A Study of Mirdametinib in Combination With Palbociclib in People With Liposarcoma

Inclusion Criteria:

Phase I only:

• A diagnosis of unresectable, recurrent, or metastatic DDLPS

• Phase II only:

• A diagnosis of unresectable, recurrent (e.g. recurrent retroperitoneal) ormetastatic DDLPS

• Any number of prior lines of therapy

• Measurable disease and evidence of progression of disease as defined by RECIST 1.1 (including newly diagnosed disease, new disease sites in a patient who waspreviously NED, or a 20% growth of existing lesions within 6 months ofregistration)

• Age ≥ 18 years

• ECOG performance status ≤ 2

• Adequate organ and marrow function as defined below (ULN indicatesinstitutional upper limit of normal):

• Absolute neutrophil count ≥ 1.5 x 109/L

• Hemoglobin ≥ 9.0 g/dL

• Platelets ≥ 100 x 109/L

• Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with totalbilirubin levels > 1.5 ULN, except patients with Gilbert's disease (≤3x ULN)

• AST (SGOT) /ALT (SGPT) ≤ 1.5 x institutional ULN

• Creatinine Clearance ≥ 60 mL/min (calculated by Cockcroft-Gault method)

• Adequate coagulation function, as determined by:

• International Normalized Ratio (INR) ≤ 1.5 × ULN (Grade ≤ 1). If the participantreceives anticoagulant therapy, the INR > 1.5 × ULN is permitted but the dose mustbe stable for at least 2 weeks before the start of the study treatments.

• PTT ≤ 1.5 × ULN.

• Adequate cardiac function, as determined by:

• Systolic blood pressure < 160 mmHg and diastolic blood pressure < 100 mmHg (Grade ≤ 2).

• LVEF ≥ 50% by MUGA or ECHO.

• No clinically significant ECG waveform abnormalities assessments at screening.

• Adequate glycemic control, as determined by:

• Fasting blood glucose level < 125 mg/dL, or

• Random blood glucose level < 200 mg/dL.

• Have normal serum calcium and phosphate levels (calcium level may be correctedfor albumin level).

• Have intraocular pressure ≤ 21 mmHg in both eyes

• Women of child-bearing potential must agree to use highly effectivecontraceptive methods (hormonal or barrier method of birth control orabstinence) during the trial period through at least six months after the lastdose. Male patients or their partners must be surgically sterile or agree touse adequate contraception while receiving trial treatment and for three monthsthereafter. Acceptable methods of contraceptive use by men or women aredetailed in Section 15.3.

• Ability to understand and the willingness to sign a written informed consentdocument.

• Ability to swallow tablets or capsules

• Patients with brain metastasis that have been treated with definitive surgeryor radiation, and have been clinically stable for 3 months are eligible.

Exclusion Criteria:

• Patients who have not recovered from clinically significant adverse events of priortherapy to ≤ NCI CTCAE v5 Grade 1, except alopecia and stable neuropathy, which musthave resolved to ≤ Grade 2 or baseline.

• Patients receiving any other investigational agents.

• Phase II only: Receipt of prior treatment with a selective CDK4 inhibitor or MEKinhibitor

• Uncontrolled intercurrent illness including, but not limited to, known ongoing oractive infection, including uncontrolled HIV, active hepatitis B or C, symptomaticcongestive heart failure, unstable angina pectoris, uncontrolled cardiacarrhythmias, psychiatric illness/social situations that would limit compliance withstudy requirements, clinically significant interstitial lung disease or activenoninfectious pneumonitis, or active infection requiring systemic therapy.

• Patients with a CD4+ count of > 300 and an undetectable viral load who arecurrently on HAART are eligible for inclusion.

• Patients with NYHA class III or IV congestive heart failure within 6 months ofstudy treatment will be excluded.

• Patients with history of clinically significant cardiac disease (New York HeartAssociation Class III or IV), myocardial infarction, severe/unstable angina,coronary/peripheral artery bypass graft, symptomatic congestive heart failure,cerebrovascular accident, clinically significant transient ischemic attack,symptomatic pulmonary embolism, unexplained syncope, or long QT syndrome within 6 months before the start of study treatment will be excluded.

• Pregnant women and women who are breast-feeding.

• Prolonged QTcF > 470ms at Screening, irrespective of sex.

• Current Chronic Kidney Disease stage > 3 or Creatinine Clearance < 60 mL/min (calculated by Cockcroft-Gault method)

• Current or history of Interstitial Lung Disease

• 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 ophthalmological finding that could be asignificant risk factor for RVO, retinopathy or neovascular macular degeneration.

• Concurrent neuromuscular disorder that is associated with the potential of elevatedCPK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateralsclerosis, spinal muscular atrophy).

• Radiation therapy within 2 weeks prior to study Day 1

• Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1,without complete recovery.

• Patient is receiving systemic (oral or IV/SC) or ocular glucocorticoid therapy (withthe exception of participants with endocrine deficiencies who are allowed to receivephysiologic or stress doses of steroids, if necessary) within 14 days prior to firstdose of study treatment

• Known prior severe hypersensitivity to investigational product or any component inits formulation. o This includes hypersensitivity to imidazoles, such as clotrimazole, ketoconazole,miconazole and others in this drug class. Subjects with hypersensitivity to theseagents will be excluded from enrollment.

• History of significant toxicity related to prior CDK4/6, MEK, or ERK inhibitorrequiring discontinuation of treatments with these agents.

• Concurrent, clinically significant, active malignancies within 12 months of studyenrollment

• Current evidence of a disorder that could reduce the ability to swallow oral dosageforms or alter absorption of orally administered drugs.

• Patients who require concomitant use of medications that strongly induce or inhibitCYP3A or UDP-glucuronosyltransferase (UGT)

• Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurologicalsymptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable Grade 2 toxicities aredefined as those with moderate symptoms that the subject is not able to endure forthe conduct of instrumental activities of daily life or that persists ≥ 7 days.