A Phase II Randomized Clinical Trial of Venetoclax Combined With FLAG IDA Induction and Consolidation Compared to Standard of Care for Newly Diagnosed Patients With Acute Myeloid Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 102
- 试验地点
- 1
- 主要终点
- Percentage of participants achieving measurable residual disease negative composite complete remission (CRc-MRD-)
研究概览
简要总结
This phase II trial compares induction and consolidation therapy with fludarabine, cytarabine, idarubicin, and venetoclax to cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of acute myeloid leukemia (AML). Patients with AML often receive induction and consolidation therapy. Induction therapy is given first to get the patient's AML under control (remission). Consolidation therapy is given after the cancer has disappeared following the initial therapy. Consolidation therapy is used to kill any cancer cells that may be left in the body. Chemotherapy drugs, such as fludarabine, cytarabine, idarubicin, and daunorubicin, 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving fludarabine, cytarabine, idarubicin, and venetoclax for induction and consolidation therapy may be more effective in treating AML.
详细描述
PRIMARY OBJECTIVE:
I. Assess the efficacy of treatment based on rates of measurable residual disease negative composite complete remission (CRc-MRD-) determined using multiparameter flow cytometry (MFC).
SECONDARY OBJECTIVES:
I. Assess the efficacy of treatment based on complete response (CR) disease remission.
II. Assess the efficacy of treatment based on overall clinical response. III. Assess the safety of treatment. IV. Assess survival in the absence of treatment failure, hematologic relapse, or progressive disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability to comprehend the investigational nature of the study and provide written informed consent
- •Age 18 to ≤ 65 years (yrs), at the time of consent
- •All gender identities, races, or ethnicities are eligible
- •Newly documented, previously untreated diagnosis of AML or myelodysplastic syndrome (MDS) with marrow blasts ≥ 10%, in agreement with 2022 European LeukemiaNet criteria (ELN22)
- •Leukapheresis and treatment with cytarabine or hydroxyurea prior to study initiation is permitted for cytoreduction in patients with proliferative disease. NOTE: Treatment with cytarabine is limited to up to 2 grams total at least 14 days prior to starting on protocol defined therapy
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Willingness to undergo hematopoietic stem cell transplant (HSCT)
- •Ability to take medications by mouth or feeding tube
- •Adequate hematologic and organ function
- •Institutional standards, New York Heart Association (NYHA) criteria for cardiac function
- •Calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40 mL/min
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 x upper limit of normal (ULN), unless considered due to leukemic involvement
- •Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x ULN, unless considered due to leukemic involvement
- •Total bilirubin ≤ 1.5 x ULN, unless due to Gilbert's disease or leukemic involvement
- •Willing and able to
- •Adhere to study schedule of activities and lifestyle restrictions while on treatment;
- •Provide bone marrow (BM) aspirate and core biopsy samples; AND
- •Accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequelae, including transfusions
- •Negative pregnancy test within 3 days of start of treatment for persons of childbearing potential (PCBP)
- •Based on animal studies and the known pharmacology of the study drugs, PCBP and sperm-producing participants who are sexually active with a PCBP must comply with study requirements for contraception
- •PCBP (participants and PCBP partners of participants) must agree to use an approved contraception and to refrain from donating / cryopreserving ova from cycle (C) 1 day (D) 1 until 6 months following the last dose of study treatment
- •Participants who produce viable sperm and who have intercourse with PCBP must agree to use an approved contraception method and to refrain from donating sperm from C1D1 until 3 months following the last dose of study treatment
排除标准
- •Documented t(15;17) (acute promyelocytic leukemia [APL]), and/or mutation(s) to FLT3 ITD or core binding factor (CBF). Point mutations within the tyrosine kinase domain (FLT3 TKD) are allowed
- •Another active malignancy within the previous 5 years, except treated early stage carcinomas of the skin, or at the investigator's discretion
- •Known, active central nervous system (CNS) involvement with AML
- •Recent and significant medical interventions, such as major surgery within 28 days of start of treatment
- •GVHD or autologous stem cell transplant within 100 days of start of treatment
- •Currently receiving investigational therapy or chemotherapy within 28 days, or 5 half-lives, whichever is longer, with the exception of hydroxyurea or cytarabine for cytoreduction purposes
- •Prior treatment with a BCL 2 inhibitor within 12 months prior to the start of treatment
- •Use of strong or moderate CYP3A4 inducers or inhibitors or P-gp inhibitors within 2 days or 3 half-lives, whichever is longer, prior to start of treatment with venetoclax or at the discretion of the investigator if dose reductions, based on the interaction, have been specified
- •History of allergic response to any of the interventional agents or any excipients in the formulations
- •Inadequate organ function, including the following (or at the discretion of the investigator):
- •History of New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
- •Unstable/uncontrolled angina pectoris, history of severe and/or uncontrolled ventricular arrhythmias, or history of myocardial infarction within the last 6 months
- •A white blood cell count (WBC) > 25 x 10^⁹/L
- •Known dysphagia in the absence of a feeding tube, short-gut syndrome, or other conditions or causes that would affect the ingestion and/or gastrointestinal absorption of drugs administered orally
- •Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV, respectively) status, except in cases of undetectable HBV/HCV viral load for at least 3 months prior to the start of treatment. (Hepatitis B or C testing is not required for eligibility assessment.)
- •Individuals with positive serology for human immunodeficiency virus (HIV) who are undergoing treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents) are not eligible. If the HIV infection is controlled with another medication type or if an acceptable alternative HIV treatment can be substituted for HAART, enrollment may proceed
- •Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to start of treatment and must be amenable to alternate treatment if current treatment will interact with investigational regimen
- •Psychiatric illness/social situations that would limit compliance with study requirements
- •Unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding is not allowed throughout the study for 6 weeks after the last dose of study drug
研究组 & 干预措施
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Multigated Acquisition Scan (Procedure)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Bone Marrow Aspiration (Procedure)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Bone Marrow Biopsy (Procedure)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Echocardiography Test (Procedure)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Cytarabine (Drug)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Fludarabine (Drug)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Idarubicin (Drug)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Venetoclax (Drug)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Cytarabine (Drug)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Multigated Acquisition Scan (Procedure)
Arm 1 (fludarabine, cytarabine, idarubicin, venetoclax)
See Detailed Description.
干预措施: Questionnaire Administration (Other)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Bone Marrow Aspiration (Procedure)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Bone Marrow Biopsy (Procedure)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Echocardiography Test (Procedure)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Questionnaire Administration (Other)
Arm 2 (cytarabine, daunorubicin)
INDUCTION: Patients receive cytarabine IV on days 1-7 and daunorubicin IV on days 1-3 of each cycle. Cycles repeat every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients achieving CR, CRh, CRi, or MLFS after one induction cycle proceed to consolidation. Patients achieving PR after one induction cycle may proceed to consolidation at the investigator's discretion. Patients with ≥ 5% blasts after one induction cycle may receive a second cycle of induction therapy.
CONSOLIDATION: Participants receive cytarabine IV over 3 hours BID on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for up to 4 post-induction cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo ECHO or MUGA scan during screening and on study as clinically indicated. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the trial.
干预措施: Daunorubicin (Drug)
结局指标
主要结局
Percentage of participants achieving measurable residual disease negative composite complete remission (CRc-MRD-)
时间窗: Up to 30 days post last dose of study drug
Will be defined as the achievement of both measurable disease negative (MRD-) by multiparameter flow cytometry and complete response (CR), CR with partial hematologic recovery (CRh), or CR with incomplete blood count recovery (CRi). Participants who do not qualify as efficacy-evaluable (usually due to early death or withdrawal because of toxicity) will be considered non-responders. A point estimate and 95% exact confidence interval (CI) for CRc MRD- will be computed for each arm (and time point) separately and the CRc MRD- rate will be statistically compared across arms with Fisher's exact test at 3 timepoints: end of induction, end of the first consolidation cycle, and end of treatment. A Hochberg multiplicity adjustment will be applied to the p-values from these 3 Fisher exact tests to control the family wise error rate (at α=0.05) for between-arm comparisons of the primary endpoint. CRc MRD- status at each of the above-specified time points will be modeled with logistic regression.
次要结局
- Event free survival (EFS)(From cycle (C)1 day(D)1 to first occurrence of treatment failure, disease progression, or death due to any cause, assessed up to 2 years)
- Overall survival (OS)(From C1D1 to date of death due to any cause, assessed up to 2 years)
- Time to HSCT referral(Up to 2 years after end of study treatment)
- Percentage of participants achieving CR(Up to 30 days post last dose of study drug)
- Percentage of participants achieving composite complete remission (CRc)(Up to 30 days post last dose of study drug)
- Percentage of participants achieving an overall response (ORR)(Up to 30 days post last dose of study drug)
- Incidence of treatment-emergent grade ≥ 3 adverse events (AEs)(Up to 30 days after the last dose of any study drug)
- Time to completed consult for HSCT(Up to 2 years after end of study treatment)
- Percentage of participants who transition to HSCT(Up to 2 years after end of study treatment)
- Cumulative incidence of HSCT(Up to 2 years after end of study treatment)
- Percentage of participants who are MRD- post-HSCT(From HSCT day 0 to day +365 post-HSCT)
- Cumulative incidence of grade 2-3 post-HSCT infections(From HSCT day 0 to day +100 post-HSCT)
- Cumulative incidence of grade ≥ II acute graft versus host disease (aGVHD)(From HSCT day 0 to day +365 post-HSCT)
- Cumulative incidence of grade ≥ 2 chronic graft versus host disease (cGVHD)(From HSCT day 0 to day +365 post-HSCT)
- GVHD-free, relapse-free survival (GRFS)(From HSCT day 0 to disease relapse, MAGIC grade III-IV aGVHD, cGVHD requiring systemic therapy, death from any cause or last known alive, or day + 365 post-HSCT, whichever occurs earliest)
研究者
Curtis Lachowiez
Principal Investigator
OHSU Knight Cancer Institute