A Study of Gilteritinib (ASP2215) Combined with Chemotherapy in Children, Adolescents and Young Adults with FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML), Trial ID 2215-CL-0603

试验摘要

The purpose of the phase 1 portion (dose escalation) of the study was to establish an optimally safe and biologically active recommended phase 2 dose (RP2D) and/or to determine maximum tolerated dose (MTD) for gilteritinib in sequential combination with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG). The purpose of the phase 2 portion (dose expansion) was to determine complete remission (CR) rates and composite complete remission (CRc) rates after two cycles of therapy. The study also assessed safety, tolerability and toxicities of gilteritinib in combination with FLAG, evaluated FLT3 inhibition, assessed pharmacokinetics (PK), performed serial measurements of minimal residual disease, obtained preliminary estimates of 1-year event free survival (EFS) and overall survival (OS) rate and assessed the acceptability as well as palatability of the formulation.

One cycle was defined as 28 days of treatment. A participant completing 1 or 2 treatment cycles in phase 1 or 2 had the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

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Scientific Results Summary

Available Language(s): English

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Plain Language Summary

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Protocol

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Statistical Analysis Plan (SAP)

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关于正在招募参与者的 A Study of Gilteritinib (ASP2215) Combined with Chemotherapy in Children, Adolescents and Young Adults with FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)，您是否想了解更多临床试验中心相关信息？请在右侧填写您的信息联系我们，我们将予以回复。

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蒙特利尔, 魁北克, 加拿大, H3T 1C5

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伯明翰, 英国, B4 6NH

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罗马, 意大利, 165

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埃森, Nordrhein-Westfalen, 德国, 45147

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Regensburg, 巴伐利亚, 德国, 93053

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格拉斯哥, 英国, G51 4TF

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蒙扎, 意大利, 20900

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博洛尼亚, 意大利, 40138

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Halle (Saale), 萨克森-安哈尔特, 德国, 06120

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塞维利亚, 西班牙, 41013

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Freiburg, Baden-Württemberg, 德国, 79106

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加的夫, 英国, CF14 4XW

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布里斯托尔, 英国, BS2 8BJ

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巴塞罗那, 西班牙, 08950

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巴塞罗那, 西班牙, 08950

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纳什维尔, 田纳西州, 美国, 37203

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Cincinnati, 俄亥俄州, 美国, 45229

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费城, 宾夕法尼亚州, 美国, 19104

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Memphis, 田纳西州, 美国, 38105

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萨顿, 英国

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巴黎, 法国

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巴黎, 法国

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Marseille cedex 05, 法国

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波尔多, 法国

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Vandoeuvre-Lès-Nancy, 法国

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试验信息

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参与者年龄

6 Months - 21 Years

疾病

白血病 - AML

参与者性别

女性和男性

试验开展时间

2020年9月 - 2025年3月

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入选标准

Subject is aged ≥ 6 months and < 21 years of age* at the time of signing informed consent and/or assent, as applicable.
- *For phase 2: Enrollment of subjects from 6 months to less than 1 year and 1 year to less than 2 years will be dependent on the establishment of recommended phase 2 dose (RP2D) in the respective age groups during phase 1.
Subject has a diagnosis of acute myeloid leukemia (AML) according to The French–American–British (FAB) classification with ≥ 5% blasts in the bone marrow, with or without extramedullary disease (except subjects with active central nervous system [CNS] leukemia).
- In the phase 1 portion of the study, subject must be in first or greater relapse or refractory to induction therapy with no more than 1 attempt at remission induction (up to 2 induction cycles).
- For the phase 2 portion of the study, subject must be in refractory to or at the first hematologic relapse after first-line remission induction AML therapy (up to 2 induction cycles).
Subject has fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
- Myelosuppressive chemotherapy:

+ For subject who relapses while receiving cytotoxic therapy, at least 21 days must have elapsed since the completion of cytotoxic therapy and prior to screening, unless the subject has recovered earlier than 21 days.

+ Cytoreduction with the following can be initiated and continued for up to 24 hours prior to the start of systemic protocol therapy (cycle 1 day -1).

hydroxyurea,
low dose cytarabine (100 mg/m^2 per dose once daily for 5 days) or
other low dose/maintenance therapies as per local site practice.

+ Subject who has received other FLT3 inhibitors (e.g., lestaurtinib, sorafenib, etc) is eligible for this study.

Hematopoietic growth factors: at least 7 days must have elapsed since the completion of therapy with a growth factor and prior to screening.
Biologic (anti-neoplastic agent): at least 7 days must have elapsed since the completion of therapy with a biologic agent and prior to screening. For agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur.
X-ray treatment (XRT):

+ 14 days must have elapsed for local palliative XRT for CNS chloromas and prior to screening; no washout period is necessary for other chloromas;

+ Prior to screening, 90 days must have elapsed if the subject had a prior traumatic brain injury or has received craniospinal XRT.

For subject undergoing hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since HSCT and subject must not have active graft-versus-host disease (GVHD).
Subject has Karnofsky score ≥ 50 (if the subject is of ≥ 16 years of age) or Lansky score of ≥ 50 (if the subject is < 16 years of age). A score < 50 is acceptable if related to the subject’s leukemia.
Subject must meet the following criteria as indicated on the clinical laboratory tests.
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit normal (ULN) for age
- Total serum bilirubin ≤ 1.5 x ULN for age
- Estimated glomerular filtration rate of > 60 mL/min/1.73 m^2.
A female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies:
- 非有生育能力的女性 (WOCBP)

或

WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study drug administration.
Female subject must agree not to breastfeed starting at Screening, and throughout the study period and for 60 days after the final study drug administration.
Female subject must not donate ova starting at Screening and throughout the study, and for 180 days after the final study drug administration.
A male subject with female partner(s) of childbearing potential must agree to use contraception during the treatment period and for at least 180 days after the final study drug administration.
A male subject must not donate sperm during the treatment period and for at least 120 days after the final study drug administration.
Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 180 days after the final study drug administration.
Subject and subject’s parent(s) or legal guardian agrees not to participate in another interventional

study while on treatment.

Live Vaccines - At least 6 weeks must have elapsed since the administration of the last dose of a live vaccine and prior to the initiation of study treatment (cycle 1, day -1)
Phase 1: Subject is positive for FLT3 (ITD and/or tyrosine kinase domain [TKD]) mutation in bone marrow or blood as determined by the local institution.
Phase 2: Subject is positive for the FLT3 (ITD) mutation in bone marrow or blood as determined by the local institution.

排除标准

Subject has active CNS leukemia.
Subject has uncontrolled or significant cardiovascular disease, including:
- Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes (TdP)); any history of arrhythmia will be discussed with the sponsor prior to subject’s entry into the study
- Prolonged Fridericia's Correction Formula (QTcF) interval on pre-entry electrocardiogram (ECG) (≥ 450 ms)
- Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)
- Heart rate < 50 beats/minute on pre-entry ECG
- Uncontrolled hypertension
- Complete left bundle branch block
Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The subject needs to be off pressors and have negative blood cultures for 48 hours.
Subject is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
Subject has active clinically significant GVHD or is on treatment with immunosuppressive drugs for treatment of active GVHD, with the exception of subjects being weaned from systemic corticosteroids where the subject is receiving ≤ 0.5 mg/kg of prednisone (or equivalent) daily dose for prior GVHD. Subject has received calcineurin inhibitors within 4 weeks prior to screening, unless used as GVHD prophylaxis.
Subject has active malignant tumors other than AML.
Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance; interfere with consent, study participation, follow-up or interpretation of study results.
Subject has hypokalemia and/or hypomagnesemia at Screening (defined as values below institutional lower limit of normal [LLN]). Repletion of potassium and magnesium levels during the screening period is allowed.
Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp).
Subject is known to have human immunodeficiency virus infection.
Subject has active hepatitis B or C, or other active hepatic disorder.
- Subjects with positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA are not eligible.
- Subjects with negative HBsAg, positive hepatitis B core antibody and negative hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable.
- Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA is undetectable.
Subject must wait for at least 5 half-lives after stopping therapy with any investigational agent and before starting gilteritinib.
Subject has a known or suspected hypersensitivity to gilteritinib, cytarabine, fludarabine, granulocyte colony-stimulating factor (G-CSF) or any components of the formulation used.

常见问题

临床试验是否只针对晚期癌症患者？

虽然某些临床试验可能侧重于更晚期的癌症，但许多试验对处于不同癌症阶段的患者开放。每项研究都有关于参与资格的规定。例如，只有特定年龄段的患者或患有特定类型肿瘤的患者才能参与。

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有时，研究人员希望参与者在临床试验期间继续接受当前治疗。有时，您可能需要暂停当前的治疗。如果研究性治疗无效，您通常可以恢复原有的治疗方案。

我是否应该担心会服用安慰剂？

在癌症临床试验中，只有当该类癌症尚无其他治疗方法时，才会使用安慰剂。这有助于将研究性治疗与安慰剂进行比较。安慰剂在癌症试验中很少使用，因为通常会采用最佳可用疗法，即所谓的“标准治疗方案”。

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A Study of Gilteritinib (ASP2215) Combined with Chemotherapy in Children, Adolescents and Young Adults with FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

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