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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
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

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.

Condition or disease Intervention/treatment Phase
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 Drug: Decitabine Other: Laboratory Biomarker Analysis Drug: Venetoclax Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 16, 2018
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 5 years ]
    Toxicity type, severity and attribution will be summarized for each patient using frequency tables.

  2. 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.

  3. 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.

  4. 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.


Other Outcome Measures:
  1. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03404193


Contacts
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Contact: Marina Konopleva, MD, PHD 713-794-1628 mkonople@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Marina Konopleva    713-794-1628    mkonople@mdanderson.org   
Principal Investigator: Marina Konopleva         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Marina Konopleva M.D. Anderson Cancer Center
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03404193    
Other Study ID Numbers: 2017-0912
NCI-2018-00752 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0912 ( Other Identifier: M D Anderson Cancer Center )
First Posted: January 19, 2018    Key Record Dates
Last Update Posted: July 23, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Venetoclax
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Leukemia, Biphenotypic, Acute
Myelodysplastic Syndromes
Syndrome
Acute Disease
Neoplasms
Disease
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Disease Attributes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action