• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

• Age ≥ 18 years at the time of consent (no upper age limit)

• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2

• Tumor Eligibility:

∙ Dose escalation cohorts: Histologically confirmed advanced solid tumor refractory to standard of care therapy, or for which there is no accepted standard of care

‣ Expansion cohort (at RP2D): metastatic pancreatic cancer or malign melanoma patients who have received at least one line of therapy in the metastatic setting

‣ Expansion cohort (at RP2D) for histologically confirmed unresectable stage III or stage IV melanoma with the following additional eligibility requirements:

⁃ Tumors molecular profiling genetic aberrations: NRASG12/G13/Q61, KRASG12/G13, HRASG12/G13, any amplifications of the NRAS, KRAS, or HRAS genes. For NF1 mutations, subjects with loss-of-function NF1mutations and without any BRAFV600 mutations will be enrolled.

• Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined as disease progression following at least two infusions of the same drug.

• Subjects with RAS-mutant and NF1-mutant (no concurrent BRAFV600 mutations) melanoma that have not taken prior immune checkpoint inhibitors will be allowed if they are not eligible to receive prior immune checkpoint inhibitors due to requirement for immunosuppression

• Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 for dose escalating cohorts; measurable disease as per RECIST v1.1 required for expansion cohort

• Life expectancy ≥ 12 weeks

• Recovered from all reversible acute toxic effects of last anti-cancer treatment (other than alopecia) to ≤Grade 1 or baseline. Patients with baseline neuropathy that is ≤ grade 2 are eligible for enrollment.

• Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 28 days prior to day -6 of ulixertinib

• Hemoglobin (Hgb) ≥ 9 g/dL Absolute Neutrophil Count (ANC) ≥ 1,500 /mm3 Platelets ≥ 100,000/mm3 Creatinine ≤1.5 x upper limit of normal (ULN) or Calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault formula Bilirubin ≤ 1.5 x ULN Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN; if tumor involvement of the liver ≤ 5 x ULN

• \*Note: Hematology and other lab parameters that are ≤ grade 2 but still meet the criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet the criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.

• Adequate cardiac function; left ventricular ejection fraction (LVEF) \>50% as assessed by ultrasound/echocardiography (ECHO); corrected QT interval (QTc) \<470ms

⁃ Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to day -6 of ulixertinib. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months

⁃ Females of childbearing potential and males must be willing to abstain from heterosexual activity\* or use effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation. Acceptable contraception methods can be comprised of an intrauterine device (IUD), vasectomy of a female subject's male partner, contraceptive rod implanted into the skin, OR use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive.\] \*Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

⁃ Subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee.

⁃ Willing to provide archival tissue (if available) and consent to mandatory pretreatment and on-treatment biopsy as deemed safe by the treating physician (expansion cohort only) for research purposes only.