Clinical Trials /

Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome

NCT04160052

Description:

This phase I/II trial studies the side effects and best dose of venetoclax when given together with azacitidine in treating patients with high-risk myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as venetoclax and azacitidine, 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:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Azacitidine for the Treatment of High-Risk Recurrent or Refractory Myelodysplastic Syndrome
  • Official Title: Phase I/II of Venetoclax in Combination With Azacitidine in Treatment Naïve and Relapse Refractory High Risk MDS Individuals

Clinical Trial IDs

  • ORG STUDY ID: 2019-0368
  • SECONDARY ID: NCI-2019-06873
  • SECONDARY ID: 2019-0368
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04160052

Conditions

  • Blasts More Than 5 Percent of Bone Marrow Nucleated Cells
  • Chronic Myelomonocytic Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Recurrent Myelodysplastic Syndrome
  • Refractory High Risk Myelodysplastic Syndrome
  • Therapy-Related Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (venetoclax, azacitidine)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (venetoclax, azacitidine)

Purpose

This phase I/II trial studies the side effects and best dose of venetoclax when given together with azacitidine in treating patients with high-risk myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as venetoclax and azacitidine, 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 azacitidine in patients with treatment-naive high-risk
      myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow
      excess blasts > 5% and patients that are relapsed/refractory to prior hypomethylating agent
      (HMA) therapy.

      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. Time to
      next MDS treatment (TTNT). XIII. Event-free survival (EFS).

      EXPLORATORY OBJECTIVES:

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

      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 1-7 or 1-14 and azacitidine
      subcutaneously (SC) or intravenously (IV) over 15 minutes on days 1-5. Cycles repeat every
      4-8 weeks in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 3-6
      months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, azacitidine)ExperimentalPatients receive venetoclax orally PO QD on days 1-7 or 1-14 and azacitidine SC or IV over 15 minutes on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  For phase I, patients can be HMA-naive high-risk MDS (Int-2 or high risk by the
             International Prognostic Scoring System [IPSS] with overall score >= 1.5) with excess
             blasts > 5%, or relapsed/refractory MDS post-HMA failure (defined as prior receipt of
             4 cycles of HMA therapy with failure to attain a response, or progression of disease
             or relapse at any time after prior response to HMA therapy) with > 5% blasts

          -  For phase II, patients will be divided into 2 cohorts: Cohort A: patients with
             HMA-naive high-risk MDS (Int-2 or high risk by the IPSS with overall score >= 1.5)
             with excess blasts > 5%. Cohort B: patients with relapsed/refractory MDS post-HMA
             failure (defined as prior receipt of 4 cycles of HMA therapy with failure to attain a
             response, or progression of disease or relapse at any time after prior response to HMA
             therapy) with > 5% blasts are eligible. Note: Patients with chronic myelomonocytic
             leukemia (CMML) and 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) < 4 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

        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)

          -  Pregnant or breastfeeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of the combination regimen of venetoclax and azacitidine (Phase I)
Time Frame:Up to 8 weeks
Safety Issue:
Description:The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.

Secondary Outcome Measures

Measure:Overall response rate (Phase 2)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as the proportion of patients who had complete remission (CR), partial remission (PR), marrow complete remission, or hematologic improvement lasting at least 4 weeks. Will estimate the overall response rate for the combination treatment, along with the 95% confidence interval.
Measure:Rate of CR
Time Frame:Up to 5 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Rate of marrow/morphologic CR
Time Frame:Up to 5 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Rate of hematologic improvement
Time Frame:Up to 5 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Rate of red blood cell transfusion independence
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Rate of platelet transfusion independence
Time Frame:Up to 5 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Rate of cytogenetic response
Time Frame:Up to 5 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Rate of bone marrow blast response
Time Frame:Up to 5 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Time to transformation to acute myeloid leukemia
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
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:Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measure:Overall survival
Time Frame:From treatment start till death or last follow-up, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measure:Progression-free survival
Time Frame:From treatment to progression or last follow-up, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measure:Time to next myelodysplastic syndrome treatment
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
Measure:Event-free survival
Time Frame:From the date of 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. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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