Venetoclax in Combination With ASTX727 for the Treatment of Treatment-Naive High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

NCT04655755 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2020-0129NCI-2020-09915
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial studies the side effects and best dose of venetoclax in combination with cedazuridine and decitabine (ASTX727) in treating patients with high risk myelodysplastic syndrome or chronic myelomonocytic leukemia who have not received prior treatment (treatment-naive). Chemotherapy drugs, such as venetoclax, cedazuridine, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Conditions

Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (2)

• Incidence and severity of all reported adverse events (Phase I)

  The overall incidence and severity of all reported adverse events using Common Toxicity Criteria version 5.0.

  Up to 28 days

• Overall response rate (ORR) (Phase II)

  ORR will be defined as the proportion of patients who had complete remission (CR), partial remission (PR) or marrow CR (mCR), or hematologic improvement (HI) lasting at least 8 weeks. Will estimate the ORR for the combination treatment, along with the 95% credible interval.

  Up to 8 weeks

Secondary Outcomes (14)

• Rate of complete remission

  Up to 5 years post treatment

• Rate of marrow/morphologic complete remission

  Up to 5 years post treatment

• Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses)

  Up to 5 years post treatment

• Rate of red blood cell transfusion independence

  Up to 5 years post treatment

• Rate of platelet transfusion independence

  Up to 5 years post treatment

Other Outcomes (1)

• Biomarker analysis

  Up to 5 years post treatment

Study Arms (1)

Treatment (venetoclax, ASTX727)

EXPERIMENTAL

Patients receive venetoclax orally PO QD on days 1-14. Patients also receive ASTX727 PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine and Cedazuridine; Drug: Venetoclax

Interventions

Decitabine and Cedazuridine DRUG

Given PO

Also known as: ASTX727, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, Inqovi

Treatment (venetoclax, ASTX727)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (venetoclax, ASTX727)

Eligibility Criteria

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

You may qualify if:

• Patients with treatment-naive high-risk (HR)-MDS or CMML (intermediate \[Int\]-2 or high risk by the International Prognostic Scoring System \[IPSS\] with overall score \>= 1.5) with excess blasts \> 5. Note: Patients with therapy-related MDS are eligible. Hydroxyurea is allowed to lower the white cell count =\< 10,000/ul prior to initiation of venetoclax
• Total bilirubin \< 3 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 3.0 x ULN unless considered due to leukemic involvement
• Creatinine \< 2 x ULN unless related to the disease
• Signed written informed consent
• Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment. Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment
• Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment
• Age \>= 18 years of age

You may not qualify if:

• Patients having received any prior BCL2 inhibitor therapy
• Patients with MDS with IPSS risk categories low or Int-1 (overall IPSS score \< 1.5)
• Patient with known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). HIV testing will be performed at screening, only if required per local guidelines or institutional standards
• Patient known to be positive for hepatitis B or C infection (hepatitis C virus antibody \[HCV Ab\] indicative of a previous or current infection; and/or positive hepatitis B surface antigen \[HBs Ag\] or detected sensitivity on hepatitis B virus-deoxyribonucleic acid \[HBV-DNA\] polymerase chain reaction \[PCR\] test for hepatis B core antibody \[HBc Ab\] and/or HBs Ab positivity) with the exception of those with an undetectable viral load within 3 months of screening. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV \[i.e., HBs Ag-, and anti-HBs+\] may participate
• Patient has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment
• Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment
• Patient has a cardiovascular disability status of New York Heart Association class \> 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain
• Patient has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients of azacitidine that in the opinion of the investigator would adversely affect his/her participating in this study
• Patient has a malabsorption syndrome or other condition that precludes enteral route of administration
• Patient exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal)
• Patient has received a live attenuated vaccine within 4 weeks prior to the first dose of study drug
• Patient has a history of other malignancies within 2 years prior to study entry, with the exception of:
• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; requires discussion with TA MD

Sponsors & Collaborators

• Genentech, Inc.: collaborator
• M.D. Anderson Cancer Center: lead
• Astex Pharmaceuticals, Inc.: collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Bataller A, Montalban-Bravo G, Bazinet A, Alvarado Y, Chien K, Venugopal S, Ishizawa J, Hammond D, Swaminathan M, Sasaki K, Issa GC, Short NJ, Masarova L, Daver NG, Kadia TM, Colla S, Qiao W, Huang X, Kanagal-Shamanna R, Hendrickson S, Ravandi F, Jabbour E, Kantarjian H, Garcia-Manero G. Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study. Lancet Haematol. 2024 Mar;11(3):e186-e195. doi: 10.1016/S2352-3026(23)00367-8. Epub 2024 Feb 2.

  PMID: 38316133 DERIVED

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes

Interventions

decitabine and cedazuridine drug combination; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Guillermo Garcia-Manero

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: November 30, 2020
• First Posted: December 7, 2020
• Study Start: January 19, 2021
• Primary Completion (Estimated): July 20, 2026
• Study Completion (Estimated): July 20, 2026
• Last Updated: February 18, 2026

Record last verified: 2026-02

Locations

US (1)