A Phase 1 Study of GRN163L (Imetelstat) in Combination With Fludarabine and Cytarabine for Patients With Acute Myeloid Leukemia That is in Second or Greater Relapse or That is Refractory to Relapse Therapy; Myelodysplastic Syndrome or Juvenile Myelomonocytic Leukemia in First or Greater Relapse or is Refractory to Relapse Therapy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 31
- 主要终点
- Dose limiting toxicities of imetelstat administered in combination with fludarabine and cytarabine
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of imetelstat in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) that has not responded to previous treatment (refractory) or that has come back after a period of improvement (recurrent). Imetelstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine 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. Giving imetelstat in combination with fludarabine and cytarabine may work better in treating patients with refractory or recurrent AML, MDS, and JMML.
详细描述
PRIMARY OBJECTIVE:
I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of imetelstat administered in combination with fludarabine and cytarabine to children with second or greater relapse of acute myeloid leukemia or first or greater relapse of myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML).
SECONDARY OBJECTIVES:
I. To define and describe the toxicities of imetelstat administered on this schedule in combination with fludarabine and cytarabine in patients with refractory and/or relapsed AML, MDS, or JMML.
II. To characterize the pharmacokinetics of imetelstat in combination with fludarabine and cytarabine in patients with refractory and/or relapsed AML, MDS, or JMML.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be ≥ 1 year and ≤ 18 years of age at the time of study enrollment
- •Patients, with or without down syndrome (DS), and with acute myeloid leukemia, therapy-related AML, MDS or JMML and meet one of the following:
- •Second or greater relapse or refractory AML, including isolated extramedullary disease (EMD), but excluding isolated central nervous system (CNS) or isolated testicular relapse
- •First or greater relapse of MDS
- •First or greater relapse of JMML
- •For flow cytometry, it's strongly recommended to enroll onto APAL2020SC or to send samples to Hematologics, Inc. Otherwise, assessments must be performed at a College of American Pathologists (CAP)/Clinical Laboratory Improvement Act (CLIA) certified lab that has expertise in AML.
- •For fluorescence in situ hybridization (FISH)/Karyotype, samples must be sent to a Children's Oncology Group (COG)-approved Cytogenetics Lab
- •Bone marrow relapse AML: (patients must meet one of the following criteria to be defined as having relapsed disease)
- •A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing, or other molecular method
- •A single bone marrow with at least two tests showing ≥ 1% leukemic blasts; examples of tests include:
- •Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
- •Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
- •FISH abnormality identical to one present at diagnosis
- •Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and ≥ 1%
- •In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/uL (i.e., a white blood cell [WBC] count ≥ 10,000/uL with ≥ 10% blasts or a WBC count of ≥ 5,000/uL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
- •Extramedullary relapse: Biopsy proven extramedullary disease after documented complete remission
- •Refractory disease AML: Following a re-induction cycle after a second relapse, or refractory to two reinduction attempts after either primary induction failure or first relapse with:
- •A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing, or other molecular method
- •A single bone marrow with at least two tests showing ≥ 1% leukemic blasts: examples of tests include:
- •Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
- •Karyotypic abnormality with at least one metaphase similar or identical to diagnosis.
- •FISH abnormality identical to one present at diagnosis
- •Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and ≥ 1%
- •In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/uL (i.e., a WBC count ≥ 10,000/uL with ≥ 10% blasts or a WBC count of ≥ 5,000/uL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
- •Extramedullary refractory disease:
- •Biopsy proven persistent extramedullary disease
- •In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ µL (i.e., a WBC count ≥ 10,000/μL with ≥ 10% blasts or a WBC count of ≥ 5,000/μL with ≥ 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed
- •Central nervous system disease: Patients with relapsed or refractory disease with central nervous system (CNS) 1 and CNS 2 status are eligible
- •MDS: Bone marrow relapse: (patients must meet one of the following criteria to be defined as having relapsed disease)
- •A single bone marrow sample showing ≥ 5% leukemic blasts by flow cytometry, FISH, or other molecular method
- •A single bone marrow with at least two tests showing ≥ 1% leukemic blasts; examples of tests include:
- •Flow cytometry showing ≥ 1% leukemic blasts by multidimensional flow cytometry (MDF)
- •Karyotypic abnormality with at least one metaphase similar or identical to diagnosis
- •FISH abnormality identical to one present at diagnosis
- •Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of MDS associated lesion identical to diagnosis and ≥ 1%
- •In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy
- •JMML: Diagnosis: Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease. The diagnosis is made based on the following criteria
- •JMML category 1 (all of the following):
- •Splenomegaly
- •> 1000 (1 x 10^9 /uL) circulating monocytes
- •< 20% Blasts in the bone marrow or peripheral blood
- •Absence of the t(9;22) or BCR/ABL fusion gene
- •The diagnostic criteria must include all features in category 1 and either (i) one of the features in category 2 or (ii) two features from category 3 to make the diagnosis
- •JMML category 2 (at least one of the following if at least two category 3 criteria are not present):
- •Somatic mutation in RAS or PTPN11
- •Clinical diagnosis of NF1 or NF1 gene mutation
- •Homozygous mutation in CBL
- •Monosomy 7
- •JMML category 3 (at least two of the following if no category 2 criteria are met):
- •Circulating myeloid precursors
- 另有 40 项未显示
排除标准
- •Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, or because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Women of childbearing potential must use highly effective contraception in addition to a barrier method during treatment and for at least 1 month after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Male patients who can father a child should use contraception during treatment and for 3 months after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Imetelstat should not be administered to nursing mothers
- •Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Patients may be on physiological doses of steroids (equivalent to ≤ 10 mg prednisone daily for patients ≥ 18 years or ≤ 10mg/m^2/day [up to a maximum of 10 mg/day] for patients < 18 years). If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid
- •Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
- •Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy
- •Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
- •Specific to MDS patients: Low-grade MDS/refractory cytopenia of childhood (RCC) - MDS with less than 2% blasts in peripheral blood (PB) or less than 5% blasts in the bone marrow (BM) by morphology
- •Uncontrolled seizure disorder that is not stabilized with anti-convulsants
- •Patient has undergone surgery that requires general anesthesia within 3 weeks before enrollment (line placement/removal/revision or tissue collection is allowed)
- •Known hypersensitivity to the study drug or excipients of the preparation
- •Patients with acute promyelocytic leukemia (APL) with PML-RARA genetic abnormality according to World Health Organization (WHO) classification or t(15;17) are not eligible
- •Patients known to have a congenital bone marrow failure syndrome where increased risk of toxicity may be expected as judged by the Investigator, for example dyskeratosis congenita, are not eligible
- •Patients with isolated or refractory CNS or isolated or refractory testicular relapse are not eligible
- •Patients who have an uncontrolled infection are not eligible
- •Patients who have received a prior solid organ transplantation are not eligible
- •Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
研究组 & 干预措施
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Cytarabine (Drug)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Fludarabine (Drug)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Hydrocortisone Sodium Succinate (Drug)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Imetelstat (Biological)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Lumbar Puncture (Procedure)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Methotrexate (Drug)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Biospecimen Collection (Procedure)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Echocardiography Test (Procedure)
Treatment (Imetelstat, fludarabine, cytarabine)
Patients receive imetelstat IV over 2 hours on days 1 and 8, fludarabine IV over 1 hour on days 2-6, and cytarabine IV over 1-3 hours on days 2-6 of each cycle. Patients also receive cytarabine IT alone or with methotrexate IT, and hydrocortisone IT at the provider's discretion. Patients may also receive leucovorin calcium IV or PO 24 and 30 hours after each IT triples dose. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, bone marrow biopsy and/or aspiration, blood sample collection, and lumbar puncture for CSF sample collection during screening and on the trial.
干预措施: Leucovorin Calcium (Drug)
结局指标
主要结局
Dose limiting toxicities of imetelstat administered in combination with fludarabine and cytarabine
时间窗: During cycle 1 of therapy (each cycle is 28 days)
Frequency percent (%) of patients with acute myeloid leukemia (AML) in second or greater relapse or refractory to relapse therapy who experience a cycle 1 dose limiting toxicity to imetelstat administered in combination with fludarabine and cytarabine stratified by dose level.
次要结局
- Incidence of adverse events of imetelstat administered in combination with fludarabine and cytarabine(Up to 2 years from study entry)
- Area under the drug concentration curve of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- Maximum serum concentration of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- Clearance of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- Half-life of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- PK parameters: Volume of distribution(Up to 24 hours)
- Antileukemic activity of imetelstat administered in combination with fludarabine and cytarabine(Up to 56 days)
- Overall survival (OS) of imetelstat administered in combination with fludarabine and cytarabine(Up to 5 years from study entry)
- Incidence of adverse events of imetelstat administered in combination with fludarabine and cytarabine(Up to 2 years from study entry)
- Area under the drug concentration curve of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- Maximum serum concentration of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- Clearance of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- Half-life of imetelstat administered in combination with fludarabine and cytarabine(Up to 24 hours)
- PK parameters: Volume of distribution(Up to 24 hours)
- Antileukemic activity of imetelstat administered in combination with fludarabine and cytarabine(Up to 56 days)
- Overall survival (OS) of imetelstat administered in combination with fludarabine and cytarabine(Up to 5 years from study entry)