Dabrafenib and Trametinib in Treating Patients With Erdheim Chester Disease and BRAF Mutation

PRIMARY OBJECTIVES:

I. To study the efficacy and safety of dabrafenib and trametinib as combination therapy in
patients with BRAFV600E positive Erdheim Chester disease.

II. To determine the clinical response rate to dabrafenib and trametinib combination therapy
in patients with BRAFV600E 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.

TERTIARY 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 orally (PO) twice daily (BID) and trametinib PO once daily (QD)
on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Inclusion Criteria:

- All patients will 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 V600E or V600K mutation

- 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 with conventional
techniques or as >= 10 mm with spiral CT scan, MRI, or calipers by clinical exam

- 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 more prior to
enrollment in this study

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- 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 BRAFV600E or BRAFV600K mutations, identified by a Food and Drug
Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments
(CLIA)-certified lab; if test at CLIA-certified lab used a non-FDA approved method,
information about the assay must be provided; (FDA approved tests for BRAF V600
mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600
Mutation Test)

- Absolute neutrophil count (ANC) >= 1.2 x 10^9/L

- Hemoglobin >= 9 g/dL

- Platelets >= 100 x 10^9/L

- Albumin >= 2.5 g/dL

- 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) =< 2.5 x
institutional ULN

- Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
formula) >= 50 mL/min

- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment
may be allowed to participate with INR established within the therapeutic range prior
to randomization

- 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

- Women of child-bearing potential must agree to use adequate contraception (barrier
method of birth control, or abstinence; hormonal contraception is not allowed) 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

- Therapeutic level dosing of warfarin can be used with close monitoring of PT/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

Exclusion Criteria:

- Inability to provide informed consent

- Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive
radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the
last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks
preceding the first dose of study treatment

- 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
study treatment and during the study; patients that have used other BRAF or
mitogen-activated protein kinase kinase (MEK) inhibitor are excluded

- Current use of a prohibited medication; patients receiving any medications or
substances that are strong inhibitors or inducers of cytochrome P450, family 3,
subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (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 4.0 (NCI CTCAE v4.0) 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

- 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 malignancy other than the study indication under this trial within 5
years of study enrollment

- Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible
regardless of interval from the current study; note: prospective RAS testing is not
required; however, if the results of previous RAS testing are known, they must be
used in assessing eligibility

- Leptomeningeal or brain metastases or metastases causing spinal cord compression that
are symptomatic or untreated or not stable for >= 3 months (must be documented by
imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids >
1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled
with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor;
subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks

- 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; breastfeeding should be discontinued
prior to treatment with dabrafenib/trametinib

- 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 National Institutes of Health (NIH) Clinical Center

- Patients with wild type BRAF gene molecular results on ECD affected tissue

- 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
Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria