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Venetoclax and Decitabine in Treating Participants With Relapsed/Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT03404193
Recruitment Status : Recruiting
First Posted : January 19, 2018
Last Update Posted : July 23, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE January 11, 2018
First Posted Date  ICMJE January 19, 2018
Last Update Posted Date July 23, 2020
Actual Study Start Date  ICMJE January 16, 2018
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
Overall response rate (ORR) [ Time Frame: Up to 4 cycles (112 days) ]
Will be defined as the proportion of patients who had CR (complete remission), CRp (complete remission with incomplete platelet recovery), CRi (complete remission with incomplete count recovery), PR (partial response) or marrow clearance of blasts within 3 months of treatment initiation among adult patients with acute myeloid leukemia (AML); and complete remission (CR), partial remission (PR) or marrow CR (mCR) lasting at least 4 weeks for patients with myelodysplastic syndrome (MDS). Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. Will estimate the ORR for the combination treatment, along with the 95% confidence interval. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Original Primary Outcome Measures  ICMJE
 (submitted: January 12, 2018)
Overall response rate (ORR) of venetoclax in combination with 10-day decitabine [ Time Frame: 3 months ]
ORR defined as the proportion of patients who had CR (complete remission), CRp (complete remission with incomplete platelet recovery), CRi (complete remission with incomplete count recovery), PR (partial response) or marrow clearance of blasts within 3 months of treatment initiation among adult patients with AML; and complete remission (CR), partial remission (PR) or marrow CR† (mCR) lasting at least 4 weeks for patients with MDS.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
  • Incidence of adverse events [ Time Frame: Up to 5 years ]
    Toxicity type, severity and attribution will be summarized for each patient using frequency tables.
  • Duration of response [ Time Frame: Up to 5 years ]
    Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.
  • Disease free survival [ Time Frame: Up to 5 years ]
    Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.
  • Overall survival [ Time Frame: Up to 5 years ]
    Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2018)
  • Duration of Response of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Disease-Free Survival (DFS) of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Overall Survival (OS) of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Determination of the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or ANC and the number of patients who achieve > 50% reduction in blasts on therapy with venetoclax/10-day decitabine. [ Time Frame: 1 year ]
  • Safety of venetoclax in combination with 10-day decitabine in patients with refractory/ relapsed AML. [ Time Frame: Baseline up to 30 days after last dose of study drug ]
    The overall incidence and severity of all reported adverse events using Common Toxicity Criteria v 4.0.
  • Determination of the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day decitabine regimen. [ Time Frame: 3 months ]
    Response assessed based by Modified IWG Response Criteria for MDS (Cheson et al, 2006).
Current Other Pre-specified Outcome Measures
 (submitted: May 22, 2020)
Biomarker analysis [ Time Frame: Baseline ]
Baseline protein, gene expression signatures/mutation profile and BH3 profiling will be summarized with descriptive statistics. The correlation with endpoints of anti tumor activity will be explored where possible.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax and Decitabine in Treating Participants With Relapsed/Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome
Official Title  ICMJE A Phase II Study of Venetoclax in Combination With 10-Day Decitabine in Newly Diagnosed Elderly or Relapsed/Refractory Acute Myeloid Leukemia and Relapsed High-Risk Myelodysplastic Syndrome and Blastic Plasmacytoid Dendritic Cell Neoplasm
Brief Summary This phase II trial studies how well venetoclax and decitabine work in treating participants with acute myeloid leukemia that has come back or does not respond to treatment, or with high-risk myelodysplastic syndrome that has come back. Drugs used in chemotherapy, such as venetoclax 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 overall response rate (ORR) of venetoclax in combination with 10-day decitabine in patients with refractory/relapsed acute myeloid leukemia (AML); elderly (> 60 year old) patients with newly diagnosed AML not eligible for intensive chemotherapy; patients with high-risk myelodysplastic syndrome (MDS) with bone marrow blasts between 10% and 20%, relapsed or refractory to prior hypomethylating agent (HMA) therapy, or chronic myelomonocytic leukemia (CMML) with bone marrow blasts >= 10% regardless of prior therapy; AML patients with prior history of MDS or CMML who received therapy for the MDS or CMML and progressed to AML, and younger patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations and patients with blastic plasmacytoid dentritic cell neoplasm (BPDCN).

SECONDARY OBJECTIVES:

I. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) and the number of patients who achieve > 50% reduction in blasts on therapy with venetoclax/10-day decitabine.

III. To determine the safety of venetoclax in combination with 10-day decitabine in patients with refractory/relapsed AML.

IV. To determine the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day decitabine regimen.

V. To determine the incidence of infectious complications per cycle with venetoclax in combination with 10-day decitabine.

EXPLORATORY OBJECTIVES:

I. To investigate possible relationships between baseline protein and gene expression signatures/mutation profile and BH3 profiling in predicting clinical response to the combination.

II. To characterize the pharmacokinetic (PK) profiles of venetoclax in combination with decitabine and antifungals in plasma samples.

OUTLINE:

Participants receive decitabine intravenously (IV) over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax orally (PO) daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Chronic Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndrome
  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Mixed Phenotype Acute Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory Mixed Phenotype Acute Leukemia
Intervention  ICMJE
  • Drug: Decitabine
    Given IV
    Other Names:
    • 5-Aza-2''-deoxycytidine
    • Dacogen
    • Decitabine for Injection
    • Deoxyazacytidine
    • Dezocitidine
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Venetoclax
    Given PO
    Other Names:
    • ABT-0199
    • ABT-199
    • ABT199
    • GDC-0199
    • RG7601
    • Venclexta
    • Venclyxto
Study Arms  ICMJE Experimental: Treatment (decitabine, venetoclax)
Participants receive decitabine IV over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax PO daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Decitabine
  • Other: Laboratory Biomarker Analysis
  • Drug: Venetoclax
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 22, 2020)
400
Original Estimated Enrollment  ICMJE
 (submitted: January 12, 2018)
160
Estimated Study Completion Date  ICMJE December 31, 2024
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with AML, BPDCN, biphenotypic or bilineage leukemia (including a myeloid component) or mixed phenotype acute leukemia (MPAL) who have failed prior therapy; patients with AML should have failed prior therapy or have relapsed after prior therapy; patients with isolated extramedullary AML are eligible
  • Elderly (> 60 year old) patients with newly diagnosed AML, BPDCN, or mixed phenotype acute leukemia (MPAL) not eligible for intensive chemotherapy
  • Patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations equal or younger than 60 year old
  • AML or BPDCN patients with prior history of MDS or CMML who received any therapy or no therapy for the MDS or CMML and progressed to AML, are eligible at the time of diagnosis of AML regardless of any prior therapy for MDS; the World Health Organization (WHO) classification will be used for AML
  • Patients with high-risk MDS with bone marrow blasts between 10% and 20%, relapsed or refractory to prior hypomethylating agent (HMA) therapy, defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or relapse after prior response to HMA therapy; patients with high risk chronic myelomonocytic leukemia (CMML) with bone marrow blasts >= 10% regardless of prior therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 3
  • White blood cell count =< 10,000
  • Adequate renal function including creatinine < 2 unless related to the disease
  • Adequate hepatic function including total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
  • Alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement
  • Provision of written informed consent
  • Oral hydroxyurea and/or one dose of cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy and while the patient is on active study treatment through cycle 1, as needed, for clinical benefit and after discussion with the principal investigator (PI); concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
  • 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 t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
  • Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia
  • Active and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physician
  • Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
  • Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator
  • Pregnant or breastfeeding
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marina Konopleva, MD, PHD 713-794-1628 mkonople@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03404193
Other Study ID Numbers  ICMJE 2017-0912
NCI-2018-00752 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0912 ( Other Identifier: M D Anderson Cancer Center )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Marina Konopleva M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP