Testing the Effectiveness of the Anti-cancer Drug, Mirdametinib, in Treating Relapsed, Refractory Chronic Lymphocytic Leukemia

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed CLL or smalllymphocytic lymphoma (SLL), as documented by a history at some point in time of anabsolute peripheral blood B cell count > 5000/mcL with a monoclonal B cellpopulation coexpressing CD19, CD5, and CD23, or if CD23 negative, then documentationof the absence of t(11;14) or cyclin D1 overexpression. Alternatively, patients withlymphadenopathy in the absence of circulating disease will also be eligible for thisstudy if lymph node biopsy or bone marrow biopsy has established the diagnosis ofCLL with the above immunophenotype

• Patients must have a current indication for treatment as defined by the iwCLL 2018Guidelines (Hallek et al., 2018):

• Massive or progressive splenomegaly; OR

• Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR

• Grade 2 or 3 fatigue; OR

• Fever ≥ 100.5°F or night sweats for greater than 2 weeks without documentedinfection; OR

• Presence of weight loss ≥ 10% over the preceding 6 months; OR

• Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or ananticipated doubling time of less than 6 months; OR

• Evidence of progressive marrow failure as manifested by the development of orworsening of anemia and or thrombocytopenia

• Patients must have measurable disease, defined as lymphocytosis > 5,000/mcL,palpable or computed tomography (CT) measurable lymphadenopathy > 1.5 cm, or bonemarrow involvement > 30%

• Patients must have received at least two prior therapies for CLL including systemictherapy containing a Bruton's tyrosine kinase (BTK) inhibitor and a BCL2 inhibitor.Patients are required to have prior BTK inhibitor-based therapy because constitutiveextracellular signal-regulated kinase (ERK) activation is seen in all patients withprogression after BTK inhibitor therapy

• Age ≥ 18 years. Because CLL is extremely rare in persons < 18 years of age, childrenare excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

• Absolute neutrophil count ≥ 500/mcL. Growth factor is allowed to achieve this level.Neutrophil count of 250 is permitted for patients with bone marrow involvement

• Unless they have significant bone marrow involvement of CLL confirmed on biopsy

• Platelets ≥ 20,000/mcL independent of transfusion within 7 days of screening.Transfusion is permitted to support platelet count for patients with bone marrowinvolvement

• Unless they have significant bone marrow involvement of CLL confirmed on biopsy

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless bilirubinrise is due to Gilbert's syndrome, autoimmune hemolytic anemia,(AIHA), or ofnon-hepatic origin

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN

• Glomerular filtration rate (GFR) 50 ml/min estimated using the Chronic KidneyDisease Epidemiology Collaboration (CKD-EPI) (Levey et al., 2009)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class II or better

• The effects of mirdametinib on the developing human fetus are unknown. For thisreason, women of child-bearing potential and men must agree to use highly effectivecontraception (hormonal and barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Women ofchild-bearing potential should also use adequate contraception for 6 months aftercompletion of mirdametinib administration. Men treated or enrolled on this protocolmust also agree to use adequate contraception prior to the study, for the durationof study participation, and 3 months after completion of mirdametinibadministration. Women of childbearing age should not donate egg(s) and men shouldnot donate sperm for the duration of study participation and 3 months aftercompletion of mirdametinib administration

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to mirdametinib

• Patients with concurrent administration of strong inhibitors and inducers ofP-glycoprotein (P-g)p or breast cancer specific resistance protein (BCRP). Ifdiscontinuation of the medication is appropriate, a washout duration ofapproximately 3 to 5 half-lives is recommended prior to the first dose ofmirdametinib

• Patients with concurrent administration of strong CYP3A4 inducers. Ifdiscontinuation of the medication is appropriate, a washout duration ofapproximately 3 to 5 half-lives is recommended prior to the first dose ofmirdametinib

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous

• Pregnant women are excluded from this study because mirdametinib is MEK inhibitoragent with the potential for teratogenic or abortifacient effects. Because there isan unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother mirdametinib, breastfeeding should be discontinued if themother is treated with mirdametinib

• Patients with active infection requiring intravenous (IV) antibiotics

• History or current evidence of glaucoma or clinically significant abnormalities onthe ophthalmological exam, including but not limited to cataract limiting theability to examine the retina or any optical coherence tomography (OCT) finding thatcould be a significant risk factor for retinal vein occlusion (RVO), retinopathy, orneovascular macular degeneration

• Patients with corrected QT (QTc) > 470 ms