Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms

Inclusion Criteria

• •Age ≥ 18 years as MDS and MDS/MPN are a very rare disease in the pediatric setting.
• •Diagnosis of MDS or MDS/MPN (including CMML, aCML, MDS/MPN-U) according to WHO and:
• •* Initial phase 1 cohorts (cohorts A): MDS participants with no response after 4 cycles of azacitidine, decitabine, guadecitabine, CC-486 or ASTX727 or relapse or progression after any number of cycles OR MDS/MPN relapsed/refractory following treatment with hydroxyurea OR at least 4 cycles of azacytidine, decitabine, guadecitabine or ASTX727 or relapse or progression after any number of cycles or who are intolerant of treatment with hydroxiurea.
• •* Phase 2 dose expansion cohort:
• •* Relapsed MDS cohort (Cohort B): no response after 4 cycles of azacitidine, decitabine, guadecitabine or ASTX727 or relapse or progression after any number of cycles.
• •* Relapsed MDS/MPN cohort (Cohort C): relapsed/refractory following treatment with hydroxyurea or at least 4 cycles of azacytidine, decitabine, guadecitabine or ASTX727 or relapse or progression after any number of cycles or who are intolerant of treatment with wih hydroxiurea.
• •Known mutation in genes leading to RAS pathway activation (NRAS, KRAS, BRAF, CBL, NF1, PTPN11).
• •Creatinine clearance ≥30ml/min based on the Cockcroft-Gault Glomerular Filtration Rate estimation.
• •Adequate hepatic function with total bilirubin ≤1.5x ULN, AST or ALT ≤3 xULN.
• •ECOG Performance Status 0-2.
• •Participant (or patient's legally authorized representative) must have signed an informed consent document indicating that the participant understands the purpose of and procedures required for the study and is willing to participate in the study. Non-English speaking participants may be consented.
• •Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (eg, G-CSF, GM-CSF, procrit, aranesp, thrombopoietins) is allowed at any time prior to cycle 1 day 1 of therapy.
• •For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• •Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. The effects of ASTX029 on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female participants, between the onset of menses (as early as 8 years of age) and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following:
• •* Postmenopausal (no menses in greater than or equal to 12 consecutive months).
• •* History of hysterectomy or bilateral salpingo-oophorectomy.
• •* Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
• •* History of bilateral tubal ligation or another surgical sterilization procedure.
• •Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• •Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ASTX727 and ASTX029 administration.
• •Ability to understand and the willingness to sign a written informed consent document.