A Phase 1b Study of Menin Inhibitor SNDX-5613 in Combination With Daunorubicin and Cytarabine in Newly Diagnosed Patients With Acute Myeloid Leukemia and NPM1 Mutated/FLT3 Wildtype or MLL/KMT2A Rearranged or NUP98 Alterations Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 38
- 试验地点
- 33
- 主要终点
- Recommended phase 2 dose for expansion cohort
研究概览
简要总结
This phase Ib trial tests the safety, side effects, and best dose of SNDX-5613 when given in combination with the standard chemotherapy treatment (daunorubicin and cytarabine) in treating patients with newly diagnosed acute myeloid leukemia that has changes in the NPM1 gene or MLL/KMT2A gene. SNDX-5613 blocks signals passed from one molecule to another inside cancer cells that are needed for cancer cell survival. Drugs used in chemotherapy, such as daunorubicin 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. Adding SNDX-5613 to the standard chemotherapy treatment may be able to shrink or stabilize the cancer for longer than the standard chemotherapy treatment alone.
详细描述
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose (RP2D) and safety of revumenib (SNDX-5613) combined with 7 + 3 induction in newly diagnosed, untreated patients with NPM1-mutated/FLT3-ITD wild type and NPM1-mutated/FLT3-TKD wild type, MLL(KMT2A)-rearranged, or NUP98 altered acute myeloid leukemia (AML) who are ≥ 18-75 years old who are candidates for intensive induction therapy.
II. To determine the RP2D and safety of SNDX-5613 combined with one cycle of consolidation with high dose cytarabine in newly diagnosed patients with AML in complete response/complete response with incomplete platelet recovery (CR/CRp) (platelet recovery ≥ 75,000) after intensive induction therapy with 7+3 for NPM1-mutated/FLT3-ITD wild type and NPM1-mutated/FLT3-TKD wild type, MLL (KMT2A)-rearranged or NUP98 alterations who are ≥ 18-75 years old and are candidates for intensive therapy.
III. To evaluate the effect of single-agent SNDX-5613 on AML cell cycle state across major differentiation states (stem/progenitor, mature blasts, etc.).
SECONDARY OBJECTIVES:
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Dose escalation: Patients ages 18-75 years at time of diagnosis with NPM1-mutated/FLT3-ITD wildtype and NPM1-mutated/FLT3-TKD wildtype with high-risk features (adverse risk genetics per European LeukemiaNet [ELN] 2022 criteria, age ≥ 60 years, or secondary AML defined as either arising from a prior hematological malignancy or therapy-related), MLL (KMT2A) rearranged or NUP98 altered, untreated AML and who are candidates for intensive induction chemotherapy. Patients with CD33+ AML are eligible for this protocol.
- •Dose expansion: Patients ages 18-75 years at time of diagnosis with NPM1-mutated/FLT3-ITD wildtype and NPM1-mutated/FLT3-TKD wildtype (any patient-does not require high-risk features), MLL (KMT2A) rearranged, or NUP98 altered, untreated AML and who are candidates for intensive induction chemotherapy. Patients with CD33+ AML are eligible for this protocol
- •Because no dosing or adverse event data are currently available on the use of SNDX-5613 in combination with daunorubicin and cytarabine in patients < 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%). Patients over the age of 65 must have an ECOG performance status of 0-1
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), except for patients with Gilbert's syndrome where required to be ≤ 3 x institutional ULN
- •Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal (ULN)
- •Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 (via the Chronic Kidney Disease Epidemiology [CKD-EPI] glomerular filtration rate estimation)
- •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- •Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- •Ejection fraction >= 50% (or >= 45% if no evidence of congestive heart failure [CHF] or other cardiac symptoms) by transthoracic echocardiogram (TTE) or multi-gated acquisition (MUGA) scan
- •White blood cells (WBC) must be < 25 x 10^9/L. Hydroxyurea and leukapheresis are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped within 24 hours of initiation of protocol therapy. Must not have had any signs of leukostasis requiring cytoreduction
- •Female patients of childbearing potential must agree to use 2 forms of contraception from screening visit until 120 days following the last dose of study treatment. Male patients of childbearing potential having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use 2 forms of contraception from screening visit until 180 days until the last dose of study treatment. They must also refrain from sperm donation from screening visit until 180 days following the last dose of study treatment
- •Patients must have previously untreated AML with no prior treatment other than hydroxyurea or intrathecal chemotherapy for central nervous system (CNS) prophylaxis/treatment. No chemotherapy for AML outside of hydroxyurea for treatment of leukostasis or all-trans retinoic acid (ATRA) for initially suspected acute promyelocytic leukemia (APL) (that is ruled out) is allowed
- •Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
排除标准
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to SNDX-5613, daunorubicin or cytarabine
- •Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
- •Patient must not have received known strong or moderate CYP3A4 inhibitors, or strong CYP3A4 inducers (with the exception of antifungal prophylaxis with azoles) within 7 days of enrollment. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •Pregnant women are excluded from this study because SNDX-5613 is a menin-KMT2A inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SNDX-5613, breastfeeding should be discontinued if the mother is treated with SNDX-
- •These potential risks may also apply to other agents used in this study
- •Isolated myeloid sarcoma (i.e., patients must have blood or marrow involvement with AML to enter the study)
- •Acute promyelocytic leukemia (French-American-British [FAB] M3)
- •Untreated, active central nervous system (CNS) involvement by AML. Patients are allowed to undergoing diagnostic lumbar puncture (LP) with intrathecal chemotherapy while on study
- •Uncontrolled symptomatic disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
- •Patients with Fridericia's correction formula (QTcF) >= 450 ms at screening; patients with right, left, or partial bundle branch blocks or a pacemaker who are asymptomatic are eligible regardless of QTC if cleared by cardiology for enrollment in the trial. Any factors that increase the risk of QTc prolongation or risk of arrhythmic event such as congenital long QT syndrome or family history of long QT syndrome
- •Patients who will exceed a lifetime anthracycline exposure of > 550 mg/m^2 daunorubicin or equivalent (or > 400 mg/m^2 daunorubicin or equivalent in the event of prior mediastinal radiation) if they receive the maximum potential exposure to anthracyclines per protocol (including both induction and reinduction cycles)
- •Patients with any gastrointestinal issue of the upper gastrointestinal (GI) tract that might affect oral drug absorption or ingestion (eg, gastric bypass, gastroparesis, etc)
- •Patients who have cirrhosis with a Child-Pugh score of B or C
- •Patients with Down Syndrome due to higher rates of chemotherapy-associated toxicities, and may have different pharmacokinetics, as well. Toxicities that occur at higher frequencies include cardiotoxicity, a known risk of SNDX-5613 treatment (i.e., QTcF prolongation)
- •Patients with myelodysplastic syndromes (MDS) treated with previous intensive induction regimens similar to 7+3
研究组 & 干预措施
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Transthoracic Echocardiography Test (Procedure)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Daunorubicin (Drug)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Biospecimen Collection (Procedure)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Multigated Acquisition Scan (Procedure)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Cytarabine (Drug)
Treatment (revumenib, daunorubicin, cytarabine)
See Detailed Description.
干预措施: Revumenib (Drug)
结局指标
主要结局
Recommended phase 2 dose for expansion cohort
时间窗: From day 1 of Induction to day 42 of Consolidation
For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the CTCAE v5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.
Maximum tolerated dose (MTD) for Induction
时间窗: From day 1 to 42 of Induction or Re-Induction
MTD of induction will be determined based on isotonic regression. Specifically, the MTD is selected as the dose for which the isotonic estimate of the toxicity rate is closest to the targeted dose-limiting toxicity (DLT) (i.e., 25%) via Bayesian Optimal Interval ("BOIN") software (MD Anderson). For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.
Maximum tolerated dose (MTD) for Consolidation
时间窗: From day 1 to 42 of Consolidation
MTD of induction will be determined based on isotonic regression. Specifically, the MTD is selected as the dose for which the isotonic estimate of the toxicity rate is closest to the targeted DLT (i.e., 25%) via "BOIN" software (MD Anderson). For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the CTCAE v5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.
Recommended dose for expansion (RDE) for Induction
时间窗: From day 1 to 42 of Induction or Re-Induction
Will be determined based on the totality of safety, tolerability, clinical activity, and pharmacokinetic (PK) data as appropriate. The tolerability of doses administered in cycles after the dose limiting toxicity (DLT) observation window should be taken into account in determination of the RDE. For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.
RDE for Consolidation
时间窗: From day 1 to 42 of Consolidation or until full count recovery with recovery to grade 1 toxicity from treatment, whichever comes first
Will be determined based on the totality of safety, tolerability, clinical activity, and PK data as appropriate. The tolerability of doses administered in cycles after the DLT observation window should be taken into account in determination of the RDE.For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the CTCAE v5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.
Recommended phase 2 dose for expansion cohort
时间窗: From day 1 of Induction to day 42 of Consolidation or until full count recovery with recovery to grade 1 toxicity from treatment, whichever comes first
RP2D of induction will be determined based on isotonic regression. Specifically, the RP2D that is selected is the dose for which the isotonic estimate of the toxicity rate is closest to the targeted DLT (i.e., 20%) via "BOIN" software \[MD Anderson\]) and will also factor in data such as PK/pharmacodynamic data to determine the biologically effective dose. For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the CTCAE v5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.
次要结局
- Pharmacokinetics (PK) of revumenib (SNDX-5613)(Cycle 1, day 2 at pre-treatment, 0.5, 1.0, 2.0, 4.0, 8.0 hours (hr); Cycle 1 day 3 at 12 hr; cycle 1 day 15 at pre-treatment, 0.5, 1.0, 2.0, 4.0, and 8.0 hr)
- Complete response/complete response with incomplete count recovery (CR/Cri) rate(At the end of cycle 1 of consolidation)