Ulixertinib in People With Histiocytic Neoplasms

Inclusion Criteria:

• Histologically confirmed histiocytic neoplasm or histologic findings consistent withhistiocytic neoplasm with confirmatory radiologic or molecular findings. Pathologicexamination can be performed at any of the enrolling institutions. Thisqualification is made because it is well known that biopsies of histiocyticneoplasms are variable and do not always demonstrate "typical" morphologicappearance with all of the classically described elements. As a result, histiocyticneoplasms are not exclusively pathologic diagnoses-rather, they are interpretationsof histologic findings in a clinical and radiologic context. These criteria wereapplied in NCT02649972 and will be applied in this trial

• Identified mutation in MAPK pathway genes, including but not limited to ARAF, BRAF,RAF1, NRAS, KRAS, MAP2K1, MAP2K2, and NF1 (primary cohort). Tumor mutation may beidentified by tumor sequencing or cfDNA-based sequencing. Concordance between cfDNAand tumor sequencing for BRAFV600E and non-BRAF mutations in histiocytic neoplasmshas been documented by our group and others

• Measurable disease according to PRC, confirmed by an investigator radiologist

• Age (a) ≥18 years prior to interim safety and efficacy analyses or (b) ≥12 yearsfollowing the interim safety and efficacy analyses

• The histiocytic neoplasm must be (a) disease that is recurrent/refractory/persistentdespite local therapies, chemotherapy, immunosuppression, or BRAF/MEK inhibitors OR (b) multisystem disease OR (c) single-system disease that is causing end-organdysfunction and is unlikely to benefit from local or conventional (chemotherapy orimmunosuppressive) therapies on the basis of evidence-based guidelines (e.g.symptomatic neurologic-only LCH)

• Prior treatment (chemotherapy, BRAF inhibitor, or MEK inhibitor) is required and thepatient must have (a) progressive disease or persistent disease (i.e. having diseasemeasurable by PRC) or (b) intolerance or contraindication to chemotherapy, BRAFinhibition, or MEK inhibition.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (age ≥ 16) orLansky 50-100 (age 12-15)

• Adequate renal function (according to the Cockcroft-Gault equation; creatinine ≤1.5times upper limit of normal [ULN] or a glomerular filtration rate of ≥50 mL/min)

• Pediatric patients (<18 years old) must have a creatinine clearance orradioisotope GFR ≥ 70 mL/min/1.73 m^2 or serum creatinine based on age/genderas follows:

• < 13 years- 1.2 (Male),1.2 (Female)

• 13 to < 16 years- 1.5 (Male), 1.4 (Female) °≥ 16 years- 1.7 (Male), 1.4 (Female)

• The threshold creatinine values in this Table were derived from the Schwartzformula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizingchild length and stature data published by the CDC.

• Patients with renal impairment deemed the direct result of disease andtherefore amenable to improvement with Ulixertinib treatment may be enrolled atthe discretion of the treating investigator

• Adequate hepatic function (total bilirubin ≤1.5 times ULN, aspartate transaminase [AST] and- alanine transaminase [ALT] ≤3 times ULN or ≤5 times ULN if attributableto liver involvement by tumor). Patients with hepatic impairment deemed the directresult of disease and therefore amenable to improvement with Ulixertinib treatmentmay be enrolled at the discretion of the treating investigator.

• Adequate bone marrow function (hemoglobin ≥9.0 g/dL, platelets ≥100 x 10^9 cells/L,absolute neutrophil count ≥1.5 x 10^9 cells/L). Patients with cytopenias deemed thedirect result of disease and therefore amenable to improvement with Ulixertinibtreatment may be enrolled at the discretion of the treating investigator.

• Adequate cardiac function

• Left ventricular ejection fraction >50% as assessed by multi-gated acquisitionor ultrasound or echocardiography and

• Corrected QT interval (QTc) <480 ms according to the Fridericia method (QTcF)

• Contraception

• For women: a negative pregnancy test for those of child-bearing potential, mustbe surgically sterile, postmenopausal (no menstrual cycle for at least 12consecutive months), or compliant with a medically approved contraceptiveregimen during and for 3 months after the treatment period

• For men: must be surgically sterile or compliant with a medically approvedcontraceptive regimen during and for 3 months after the treatment period

• For patients aged <18 years who are not sexually active: abstinence is anacceptable form of contraception. The reliability of sexual abstinence needs tobe evaluated in relation to the duration of the study and the preferred andusual lifestyle of the participant.

• Willing and able to participate in the trial and comply with all trial requirements

• Patients with a prior or concurrent malignancy whose natural history or treatment

• does not have the potential to interfere with the safety or efficacy assessmentof

• the investigational agent may be included at the discretion of the site PI

Exclusion Criteria:

• Uncontrolled or severe intercurrent medical condition

• Receipt of any histiocytic neoplasm-directed therapy (chemotherapy, targetedtherapy, biologic) within 28 days or 5 half-lives (whichever is shorter) before thefirst dose of ulixertinib. Patients previously treated with radiotherapy must haverecovered from acute toxicities associated with such treatment

• Histiocytic neoplasm mandated for observation-only or first-line local therapy perestablished guidelines. Examples would include asymptomatic nodal RDD, asymptomaticosseous ECD, or limited cutaneous LCH

• Major surgery within 4 weeks of the first dose of ulixertinib

• Pregnant, lactating, or breast-feeding (for women)

• Any evidence of serious active infections. Patients are allowed to enroll if theyhave been fever free for at least 48 h

• History or current evidence of risk of retinal vein occlusion or central serousretinopathy. Examples of risk factors to be considered would include uncontrolledocular hypertension or history of hyperviscosity.

• Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2,CYP2D6, and CYP3A4

• Concurrent therapy with p-glycoprotein inhibitors and sensitive substrates ofCYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 with narrow therapeutic indices

• Inability to swallow oral medications

• Prior stomach or duodenal resection that, in the opinion of the site PI, wouldaffect the breakdown and absorption of the study medications. Patients with afeeding tube will also be excluded, as ulixertinib tablets cannot be taken broken,cracked or otherwise not intact. Note: ulixertinib is primarily absorbed in theduodenum, and therefore the potential inclusion of a patient with any prior stomachor duodenal resection should be discussed with the MSK PI

• Concurrent therapy with any investigational agent

• Any use of an investigational drug within 28 days or 5 half-lives (whichever isshorter). In addition, any drug toxicities should have recovered to grade 1 or lessbefore start of the trial medication