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

NCT03794297 | Withdrawn Phase 2 DMC FDA Drug

• 4 other identifiers: NCI-2018-03659NCI9598B9598BP30CA016672
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Erdheim-Chester Disease

Outcome Measures

Primary Outcomes (2)

• 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.

  Up to 48 weeks after completion of study treatment

• Incidence of toxicities

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

  Up to 48 weeks after completion of study treatment

Secondary Outcomes (15)

• Time to response

  Up to 48 weeks after completion of study treatment

• Duration of response

  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

• Progression-free survival

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

• Overall survival

  Up to 48 weeks after completion of study treatment

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

  Up to 48 weeks after completion of study treatment

Study Arms (1)

Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)

EXPERIMENTAL

Patients 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.

Drug: Dabrafenib Mesylate; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Trametinib Dimethyl Sulfoxide

Interventions

Dabrafenib Mesylate DRUG

Given PO

Also known as: Dabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, Tafinlar

Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)

Questionnaire Administration OTHER

Ancillary studies

Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)

Trametinib Dimethyl Sulfoxide DRUG

Given PO

Also known as: Mekinist

Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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)

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Erdheim-Chester Disease

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Filip Janku

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 1, 2019
• First Posted: January 7, 2019
• Study Start: January 4, 2019
• Primary Completion: February 18, 2021
• Study Completion: February 18, 2021
• Last Updated: March 17, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)