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

NCT06284460 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 2022-0622NCI-2024-01692
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of ASTX029 that can be given in combination with ASTX727 to participants who have RAS-mutant MDS or MDS/MPN. The goal of Part 2 of this clinical research study is to learn if the dose of ASTX029 found in Part 1 can help to control the disease when used in combination with ASTX727.

Conditions

Myelodysplastic Neoplasm; Myeloproliferative Neoplasm; Pathway Mutant Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (1)

• Safety and adverse events (AEs)

  Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0

  Through study completion; an average of 1 year

Study Arms (2)

Cohort A: Single agent ASTX029

EXPERIMENTAL

Participants will take ASTX029 daily on days 1-21 of each 28-day cycle. ASTX029 should be taken with water on an empty stomach, no food 2 hours before and 2 hours after dose.

Drug: ASTX029

Cohorts B and C: Combination of ASTX727 + ASTX029

EXPERIMENTAL

Participants will take ASTX029 daily on days 1-21 of each 28-day cycle. ASTX727 daily on days 1-5 of each 28-day cycle. Both ASTX029 and ASTX727 should be taken with water on an empty stomach, no food 2 hours before and 2 hours after dose.

Drug: ASTX029; Drug: ASTX727

Interventions

ASTX029 DRUG

Given by PO

Cohort A: Single agent ASTX029; Cohorts B and C: Combination of ASTX727 + ASTX029

ASTX727 DRUG

Given by PO

Also known as: Inqovi

Cohorts B and C: Combination of ASTX727 + ASTX029

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Postmenopausal (no menses in greater than or equal to 12 consecutive months).

You may not qualify if:

• Participants 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). Participants 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.
• Participants who are receiving any other investigational agents.
• Participants who have an active, life-threatening, or clinically-significant uncontrolled systemic infection requiring hospitalization.
• Participants 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.
• Participants 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 participants with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.
• Participants receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy within 7 days of therapy initiation.
• Participants 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).
• Participants 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. Participants 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.
• Participants with QTc interval \>480 msec based on average of triplicate ECG readings at the Screening Visit using the Fridericia formula (QTcF), with the exception of participants with right bundle branch block or left bundle branch block.
• New York Heart Association (NYHA) Class III or IV congestive heart failure or 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.
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

MD Anderson Cancer Cente

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Anemia, Refractory, with Excess of Blasts; Myeloproliferative Disorders

Interventions

ASTX029; decitabine and cedazuridine drug combination

Condition Hierarchy (Ancestors)

Anemia, Refractory; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases

Study Officials

• Guillermo Montalban Bravo

  MD Anderson Cancer Cente

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2024
• First Posted: February 29, 2024
• Study Start: January 31, 2025
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: February 13, 2026

Record last verified: 2026-02

Locations

US (1)