Clinical Trials /

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

NCT04655755

Description:

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.

Related Conditions:
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax in Combination With ASTX727 for the Treatment of Treatment-Naive High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 2020-0129
  • SECONDARY ID: NCI-2020-09915
  • SECONDARY ID: 2020-0129
  • NCT ID: NCT04655755

Conditions

  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Decitabine and CedazuridineASTX727, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, InqoviTreatment (venetoclax, ASTX727)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (venetoclax, ASTX727)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, ASTX727)ExperimentalPatients 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.
  • Decitabine and Cedazuridine
  • Venetoclax

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence and severity of all reported adverse events (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:The overall incidence and severity of all reported adverse events using Common Toxicity Criteria version 5.0.

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 7, 2020