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

A Phase I/II Study of Venetoclax in Combination With ASTX727 (Cedazuridine/Decitabine) in Treatment-Naïve High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Venetoclax; Drug: Decitabine and Cedazuridine

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of venetoclax in combination with ASTX727 in patients with treatment-naive high-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow excess blasts > 5%.

SECONDARY OBJECTIVES:

I. Rate of complete remission (CR). II. Rate of marrow/morphologic complete remission (mCR). III. Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses).

IV. Rate of red blood cell (RBC) transfusion independence. V. Rate of platelet (PLT) transfusion independence. VI. Rate of cytogenetic response. VII. Rate of bone marrow blast response. VIII. Time to transformation to acute myeloid leukemia (AML). IX. Duration of response (DOR). X. Overall survival (OS). XI. Progression-free survival (PFS). XII. Disease-free survival (DFS). XIII. Time to next MDS treatment (TTNT). XIV. Event-free survival (EFS).

EXPLORATORY OBJECTIVE:

I. To investigate the effects of therapy on MDS and to identify biological markers of response to venetoclax and/or its combination with ASTX727.

OUTLINE: This is a phase I, dose-escalation study of venetoclax, followed by a phase II study.

Patients receive venetoclax orally (PO) once daily (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.

After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Guillermo Garcia-Manero; Phone Number: 713-745-3428; Email: ggarciam@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Principal Investigator: Guillermo Garcia-Manero
      • Contact: Guillermo Garcia-Manero; Phone Number: 713-745-3428; Email: ggarciam@mdanderson.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• Patient has a white blood cell count > 25 x 10^9/L. (Hydroxyurea or leukapheresis are permitted to meet this criterion)
• Female subject has positive results for pregnancy test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (venetoclax, ASTX727); 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: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Decitabine and Cedazuridine; Given PO; Other Names: ASTX727; CDA Inhibitor E7727/Decitabine Combination Agent ASTX727; Cedazuridine/Decitabine Combination Agent ASTX727; Cedazuridine/Decitabine Tablet; Inqovi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete remission	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Rate of marrow/morphologic complete remission	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses)	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Rate of red blood cell transfusion independence	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Rate of platelet transfusion independence	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Rate of cytogenetic response	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Rate of bone marrow blast response	Will be estimated with the 95% credible interval.	Up to 5 years post treatment
Duration of response		From the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first, assessed up to 5 years
Time to transformation to acute myeloid leukemia	Time to transformation to acute myeloid leukemia is defined as the period from treatment till transformed to acute myeloid leukemia.	Up to 5 years post treatment
Overall survival	Will be estimated using the method of Kaplan and Meier.	From treatment start till death, assessed up to 5 years
Progression-free survival	Will be estimated using the method of Kaplan and Meier.	From treatment start till disease progression or death, assessed up to 5 years
Disease-free survival		Up to 5 years post treatment
Time to next myelodysplastic syndrome (MDS) treatment	Will be estimated using the method of Kaplan and Meier.	From initial treatment start till the next MDS treatment, assessed up to 5 years
Event-free survival	Will be estimated using the method of Kaplan and Meier.	From treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, assessed up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker analysis	The association between cellular biomarker, and antitumor activity will be compared using Wilcoxon's rank sum test or Fisher's exact test, as appropriate.	Up to 5 years post treatment

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Genentech, Inc.; Astex Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Guillermo Garcia-Manero, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2021
• Primary Completion (Estimated): July 20, 2026
• Study Completion (Estimated): July 20, 2026

Study Registration Dates

• First Submitted: November 30, 2020
• First Submitted That Met QC Criteria: November 30, 2020
• First Posted (Actual): December 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Chronic Disease; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Venetoclax; Decitabine and cedazuridine drug combination
• Other Study ID Numbers: 2020-0129 (Other Identifier: M D Anderson Cancer Center); NCI-2020-09915 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No