A Pilot/Phase 1b Study of Glasdegib-Based Treatment Combinations in Adult Patients With Relapsed AML Post Allogeneic Hematopoietic Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 试验地点
- 1
- 主要终点
- Ability to obtain a molecular diagnosis (Molecular Diagnosis Segment)
研究概览
简要总结
This phase Ib trial evaluates the best dose and effect of glasdegib in combination with venetoclax and decitabine, or gilteritinib, bosutinib, ivosidenib, or enasidenib in treating patients with acute myeloid leukemia that has come back (relapsed) after stem cell transplantation. Chemotherapy drugs, 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. Glasdegib, bosutinib, ivosidenib, and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Glasdegib inhibits the Sonic the Hedgehog gene. Venetoclax inhibits BCL-2 gene. Bosutinib is a tyrosine kinase inhibitor that inhibits BCR-ABL gene fusion. Ivosidenib inhibits isocitrate dehydrogenase-1 gene or IDH-1. Enasidenib inhibits isocitrate dehydrogenase-2 gene or IDH-2. This study involves an individualized approach that may allow doctors and researchers to more accurately predict which treatment plan works best for patients with relapsed acute myeloid leukemia.
详细描述
PRIMARY OBJECTIVES:
I. Evaluate study feasibility through:
Ia. The ability to obtain a molecular diagnosis within 10 calendar days from study enrollment in at least 90% of participants. (Molecular Diagnosis Segment) Ib. The ability to make a treatment arm assignment within 14 calendar days from study enrollment in at least 90% of participants. (Molecular Diagnosis Segment) II. Assess the safety and tolerability of the drug combination by evaluation of toxicities including: type, frequency, severity, attribution, and duration of the toxicity. (Treatment Segment)
SECONDARY OBJECTIVES:
I. Determine the proportion of participants with successful sequencing by City of Hope (COH) Pathology among those with less than 10% blasts in the marrow aspirate. (Molecular Diagnosis Segment) II. Determine the proportion of participants with successful treatment arm registration based on Treatment Assignment Committee (TAC) assignment. (Molecular Diagnosis Segment) III. Assess the safety of monotherapy glasdegib by evaluation of toxicities including, type, frequency, severity and attribution. (Molecular Diagnosis Segment) IV. Obtain preliminary estimates of remission (complete response [CR] + CR with incomplete blood count recovery [CRi]) rate and duration of remission. (Treatment Segment)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •MOLECULAR DIAGNOSIS SEGMENT: Documented informed consent of the participant and/or legally authorized representative
- •MOLECULAR DIAGNOSIS SEGMENT: Age: >= 18 years on the day of signing informed consent
- •MOLECULAR DIAGNOSIS SEGMENT: Eastern Cooperative Oncology Group (ECOG) =< 2
- •MOLECULAR DIAGNOSIS SEGMENT: Patients with histologically confirmed acute myeloid leukemia (AML), according to World Health Organization (WHO) criteria, with relapsed disease after allogeneic hematopoietic cell transplantation (alloHCT)
- •Patients with non-central nervous system (CNS) extramedullary disease may be included if they also have marrow disease
- •Patients with acute promyelocytic leukemia (APL) will not be eligible
- •MOLECULAR DIAGNOSIS SEGMENT: Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 of prior anti-cancer therapy
- •MOLECULAR DIAGNOSIS SEGMENT: Total bilirubin =< 2 x ULN (unless has Gilbert's disease) (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: Aspartate aminotransferase (AST)=< 2 x ULN (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: Alanine aminotransferase (ALT) =< 2 x ULN (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar) (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: Creatinine clearance of >= 50 mL/min per 24-hour urine test or the Cockcroft-Gault formula (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: If not receiving anticoagulants: international normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: If not receiving anticoagulants: activated partial thromboplastin Time (aPTT) =<1.5 x ULN. If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: Left ventricular ejection fraction (LVEF) >= 45% (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •Note: Echocardiogram to be performed within 28 days prior to day 1 of protocol therapy
- •MOLECULAR DIAGNOSIS SEGMENT: Corrected QT (QTc) =< 470 milliseconds (ms) (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •Note: Electrocardiogram (ECG) to be performed within 14 days prior to day 1 of protocol therapy
- •MOLECULAR DIAGNOSIS SEGMENT: Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •MOLECULAR DIAGNOSIS SEGMENT: Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity from 4 weeks prior to first dose of treatment throughout the study treatment period and 1 month (females) or 1 month (males) from the last dose of study drug
- •Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
- •CHAPTER 1: Documented informed consent of the participant and/or legally authorized representative
- •CHAPTER 1: Age: >= 18 years on the day of signing informed consent
- •CHAPTER 1: ECOG =< 2
- •CHAPTER 1: Patients with histologically confirmed AML, according to WHO criteria, with relapsed disease after alloHCT
- •Patients with non-central nervous system (CNS) extramedullary disease may be included if they also have marrow disease
- •Patients with acute promyelocytic leukemia (APL) will not be eligible
- •CHAPTER 1: Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 of prior anti-cancer therapy
- •CHAPTER 1: White blood cell count less than 25 x 10^9 /L prior to initiation of venetoclax. Cytoreduction with hydroxyurea prior to treatment and/or up to 1 week after start of this treatment arm may be required (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: Total bilirubin =< 2 x ULN (unless has Gilbert's disease) (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: AST =< 2 x ULN (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: ALT =< 2 x ULN (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: Creatinine clearance of >= 50 mL/min per 24-hour urine test or the Cockcroft-Gault formula (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5 x ULN If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 1: QTc =< 470 milliseconds (ms) (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •Note: ECG to be performed within 14 days prior to day 1 of protocol therapy
- •CHAPTER 1: Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- •CHAPTER 1: Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity from 4 weeks prior to first dose of treatment throughout the study treatment period and 6 months (females) or 3 months (males) from the last dose of study drug
- •Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
- •CHAPTER 2: Documented informed consent of the participant and/or legally authorized representative
- •CHAPTER 2: Age: >= 18 years on the day of signing informed consent
- •CHAPTER 2: ECOG =< 2
- •CHAPTER 2: Patients with histologically confirmed AML, according to WHO criteria, with relapsed disease after alloHCT
- •Patients with non-central nervous system (CNS) extramedullary disease may be included if they also have marrow disease
- •Patients with acute promyelocytic leukemia (APL) will not be eligible
- •CHAPTER 2: Patients with a confirmed susceptible FLT3 mutation (m) (internal tandem duplications (ITD), tyrosine kinase domain (TKD) mutations D835 or I836), or AXL variant expression
- •CHAPTER 2: Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 of prior anti-cancer therapy
- •CHAPTER 2: Total bilirubin =< 2 x ULN (unless has Gilbert's disease) (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 2: AST =< 2 x ULN (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- •CHAPTER 2: ALT =< 2 x ULN (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated in the study calendar)
- 另有 41 项未显示
排除标准
- 未提供
研究组 & 干预措施
Chapter 1 (glasdegib, decitabine, venetoclax)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD on days 1-28,decitabine IV over 1 hour on days 1-5, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Decitabine (Drug)
Chapter 1 (glasdegib, decitabine, venetoclax)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD on days 1-28,decitabine IV over 1 hour on days 1-5, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Glasdegib Maleate (Drug)
Chapter 1 (glasdegib, decitabine, venetoclax)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD on days 1-28,decitabine IV over 1 hour on days 1-5, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
Chapter 2 (glasdegib, gilteritinib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and gilteritinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Gilteritinib Fumarate (Drug)
Chapter 2 (glasdegib, gilteritinib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and gilteritinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Glasdegib Maleate (Drug)
Chapter 3 (glasdegib, bosutinib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and bosutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Bosutinib Monohydrate (Drug)
Chapter 3 (glasdegib, bosutinib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and bosutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Glasdegib Maleate (Drug)
Chapter 4 (glasdegib, ivosidenib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Glasdegib Maleate (Drug)
Chapter 4 (glasdegib, ivosidenib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and ivosidenib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Ivosidenib (Drug)
Chapter 5 (glasdegib, enasidenib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and enasidenib PO QD on days 1-28 .Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Enasidenib Mesylate (Drug)
Chapter 5 (glasdegib, enasidenib)
MOLECULAR DIAGNOSIS SEGMENT: Patients receive glasdegib PO QD for at least 14 days until their AML TAC recommendation is made and they are either consented to a treatment arm in the Treatment Segment or go off study.
TREATMENT SEGMENT: Patients receive glasdegib PO QD and enasidenib PO QD on days 1-28 .Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Glasdegib Maleate (Drug)
结局指标
主要结局
Ability to obtain a molecular diagnosis (Molecular Diagnosis Segment)
时间窗: From study enrollment to return of Molecular Diagnosis Report, assessed up to 30 days
Outcome will be dichotomized based on return in =\< 10 calendar days (Yes/No). Assessed by the proportion of successful participants.
Ability to make a treatment arm assignment by the Treatment Assignment Committee (TAC) (Molecular Diagnosis Segment)
时间窗: From enrollment to treatment arm assignment by the TAC, assessed up to 30 days
Outcome will be dichotomized based on return in =\< 14 calendar days (Yes/No). Assessed by the proportion of participants who receive treatment assignment from TAC.
Incidence of adverse events (Treatment Segment)
时间窗: Up to 30 days
Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Safety will be based on the assessment of dose limiting toxicity during cycle 1 and cycle 2. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
次要结局
- Proportion of patients with successful treatment arm registration (Molecular Diagnosis Segment)(Up to 30 days)
- Duration of remission (Treatment Segment)(Time from the first of two consecutive bone marrow aspirates showing CR or CRi until such time as the bone marrow or peripheral blood mononuclear cells shows signs of relapse, assessed up to 30 days)
- Proportion of patients with successful sequencing (Molecular Diagnosis Segment)(Up to 30 days)
- Incidence of adverse events (Molecular Diagnosis Segment)(Up to 30 days)
- Overall response (Treatment Segment)(Up to the date of the first of 2 successive bone marrows showing said response, assessed up to 30 days)