A Phase 1 Study of M3814 in Combination With MEC in Patients With Relapsed or Refractory Acute Myeloid Leukemia
概览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 48
- 试验地点
- 30
- 主要终点
- Incidence of adverse events
概览
简要总结
This phase I trial studies the best dose and side effects of M3814 when given in combination with mitoxantrone, etoposide, and cytarabine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). M3814 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as mitoxantrone and cytarabine, 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. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Giving M3814 in combination with mitoxantrone, etoposide, and cytarabine may lower the chance of the acute myeloid leukemia growing or spreading.
详细描述
PRIMARY OBJECTIVE:
I. To assess the safety and tolerability and determine the recommended phase two dose (RP2D) of peposertib (M3814) in combination with mitoxantrone, etoposide, and cytarabine (MEC) in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).
SECONDARY OBJECTIVES:
I. To characterize the pharmacokinetic (PK) profile of MEC alone and of M3814 in combination with MEC.
II. To evaluate the preliminary efficacy of M3814 in combination with MEC in patients with R/R AML as measured by the response rate (complete remission [CR] plus CR with incomplete count recovery [CRi]), duration of CR/CRi (DOR), event-free survival (EFS) and overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To evaluate correlative biomarkers of M3814 target engagement and response. II. To correlate cytogenetic and molecular abnormalities with response. III. To evaluate the rates of early mortality and allogeneic hematopoietic cell transplantation.
IV. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to:
IVa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned; IVb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.
V. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.
OUTLINE: This is a dose-escalation study of peposertib followed by a dose-expansion study.
Patients receive peposertib orally (PO) twice daily (BID) on days 2-21, mitoxantrone intravenously (IV) over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo echocardiogram (ECHO) or multigated acquisition scan (MUGA) during baseline, and blood collection and bone marrow biopsy throughout the study.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, then every 6 months thereafter up to 5 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •An established and confirmed diagnosis of AML by World Health Organization criteria, excluding acute promyelocytic leukemia (APL) (with promyelocytic leukemia -retinoic acid receptor alpha \[PML-RARA\])
- •Patients with R/R AML, defined as:
- •Relapsed: \>= 5% bone marrow blasts by morphology, reappearance of peripheral blood blasts, or development of extramedullary leukemia after achieving prior CR or CRi. First or second relapse is eligible. First relapse is restricted to participants with CR 1 duration of less than 9-12 months
- •Refractory: no CR or CRi after one or more cycles of induction. Induction cycles include regimens with the intent to achieve remission and can include high intensity and/or low intensity regimens
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of M3814 in combination with mitoxantrone, etoposide, and cytarabine in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (or Karnofsky \>= 60%)
- •Serum bilirubin =\< 1.5 institutional upper limit of normal (ULN) (For patients with hemolysis, Gilbert's syndrome or liver infiltration with leukemia, serum bilirubin =\< 3 x institutional ULN)
- •Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN (For patients with liver infiltration with leukemia, AST\[SGOT\]/ALT\[SGPT\] =\< 5 x institutional ULN)
- •Glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
- •Patients must be medically eligible to receive MEC, including acceptable pre-study cardiac function (left ventricular ejection fraction of \>= 45%) and lifetime anthracycline exposure (=\< 360 mg/m\^2 daunorubicin equivalents)
排除标准
- •Patients must not have had prior treatment with MEC
- •Patients must not have documented active central nervous system (CNS) involvement by leukemia. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs)
- •Patients must not have received any other investigational or commercial agents or therapies administered with the intention to treat their leukemia within 14 days or 5 elimination half-lives (whichever is shorter) of first receipt of study drug, with the exception of hydroxyurea and/or leukapheresis used to control white blood cell counts
- •Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2C9 and CYP2C19 during treatment with M
- •Concomitant use of CYP1A2, CYP2B6 and CYP3A4/5 substrates with a narrow therapeutic index are also excluded during treatment with M
- •Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time prior to the first dose of M3814:
- •Strong inducers of CYP3A4/5, CYP2C9 and CYP2C19: \>= 3 weeks or 5 elimination half-lives (whichever is shorter) prior to the first dose of M3814
- •Strong inhibitors of CYP3A4/5, CYP2C9 and CYP2C19: \>= 1 week or 5 elimination half-lives (whichever is shorter) prior to the first dose of M3814
- •Substrates of CYP1A2, CYP2B6 and CYP3A4/5 with a narrow therapeutic index: \>= 1 day prior to the first dose of M3814
- •Concomitant use of histamine-2 (H2)-blockers or proton pump inhibitors should be avoided as these might affect absorption of M3814; administrations have to be discontinued at least 5 days or 5 elimination half-lives (whichever is shorter) prior to the first dose of M
研究组 & 干预措施
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Peposertib (Drug)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Echocardiography Test (Procedure)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Etoposide Phosphate (Drug)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Cytarabine (Drug)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (peposertib, mitoxantrone, etoposide, cytarabine)
Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO or MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.
干预措施: Mitoxantrone Hydrochloride (Drug)
结局指标
主要结局
Incidence of adverse events
时间窗: Up to 5 years
Coded according to the Common Terminology Criteria for Adverse Events version 5.
次要结局
- Pharmacokinetic (PK) profile of M3814 in combination with mitoxantrone, etoposide, and cytarabine (MEC)(Days 1 and 5)
- Overall response rate(Up to 5 years)
- Duration of CR/CRi(From first documented CR/CRi response to relapse, assessed up to 5 years)
- Event-free survival(From study entry to treatment failure (lack of response, i.e., no CR or CRi), relapse from CR or CRi, or death from any cause, assessed up to 5 years)
- Overall survival(From study entry to death from any cause, assessed up to 2 years)
- Duration of CR/CRi(From first documented CR/CRi response to relapse, assessed up to 5 years)
- Overall survival(From study entry to death from any cause, assessed up to 2 years)
- Pharmacokinetic (PK) profile of M3814 in combination with mitoxantrone, etoposide, and cytarabine (MEC)(Days 1 and 5)
- Overall response rate(Up to 5 years)
- Event-free survival(From study entry to treatment failure (lack of response, i.e., no CR or CRi), relapse from CR or CRi, or death from any cause, assessed up to 5 years)