Phase 3 Randomized, Double-blind, Placebo-controlled Studies Assessing Ziftomenib in Combination With Either Standard of Care Nonintensive (Venetoclax+Azacitidine) or Intensive (7+3) Therapy in Patients With Untreated NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,300
- 试验地点
- 122
- 主要终点
- Nonintensive Therapy Study: (Primary Endpoint for all countries): Overall survival (OS)
研究概览
简要总结
Ziftomenib is an investigational drug in development for the treatment of patients with acute myeloid leukemia (AML) with eligible genetic alterations. Ziftomenib is a type of therapy known to target the menin pathway in cancer cells.
This protocol has 2 separate studies that will investigate the benefits and risks of adding ziftomenib to standard-of-care (SOC) AML treatments in patients with certain genetic mutations who have not received any treatment for their AML. In the first study, the Nonintensive Therapy Study, older patients or those with serious medical problems will receive the SOC therapies venetoclax (ven) and azacitidine (aza), plus either ziftomenib or a placebo. In the second study, the Intensive Therapy Study, medically fit patients will receive (a) the SOC therapies cytarabine and daunorubicin, plus either ziftomenib or a placebo during a first treatment phase called induction, (b) cytarabine plus either ziftomenib or a placebo during a second treatment phase called consolidation, and (c) ziftomenib or a placebo during a third treatment phase called maintenance.
The physician will determine which study is the appropriate treatment for the patient, but neither the patient nor their physician will know whether the patient has been assigned to receive ziftomenib or a placebo. This design is called "double-blinded".
详细描述
This protocol encompasses two phase 3, randomized, double-blind, placebo-controlled clinical studies to assess the efficacy, safety, and tolerability of ziftomenib in combination with: (a) the standard of care (SOC) nonintensive regimen (venetoclax [ven]+azacitidine [aza]) in untreated adults with nucleophosmin 1 mutated (NPM1-m) acute myeloid leukemia (AML); or (b) the SOC intensive regimen (cytarabine+daunorubicin induction, referred to here as 7+3, and cytarabine consolidation) in untreated adults with NPM1-m or lysine[K]-specific methyltransferase 2A rearranged (KMT2A-r) AML, as well as a maintenance phase.
Nonintensive Therapy Study (Ven+Aza)
Eligible NPM1-m patients will be enrolled and randomized to receive:
- Arm A: Ziftomenib in combination with ven+aza or
- Arm B: Placebo in combination with ven+aza.
Patients will be randomized to treatment arms in a double-blind manner.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The following criteria apply to both the Nonintensive Therapy Study and the Intensive Therapy Study unless otherwise noted:
- •Age ≥18 years at time of signing the informed consent form.
- •Diagnosis of AML per the 2022 WHO Classification of Hematolymphoid Tumors (5th Edition).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •Adequate liver and kidney function according to protocol requirements.
- •A female of childbearing potential must agree to use adequate contraception from the time of screening through 180 days following the last dose of study intervention. A male with a female partner of childbearing potential must agree to use abstinence or adequate contraception from the time of screening through 90 days following the last dose of study intervention.
- •NONINTENSIVE THERAPY STUDY ONLY (VEN+AZA):
- •Documented NPM1-m.
- •Patients considered ineligible for Intensive Therapy defined by the following:
- •i. Age ≥75, OR
- •ii. Age <75 with an ECOG performance status of 2 or cardiac, renal, or hepatic impairment per protocol criteria.
- •INTENSIVE THERAPY STUDY ONLY (7+3):
- •Documented NPM1-m or KMT2A-r (KMT2A-r patients with a partial tandem duplication are not eligible).
- •Documented FLT3 wild-type or ITD ratio <0.05 OR ineligible to receive FLT3-targeted therapy (medically ineligible or mutation in which FLT3 inhibition is not SOC). Lack of access to an FLT3 inhibitor is not considered "ineligible" for FLT3-targeted therapy.
- •Ejection fraction of ≥50%.
- •Fit for Intensive Therapy per Investigator opinion.
排除标准
- •Prior therapy for AML (except hydroxyurea or leukapheresis for WBC control).
- •Diagnosis of acute promyelocytic leukemia (APL), blast phase chronic myeloid leukemia, or isolated myeloid sarcoma.
- •Known history of BCR-ABL mutation.
- •History of other active concurrent malignancies prior to study entry except:
- •Basal cell skin cancer or localized squamous cell cancer of the skin
- •Previous malignancy confined and locally resected (or treated with other modalities) with curative intent
- •Prostate or breast cancer receiving adjuvant hormonal therapy.
- •Active central nervous system (CNS) involvement by AML.
- •Clinical signs/symptoms of leukostasis or white blood cells (WBC) >25×10^9/L prior to start of ziftomenib/placebo. Note: Hydroxyurea and/or leukapheresis are permitted to meet this criterion.
- •Known uncontrolled HIV infection or known active hepatitis B virus, hepatitis C virus infection, or other uncontrolled infection.
- •Uncontrolled intercurrent illness including but not limited to, cardiac illness as defined in the protocol.
- •Women who are pregnant or lactating.
研究组 & 干预措施
Nonintensive Therapy Study, Arm A
Ziftomenib in combination with venetoclax+azacitidine
干预措施: Ziftomenib (Drug)
Intensive Therapy Study, Arm A
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), ziftomenib (maintenance)
干预措施: Daunorubicin (Drug)
Intensive Therapy Study, Arm C
Placebo+cytarabine+daunorubicin (induction), placebo+cytarabine (consolidation), placebo (maintenance)
干预措施: Daunorubicin (Drug)
Intensive Therapy Study, Arm B
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance)
干预措施: Cytarabine (Ara-C) (Drug)
Nonintensive Therapy Study, Arm B
Placebo in combination with venetoclax+azacitidine
干预措施: Venetoclax (Drug)
Nonintensive Therapy Study, Arm B
Placebo in combination with venetoclax+azacitidine
干预措施: Placebo (Drug)
Nonintensive Therapy Study, Arm B
Placebo in combination with venetoclax+azacitidine
干预措施: Azacitidine (AZA) (Drug)
Intensive Therapy Study, Arm B
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance)
干预措施: Placebo (Drug)
Intensive Therapy Study, Arm C
Placebo+cytarabine+daunorubicin (induction), placebo+cytarabine (consolidation), placebo (maintenance)
干预措施: Placebo (Drug)
Intensive Therapy Study, Arm B
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance)
干预措施: Ziftomenib (Drug)
Intensive Therapy Study, Arm B
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance)
干预措施: Daunorubicin (Drug)
Nonintensive Therapy Study, Arm A
Ziftomenib in combination with venetoclax+azacitidine
干预措施: Venetoclax (Drug)
Intensive Therapy Study, Arm A
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), ziftomenib (maintenance)
干预措施: Ziftomenib (Drug)
Intensive Therapy Study, Arm A
Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), ziftomenib (maintenance)
干预措施: Cytarabine (Ara-C) (Drug)
Nonintensive Therapy Study, Arm A
Ziftomenib in combination with venetoclax+azacitidine
干预措施: Azacitidine (AZA) (Drug)
Intensive Therapy Study, Arm C
Placebo+cytarabine+daunorubicin (induction), placebo+cytarabine (consolidation), placebo (maintenance)
干预措施: Cytarabine (Ara-C) (Drug)
结局指标
主要结局
Nonintensive Therapy Study: (Primary Endpoint for all countries): Overall survival (OS)
时间窗: Defined as the time from randomization to date of death from any cause, assessed up to 36 months after last patient inclusion
OS
Nonintensive Therapy Study: (Dual Primary Endpoint for US & US reference countries only): Complete remission (CR)
时间窗: Assessed up to 36 months after last patient inclusion
CR rate per European Leukemia Network (ELN) 2022 criteria per Investigator assessment
Intensive Therapy Study: (Primary Endpoint for all countries): Event-free survival (EFS)
时间窗: Defined as the time from randomization to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 36 months after last patient inclusion
EFS
Intensive Therapy Study: (Dual Primary Endpoint for US & US reference countries only): Complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) negativity in NPM1-m patients
时间窗: Assessed up to 36 months after last patient inclusion
CR rate per ELN 2022 criteria per Investigator assessment with central BM MRD negativity
次要结局
- Nonintensive Therapy Study: (EU & EU reference countries only): Complete remission (CR)(Up to 36 months after last patient inclusion)
- Nonintensive Therapy Study: Bone marrow (BM) measurable residual disease (MRD) negativity(Up to 36 months after last patient inclusion)
- Nonintensive Therapy Study: Complete remission (CR) + complete remission with partial hematologic recovery (CRh)(Up to 36 months after last patient inclusion)
- Nonintensive Therapy Study: Descriptive statistics of Adverse Events (AEs)(From start of treatment to 28 days from last dose of ziftomenib or placebo)
- Nonintensive Therapy Study: Area under the concentration-time curve (AUC) of ziftomenib and venetoclax(During treatment for up to 36 months after last patient inclusion)
- Nonintensive Therapy Study: Trough concentration (Ctrough) of ziftomenib and venetoclax(During treatment for up to 36 months after last patient inclusion)
- Intensive Therapy Study: (EU & EU reference countries only): Complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) negativity in NPM1-m patients(Up to 36 months after last patient inclusion)
- Intensive Therapy Study: Overall survival (OS)(Defined as the time from randomization to date of death from any cause, up to 36 months after last patient inclusion)
- Intensive Therapy Study: Descriptive statistics of Adverse Events (AEs)(From start of treatment to 28 days from last dose of ziftomenib or placebo)
- Intensive Therapy Study: Area under the concentration-time curve (AUC) of ziftomenib(During treatment for up to 36 months after last patient inclusion)
- Intensive Therapy Study: Trough concentration (Ctrough) of ziftomenib(During treatment for up to 36 months after last patient inclusion)
- Nonintensive Therapy Study: Health-related patient-reported outcomes (PRO) assessments(Up to 36 months after last patient inclusion)
- Intensive Therapy Study: Health-related patient-reported outcomes (PRO) assessments(Up to 36 months after last patient inclusion)