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 : October 27, 2022
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|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|
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).
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.
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.
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||400 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 18, 2018|
|Estimated Primary Completion Date :||December 31, 2023|
|Estimated Study Completion Date :||December 31, 2024|
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.
Other: Laboratory Biomarker Analysis
- 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.
- 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.
- 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.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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
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
|Contact: Abhishek Maiti, MBBS||(346) firstname.lastname@example.org|
|United States, Texas|
|M D Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Abhishek Maiti, MBBS 346-725-0901 email@example.com|
|Principal Investigator: Abhishek Maiti, MBBS|
|Principal Investigator:||Abhishek Maiti, MBBS||M.D. Anderson Cancer Center|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||M.D. Anderson Cancer Center|
|Other Study ID Numbers:||
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:||October 27, 2022|
|Last Verified:||October 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Leukemia, Biphenotypic, Acute
Neoplasms by Histologic Type
Bone Marrow Diseases
Immune System Diseases