• Male or female subject aged ≥ 18 years.

• Newly diagnosed or hypomethylating agent (HMA) refractory chronic myelomonocytic leukemia (CMML -0/-1/-2; 2016 WHO classification) with RAS pathway activation as determined by standard of care hematopoietic cell sequencing results on peripheral blood or bone marrow demonstrating NRAS, KRAS, PTPN11, FLT3, CBL, JAK2, BRAF or NF1 mutations at variant allele frequency ≥ 5%. BMBx, NGS, FISH or BCR-ABL1 PCR, and cytogenetics should be done at the primary trial site within 21 days prior to C1D1. 5.1.2 If the patient is FLT3-ITD positive, the FLT3-ITD PCR allelic ratio must be ≥ 0.05 on testing done on screening biopsy (NOTE: cannot quantitate FLT3-ITD VAF by NGS, must be a separate PCR test).

• ECOG Performance Status ≤ 3.

• Adequate organ function as defined as:

‣ Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

∙ Unless elevation is related to Gilbert's syndrome, hemolysis, or thought to be due to leukemic hepatic involvement.

∙ AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN ----Unless elevation is related to leukemic hepatic involvement.

⁃ Renal:

∙ --Serum creatinine ≤ 2x ULN

⁃ OR

• Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:

∙ Males: ((140-age)×weight\[kg\])/(serum creatinine \[mg/dL\]×72)

∙ Females: (((140-age)×weight\[kg\])/(serum creatinine \[mg/dL\]×72))×0.85

• Left ventricular function ≥ 50% as assessed by echocardiogram.

• Negative pregnancy test for women of childbearing potential or evidence of post-menopausal status. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

‣ Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

⁃ Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

• Highly effective contraception for both male and female subjects throughout the study and at least 3 months after the last dose of study therapy as described in Section 7.4 of the protocol.

• Recovery to baseline or Grade ≤ 1 CTCAE v5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.

• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.