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
概览
- 阶段
- 2 期
- 干预措施
- Decitabine
- 疾病 / 适应症
- Acute Myeloid Leukemia
- 发起方
- M.D. Anderson Cancer Center
- 入组人数
- 235
- 试验地点
- 1
- 主要终点
- Overall response rate (ORR)
- 状态
- 终止
- 最后更新
- 上个月
概览
简要总结
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.
详细描述
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.
研究者
入排标准
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Decitabine
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.
干预措施: Laboratory Biomarker Analysis
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.
干预措施: Venetoclax
结局指标
主要结局
Overall response rate (ORR)
时间窗: 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.
次要结局
- Duration of response(Up to 5 years)
- Overall survival(Up to 5 years)
- Incidence of adverse events(Up to 5 years)
- Disease free survival(Up to 5 years)