A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Lesions in Erdheim Chester Disease
Overview
- Phase
- Phase 2
- Status
- Withdrawn
- Locations
- 1
- Primary Endpoint
- Clinical response rate
Overview
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.
Detailed Description
PRIMARY OBJECTIVES:
I. 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:
I. To determine time response, progression free survival and overall survival. II. To assess disease resistance to this combination therapy.
EXPLORATORY OBJECTIVES:
I. 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.
V. 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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
Exclusion Criteria
- •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:
Arms & Interventions
Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
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.
Intervention: Dabrafenib Mesylate (Drug)
Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
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.
Intervention: Quality-of-Life Assessment (Other)
Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
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.
Intervention: Questionnaire Administration (Other)
Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
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.
Intervention: Trametinib Dimethyl Sulfoxide (Drug)
Outcomes
Primary Outcomes
Clinical response rate
Time Frame: Up to 48 weeks after completion of study treatment
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.
Incidence of toxicities
Time Frame: Up to 48 weeks after completion of study treatment
Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Secondary Outcomes
- Levels of cytokines(Up to 48 weeks after completion of study treatment)
- Change in fine motor dexterity(Baseline 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)
- Levels of C-reactive protein(Up to 48 weeks after completion of study treatment)
- Change in fatigue(Baseline up to 48 weeks after completion of study treatment)
- Resistance to therapy(Up to 1 year)
- 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)
- Levels of estrogen receptor (ESR)(Up to 48 weeks after completion of study treatment)
- Change in pain(Baseline up to 48 weeks after completion of study treatment)
- Change in overall quality of life(Baseline up to 48 weeks after completion of study treatment)
- Change in level of functioning(Baseline up to 48 weeks after completion of study treatment)
- Change in ability to perform routine activities(Baseline up to 48 weeks after completion of study treatment)