ASTX029 and Decitabine and Cedazuridine (ASTX727) for the Treatment of Relapsed or Refractory Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms with RAS Pathway Mutation
This phase I/II trial the safety and side effects of ASTX029 and decitabine and cedazuridine (ASTX727) in treating patients with myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms that has come back after a period of improvement (relapsed) or has not responded to the treatment (refractory) and harbors a mutation (a type of genetic change) in the RAS pathway. ASTX029 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. ASTX727 is an oral combination pill made of decitabine and cedazuridine. Decitabine is thought to work by helping the bone marrow make normal blood cells. Decitabine also slows or stops the growth of abnormal blood cells that grow too fast and do not work properly. Because the abnormal cells cannot divide and grow, they die. Cedazuridine helps decitabine work better by helping to prevent its breakdown in the body. Giving ASTX029 and ASTX727 may be a safe and effective treatment option for patients with relapsed or refractory myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with RAS pathway mutations.
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 World Health Organization (WHO) and: * Initial phase 1 cohorts (cohorts A): MDS patients 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 >= 30 ml/min based on the Cockcroft-Gault Glomerular Filtration Rate estimation
- Total bilirubin =< 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x ULN
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study. Non-English speaking patients may be consented
- Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], procrit, aranesp, thrombopoietins) is allowed at any time prior to cycle 1 day 1 of therapy
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Patients 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 patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient 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
Exclusion Criteria
- Patients who are currently receiving treatment for a malignancy (not including basal cell carcinoma, nonmelanoma skin cancer, cervical carcinoma in situ, early stage breast cancer or localized prostate cancer treated with hormone therapy). Patients with history of other cancers should be free of disease for at least 2 years prior to the screening visit or not requiring active treatment at the time of enrollment
- Patients who are receiving any other investigational agents
- Patients who have an active, life-threatening, or clinically-significant uncontrolled systemic infection requiring hospitalization
- Patients who have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy)
- Pregnant women are excluded from this study because ASTX029 and ASTX727 are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study. These potential risks may also apply to other agents used in this study
- Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine devices [IUD], double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the study
- Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening
- Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy within 7 days of therapy initiation
- Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months)
- Patients with history of HIV with CD4+ T-cell (CD4+) counts < 350 cell/mcL or with AIDS-defining opportunistic infections in the last 12 months are also excluded. Patients with well controlled HIV (defined as CD4+ counts > 350 cells/mcL with undetectable viral load prior to enrollment with no AIDS-defining opportunistic infections in the past 12 months) on therapy with antiretroviral therapies known to be metabolites of cytochrome P450 (CYP3A4) enzymes will also be excluded
- Patients with corrected QT (QTc) interval > 480 msec based on average of triplicate electrocardiogram (ECG) readings at the screening visit using the Fridericia formula (QTcF), with the exception of patients with right bundle branch block or left bundle branch block
- New York Heart Association (NYHA) Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50 by echocardiogram or multigated acquisition (MUGA) scan
- History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
- Patients with psychiatric illness/social situations that would limit compliance with study requirements
Additional locations may be listed on ClinicalTrials.gov for NCT06284460.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To determine safety, tolerability and maximum tolerated dose (MTD) of ERK 1/2 inhibitor ASTX029 (ASTX029) in RAS mutant myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and other MDS/myeloproliferative neoplasms (MPN). (Phase I Dose Escalation)
II. To determine the safety, tolerability and overall response rate (ORR) of ASTX727 in combination with ASTX029 in RAS mutant MDS, CMML and other MDS/MPN. (Phase II Dose Expansion)
SECONDARY OBJECTIVES:
I. To determine other efficacy outcomes such as duration of response, leukemia-free survival (LFS), progression-free survival (PFS) and overall survival (OS).
II. To evaluate differences in response and efficacy outcomes by MDS/MPN International Working Group (IWG) response criteria based on disease subtypes and genomic features.
III. Correlative studies.
IV. To evaluate changes in clonal composition and VAF of identified mutations with therapy.
V. To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ASTX029 and the combination of ASTX727 with ASTX029 in patients with RAS mutant MDS, CMML and other MDS/MPN.
OUTLINE: This is a phase I, dose-escalation study of ASTX029 followed by a phase II dose-expansion study.
PHASE I: Patients receive ASTX029 orally (PO) on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients receive ASTX029 PO on days 1-21 of each cycle and decitabine and cedazuridine PO on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients may undergo spleen ultrasound during screening and on the trial. Patents also undergo bone marrow biopsy and aspiration and blood sample collection during screening and on the trial.
After completion of study intervention, patients are followed up at 30 days, and then every 3 months for up to 5 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorGuillermo Montalban Bravo
- Primary ID2022-0622
- Secondary IDsNCI-2024-01692
- ClinicalTrials.gov IDNCT06284460