Clinical Trials /

Venetoclax and Azacitidine for the Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

NCT04550442

Description:

This phase I/II trial investigates the side effects and best dose of venetoclax when given together with azacitidine and to see how well it works in treating patients with high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as 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. Giving venetoclax and azacitidine together may help to control myelodysplastic syndrome or chronic myelomonocytic leukemia.

Related Conditions:
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Therapy-Related Myelodysplastic Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Azacitidine for the Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
  • Official Title: A Phase I/II Study of Venetoclax in Combination With Azacitidine in Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Clinical Trial IDs

  • ORG STUDY ID: 2020-0128
  • SECONDARY ID: NCI-2020-06538
  • SECONDARY ID: 2020-0128
  • NCT ID: NCT04550442

Conditions

  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory 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 investigates the side effects and best dose of venetoclax when given together with azacitidine and to see how well it works in treating patients with high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as 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. Giving venetoclax and azacitidine together may help to control myelodysplastic syndrome or chronic myelomonocytic leukemia.

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 high risk myelodysplastic
      syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow excess blasts > 5%
      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 OBJECTIVE:

      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) daily on days 1-14 and azacitidine intravenously (IV)
      over 15 minutes or subcutaneously (SC) 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 within 30 days and then every
      3-6 months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, azacitidine)ExperimentalPatients receive venetoclax PO daily on days 1-14 and azacitidine IV over 15 minutes or SC 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:

          -  Patients with post HMA-failure high-risk MDS (intermediate [Int]-2 or high risk by the
             International Prognostic Scoring System for Myelodysplastic Syndrome [IPSS] with
             overall score >= 1.5) with excess blasts > 5% with 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

          -  Patients with relapsed/refractory chronic myelomonocytic leukemia (CMML) and
             therapy-related MDS are also eligible

          -  Hydroxyurea is allowed to lower the white cell count =< 10,000/ul prior to initiation
             of venetoclax

          -  Total bilirubin =< 2.0 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

          -  Adequate renal function as calculated using the modified Cockcroft-Gault equation of
             >= 30 ml/min, OR 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

          -  Eastern Cooperative Oncology Group (ECOG)/performance status (PS) =< 2

        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 virus surface antigen [HBs Ag] or detected sensitivity on hepatitis B
             virus-deoxyribonucleic acid [HBV-DNA] polymerase chain reaction [PCR] test for
             hepatitis B virus core antibody [HBc Ab] and/or hepatitis B virus surface antibody
             [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 Doctor of Medicine
                  (MD)

          -  Patient has a white blood cell count > 10 x 10^9/L. (Hydroxyurea or leukapheresis are
             permitted to meet this criterion)

          -  Female subject has positive results for pregnancy test

          -  Patients with (grade > 1) unresolved from prior treatment (including chemotherapy,
             targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity (DLT).

Secondary Outcome Measures

Measure:Rate of CR
Time Frame:Up to 5 years post-treatment
Safety Issue:
Description:The association between CR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Rate of mCR
Time Frame:Up to 5 years post-treatment
Safety Issue:
Description:The association between mCR 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 post-treatment
Safety Issue:
Description:
Measure:Rate of platelet transfusion independence
Time Frame:Up to 5 years post-treatment
Safety Issue:
Description:
Measure:Rate of red blood cell transfusion independence
Time Frame:Up to 5 years post-treatment
Safety Issue:
Description:
Measure:Rate of cytogenetic response
Time Frame:Up to 5 years post-treatment
Safety Issue:
Description:The association between cytogenetic 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 post-treatment
Safety Issue:
Description:The association between bone marrow blast response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Duration of response
Time Frame:The number of days 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 post-treatment
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Measure:Event-free survival
Time Frame:The number of days 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 post-treatment
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Measure:Overall survival
Time Frame:The time from treatment start till death or last follow-up, assessed up to 5 years post-treatment
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Measure:Progression free survival
Time Frame:The time from treatment to progression or last follow-up, assessed up to 5 years post-treatment
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests.
Measure:Time to transformation to acute myeloid leukemia (AML)
Time Frame:The time from treatment till transformation of AML or last follow-up, assessed up to 5 years post-treatment
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. Comparisons 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

Last Updated

September 9, 2020