難治性または再発性急性骨髄性白血病の小児および若年成人患者における化学療法と組み合わせたセリネキサーおよびベネトクラクスの研究
難治性または再発性急性骨髄性白血病の小児および若年成人患者における化学療法と組み合わせたセリネキサーおよびベネトクラクスの第I相および拡張コホート研究
The purpose of this study is to test the safety and determine the best dose of venetoclax and selinexor when given with chemotherapy drugs in treating pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has come back (relapsed) or did not respond to treatment (refractory).
Primary Objective
- To determine the safety and tolerability of selinexor and venetoclax in combination with chemotherapy in pediatric patients with relapsed or refractory AML or ALAL.
Secondary Objectives
- Describe the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the recommended phase 2 dose (RP2D).
- Describe the overall survival of patients treated at the RP2D.
Exploratory Objectives
- Explore associations between leukemia cell genomics, BCL2 family member protein quantification, BH3 profiling, and response to therapy as assessed by minimal residual disease (MRD) and variant clearance using cell-free deoxyribonucleic acid (DNA) (cfDNA).
- Describe the quality of life of pediatric patients undergoing treatment with selinexor and venetoclax in combination with chemotherapy and explore associations of clinical factors with patient-reported quality of life outcomes.
- Describe the clinical and genetic features associated with exceptional response to the combination of venetoclax and selinexor without the addition of chemotherapy.
調査の概要
状態
詳細な説明
This study will include two phases. The dose-escalation phase will characterize the dose-limiting toxicity (DLT) and determine the recommended phase 2 dose (RP2D) of venetoclax plus selinexor with and without chemotherapy. Two expansion cohorts (cohort A, patients without prior exposure to venetoclax; cohort B, patients with prior exposure to venetoclax) will further assess the safety and will explore the efficacy at the RP2D.
Dosing of venetoclax and selinexor will be based on tolerability. Venetoclax will be given orally (po) once daily on days 1 through 21 and selinexor will be given orally (po) starting on days 1, 8, and 15 OR 1, 3, 8, 10, 15, and 17. Beginning on day 16, patients also receive fludarabine phosphate intravenously (IV) daily on days 16-20, cytarabine IV daily on days 16-20, and granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) daily on days 16-20. G-CSF may be omitted or extended at the discretion of the treating physician. Intrathecal (IT) chemotherapy will be given prior to cycle 1, but may be delayed if clinically indicated. IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are all acceptable. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly IT therapy beginning on day 8, until the cerebrospinal fluid becomes free of leukemia.
Chemotherapy is scheduled to begin on Day 16; however, patients with exceptional responses may, at the discretion of the treating physician, receive chemotherapy (fludarabine and cytarabine) on days 16-20 and continue venetoclax through day 21 and selinexor through day 15 or 17 according to dose level. Alternatively, exceptional responders may continue venetoclax through day 28 and selinexor once or twice weekly according to dose level without chemotherapy and then undergo re-evaluation at day 29. For patients who do not receive chemotherapy on day 16-20, chemotherapy may be omitted completely or may be given on days 30-34 at the discretion of the treating physician.
Patients may receive up to 4 cycles of therapy in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
研究の種類
入学 (実際)
段階
- フェーズ 1
連絡先と場所
研究場所
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California
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San Diego、California、アメリカ、92123
- Rady Children's Hospital-San Diego
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Massachusetts
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Boston、Massachusetts、アメリカ、02215
- Dana-Farber Cancer Institute
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New York
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New York、New York、アメリカ、10065
- Memorial Sloan-Kettering Cancer Center
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Pennsylvania
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Philadelphia、Pennsylvania、アメリカ、19104
- Childrens Hospital of Philadelphia
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Tennessee
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Memphis、Tennessee、アメリカ、38105
- St. Jude Children's Research Hospital
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Nashville、Tennessee、アメリカ、37232
- Vanderbilt University Medical Center
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Texas
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Dallas、Texas、アメリカ、75390
- UT Southwestern/Simmons Cancer Center
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Fort Worth、Texas、アメリカ、76104
- Cook Children's Medical Center
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
-
Participants must have a diagnosis of AML or ALAL and meet the criteria below:
- Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR
- Early relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission and within one year of diagnosis, OR
- Relapsed leukemia that is refractory to at least one course of salvage therapy (i.e., therapy given after the relapse has occurred), OR
- Relapsed leukemia following HCT, OR
- Second or greater relapse
- Patients with late first relapses, defined as the re-appearance of leukemia after the achievement of remission and greater than one year of diagnosis, may be enrolled in the dose expansion portion of the study after safety data from the dose escalation portion is available.
Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if flow cytometry cannot be performed or if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the blood.
In addition, patients in all categories must not be eligible to undergo curative therapy, such as immediate HCT, because of disease burden, time to identify a stem cell donor, or other reasons.
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Adequate organ function defined as the following:
- Direct bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- Normal creatinine for age or a calculated creatinine clearance ≥ 30 mL/min/1.73m^2
- Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%
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Patients must be ≥ 2 years of age and ≤ 30 years old. The upper age limit may be defined by each institution but may not exceed 30 years. Patients treated at St. Jude Children's Research Hospital must be ≤ 24 years old.
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Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are > 16 years old.
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At least 14 days must have elapsed since the completion of myelosuppressive therapy or hypomethylating agents and the first doses of venetoclax and selinexor.
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At least 24 hours must have elapsed since the completion of low-dose or non- myelosuppressive therapy, such as hydroxyurea, low-dose cytarabine (up to 100 mg/m^2/day), FLT3 inhibitor, or leukapheresis, and the first doses of venetoclax and selinexor.
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For patients who have received prior HCT, there can be no evidence of GVHD and greater than 60 days must have elapsed since the HCT.
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At least 14 days must have elapsed since the completion of any calcineurin inhibitors (e.g. tacrolimus, cyclosporine).
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Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of the first dose of venetoclax or during the administration of venetoclax. During the dose-escalation portion of the trial, we discourage the use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of the first dose of venetoclax or during the administration of venetoclax. However, if an azole is required for the treatment or prevention of fungal infection during any phase of the trial, venetoclax dosing will be reduced to 60 mg/m^2 (100 mg max) in patients who require treatment with voriconazole and reduced to 40 mg/m^2 (70 mg max) in patients who require posaconazole.
Exclusion Criteria:
- Must not be pregnant or breastfeeding. Male or female of reproductive potential must agree to use effective contraception for the duration of study participation.
- Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible.
- Uncontrolled infection. Patients with infections that are controlled on concurrent anti-microbial agents are eligible.
- Impairment of GI function or GI disease that, in the opinion of the treating physician, may significantly alter the absorption of venetoclax or selinexor.
- History of cerebellar toxicity or cerebellar neurological findings on exam.
- Previous toxicity or hypersensitivity directly attributed to venetoclax.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：Treatment
Dose Escalation Phase: Venetoclax plus selinexor will initially be given at dose level 1 in combination with intravenous (IV) cytarabine and fludarabine. Dosing of venetoclax and selinexor will be based on tolerability. Intrathecal (IT) chemotherapy (IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are all acceptable) will be given. G-CSF SC may be given. Part 1 has been completed and RP2D has been determined to be Dose Level 2. All participants will be treated at Dose Level 2. Dose Expansion Phase: Two expansion cohorts will be treated at the recommended phase 2 dose (RP2D). Cohort A will include venetoclax-naïve patients, whereas Cohort B will include patients with prior exposure to venetoclax. |
Given orally (PO)
他の名前：
Given Orally (PO)
他の名前：
Given in to the vein (IV) or intrathecal (IT)
他の名前：
Given in to the vein (IV) - Because of the ongoing nationwide shortage of fludarabine, this agent may be omitted during the dose expansion phase of the trial.
他の名前：
Given subcutaneous (SubQ, SC)
他の名前：
Given intrathecal (IT)
他の名前：
Given intrathecal (IT)
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
The recommended phase 2 dose (RP2D) of venetoclax plus selinexor plus chemotherapy.
時間枠：For each patient, the monitoring time period for dose-limiting toxicity will extend for 35 days from receipt of the first dose of protocol-directed selinexor or venetoclax.
|
The primary endpoint is the recommended phase 2 dose (RP2D) of venetoclax plus selinexor plus chemotherapy. |
For each patient, the monitoring time period for dose-limiting toxicity will extend for 35 days from receipt of the first dose of protocol-directed selinexor or venetoclax.
|
|
Number of patients treated
時間枠：35 days from the receipt of the first dose of protocol-directed selinexor or venetoclax
|
A count of the number of patients treated at each dose level during the dose escalation phase will be provided |
35 days from the receipt of the first dose of protocol-directed selinexor or venetoclax
|
|
Number of patients who experience a Non-Hematologic dose limiting toxicity (DLT) during the dose escalation phase
時間枠：Within 35 days of the first dose of chemotherapy
|
A count of the number of patients at each dose level who experience a Non-Hematologic DLT defined as any grade 3 or higher event that occurs within 35 days of the first dose and is at least possibly attributable to study drug administration (venetoclax, selinexor, fludarabine and/or cytarabine). |
Within 35 days of the first dose of chemotherapy
|
|
Number of patients who experience a Hematologic DLT during the dose escalation phase
時間枠：From the start of chemotherapy up to day 43
|
A count of the number of patients at each dose level who experience a Hematologic DLT defined as failure to recover counts (ANC > 500/µl and platelet count > 25,000/µl) by day 43 from the start of chemotherapy unless the delay in count recovery is due to another identifiable factor. |
From the start of chemotherapy up to day 43
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
The rates of complete remission (CR) for patients treated with selinexor and venetoclax in combination with chemotherapy at the RP2D.
時間枠：The final response of each patient will be determined no later than day 42 from the start of chemotherapy.
|
CR is defined as bone marrow with < 5% blasts confirmed by flow cytometry, ANC ≥ 500/μL and platelets ≥ 50,000/μL without transfusions, and no evidence of extramedullary disease. |
The final response of each patient will be determined no later than day 42 from the start of chemotherapy.
|
|
The rates of complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the RP2D.
時間枠：The final response of each patient will be determined no later than day 42 from the start of chemotherapy.
|
CRi is defined as bone marrow with < 5% blasts confirmed by flow cytometry, ANC < 500/μL or platelets < 50,000/μL without transfusions, and no evidence of extramedullary disease |
The final response of each patient will be determined no later than day 42 from the start of chemotherapy.
|
|
The overall survival of patients treated at the RP2D.
時間枠：Survival of each patient will be determined one year from enrollment.
|
Overall survival is defined as the time elapsed from protocol enrollment to death, with data for living patients censored at last follow-up. We will report KM estimates with 95% CIs. |
Survival of each patient will be determined one year from enrollment.
|
|
The rates of exceptional response for those patients treated during the Dose-escalation phase.
時間枠：Day 15
|
Exceptional Response is defined as patients who have at least 2-log (100-fold) reduction in bone marrow MRD at day 15 compared to bone marrow blast percentage at enrollment. |
Day 15
|
|
The rates of exceptional response for those patients treated during the Dose Expansion Phase (Cohort A).
時間枠：Day 15
|
Exceptional Response is defined as patients who have at least 2-log (100-fold) reduction in bone marrow MRD at day 15 compared to bone marrow blast percentage at enrollment. |
Day 15
|
|
The rates of exceptional response for those patients treated during the Dose Expansion Phase (Cohort B).
時間枠：Day 15
|
Exceptional Response is defined as patients who have at least 2-log (100-fold) reduction in bone marrow MRD at day 15 compared to bone marrow blast percentage at enrollment. |
Day 15
|
協力者と研究者
捜査官
- 主任研究者：Seth Karol, MD、St. Jude Children's Research Hospital
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
- 新生物
- 免疫系疾患
- 組織型別の新生物
- 血液疾患
- リンパ疾患
- リンパ増殖性疾患
- 免疫増殖性疾患
- 白血病、骨髄性
- 白血病、リンパ
- 白血病
- ヘミックおよびリンパ疾患
- 白血病、骨髄性、急性
- 白血病、二表現型、急性
- ペプチド
- アミノ酸、ペプチド、およびタンパク質
- タンパク質
- 複素環化化合物、1リング
- 複素環化化合物
- 複素環化化合物、2リング
- 複素環化化合物、融合リング
- 核酸、ヌクレオチド、およびヌクレオシド
- 生物学的要因
- 炭水化物
- シチジン
- ピリミジンヌクレオシド
- ピリミジン
- ヌクレオシド
- 羽毛
- プテリジン
- 細胞間シグナル伝達ペプチドとタンパク質
- アラビノヌクレオシド
- アミノプテリン
- 糖タンパク質
- グリココンジュゲート
- コロニー刺激因子
- 造血細胞成長因子
- サイトカイン
- メトトレキサート
- シタラビン
- フルダラビン
- ベネトクラックス
- フルダラビンリン酸
- Selinexor
- 顆粒球コロニー刺激因子
- Filgrastim
その他の研究ID番号
- SELCLAX
- NCI-2021-03435 (レジストリ識別子：NCI Clinical Trial Registration Program)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
IPD 共有時間枠
Data will be made available at the time of article publication.
IPD 共有アクセス基準
Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
IPD 共有サポート情報タイプ
- STUDY_PROTOCOL
- SAP
- ICF
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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