trametinib Dimethyl SulfoxideDrug

    Also called Mekinist

    Given PO

Study groups in NCT03794297
Study groupRoleWhat they receive
Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)ExperimentalPatients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Dabrafenib Mesylate; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Trametinib Dimethyl Sulfoxide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical response rate

    Measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response to therapy will be evident on follow up imaging studies revealing a decrease in lesion size of 30% or more, which is defined as a partial response as per RECIST criteria, when compared to baseline studies.

    Measured: Up to 48 weeks after completion of study treatment

  2. Incidence of toxicities

    Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

    Measured: Up to 48 weeks after completion of study treatment

Secondary outcomes (15)

  1. Time to response

    Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

    Measured: Up to 48 weeks after completion of study treatment

  2. Duration of response

    Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

    Measured: From the time measurement criteria are met for complete or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 48 weeks after completion of study treatment

  3. Progression-free survival

    Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

    Measured: From start of treatment to time of progression or death, whichever occurs first, assessed up to 48 weeks after completion of study treatment

  4. Overall survival

    Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

    Measured: Up to 48 weeks after completion of study treatment

  5. Degree of histiocytic infiltration using fludeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and bone scans

    Measured: Up to 48 weeks after completion of study treatment

  6. Levels of C-reactive protein

    Measured: Up to 48 weeks after completion of study treatment

  7. Levels of estrogen receptor (ESR)

    Measured: Up to 48 weeks after completion of study treatment

  8. Levels of cytokines

    Measured: Up to 48 weeks after completion of study treatment

  9. Change in fatigue

    Patients will be evaluated using the multi-dimensional fatigue inventory.

    Measured: Baseline up to 48 weeks after completion of study treatment

  10. Change in level of functioning

    Patients will be evaluated using the 6 minute walk test, single leg stance, and functional reach and grip strength using a dynamometer.

    Measured: Baseline up to 48 weeks after completion of study treatment

  11. Change in ability to perform routine activities

    Patients will be evaluated using the human activity profile and activity card sort.

    Measured: Baseline up to 48 weeks after completion of study treatment

  12. Change in pain

    Patients will be evaluated using the comparative pain scale.

    Measured: Baseline up to 48 weeks after completion of study treatment

  13. Change in fine motor dexterity

    Patients will be evaluated using the the group peg board test.

    Measured: Baseline up to 48 weeks after completion of study treatment

  14. Change in overall quality of life

    Improvement of patients' overall quality of life will be evidence of response, and assessments will be made at baseline and throughout the trial, as well as at the conclusion of the trial, to evaluate for any improvement in quality of life. Patients will be evaluated using the National Institute of Neurological Disorders and Stroke-Neuro-Quality of Life scale.

    Measured: Baseline up to 48 weeks after completion of study treatment

  15. Resistance to therapy

    Resistance to therapy will be evaluated through imaging studies and patient follow up for at least one year, but this is not expected with the combination therapy.

    Measured: Up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Jan 2019
  2. Study start4 Jan 2019
  3. Primary completion18 Feb 2021
  4. Study completion18 Feb 2021

Why it stopped: Inadequate accrual rate

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03794297
Sponsor's protocol ID
NCI-2018-03659
Other IDs
NCI-2018-03659, NCI9598B, 9598B, 9598B, P30CA016672
Status last verified
Mar 2021
First submitted
1 Jan 2019
Last updated
17 Mar 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Dabrafenib Mesylate, Quality-of-Life Assessment and Questionnaire Administration in people with Erdheim-Chester Disease, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 17 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical response rate (time frame: Up to 48 weeks after completion of study treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03794297.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Mar 2021.

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