NCT04065399招募中1 期
A Phase 1/2, Open-label, Dose-Escalation and Dose-Expansion Cohort Study of SNDX-5613 in Patients With Relapsed/Refractory Leukemias, Including Those Harboring an MLL/KMT2A Gene Rearrangement or Nucleophosmin 1 (NPM1) Mutation
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 447
- 试验地点
- 98
- 主要终点
- Cmax (Phase 1)
研究概览
简要总结
Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of revumenib in participants with acute leukemia.
In Phase 2, participants will be enrolled in 4 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib.
详细描述
Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. Participants will be enrolled in one of six dose-escalation arms:
Arm A: Participants not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers or fluconazole.
Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
Arm C: Participants receiving revumenib and cobicistat.
Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.
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
- 30 Days 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020), or acute leukemia harboring KMT2A rearrangement, NUP98 rearrangement, or NPM1 mutation that have detectable disease in the bone marrow.
- •Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
- •Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
- •Arm C: Participants receiving revumenib in combination with cobicistat.
- •Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).
- •Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
- •Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.
- •Documented R/R active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the NCCN Guidelines® for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).
- •Cohort 2A: Documented R/R ALL/MPAL with KMT2A rearrangement.
- •Cohort 2B: Documented R/R AML with KMT2A rearrangement.
- •Cohort 2C: Documented R/R AML with NPM1m.
- •Cohort 2D: Documented R/R acute leukemia with a genetic mutation expected to lead to HOX/MEIS upregulation (for example, KMT2Ar, NPM1m, and NUP98r), including participants who are MRD-positive by multiparametric flow cytometry or molecular methods only, and including participants with isolated extramedullary disease.
- •White blood cell count below 25,000/ microliter at time of enrollment. Participants may receive cytoreduction prior to enrollment per protocol-specified criteria.
- •Male or female participants aged ≥30 days old. Participants intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kilograms (kg). Participants in Cohort 2D must be ≥18 years of age and have a body weight ≥40 kg.
- •Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥
- •Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
- •Phase 1 and Phase 2 Cohorts 2A-2C only:
- •Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port).
- •Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant and at least 4 weeks must have elapsed from donor lymphocyte infusion.
- •Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T or NK cell therapy.
- •Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy.
- •Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors.
- •Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent.
- •Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing or cytoreductive therapy.
- •Phase 2 Cohort 2D only:
- •At least 14 days since any other investigational or commercially available antileukemic therapy, with the following exceptions:
- •Cytoreductive therapy with hydroxyurea, low-dose cytarabine (20 mg/square meter (m^2)/day subcutaneously [SC] for 10 days) or low-dose etoposide (up to 200 mg/day orally for 10 days) may be administered concurrently with SNDX-
- •Intrathecal chemotherapy for CNS prophylaxis is permitted at the treating physician's discretion.
- •Steroids at physiologic dosing (equivalent to ≤10 mg prednisone daily for participants ≥18 years or ≤10 mg/m^2/day for participants <18 years) or for cytoreductive therapy.
- •Adequate organ function.
- •If of childbearing potential, willing to use a highly effective method of contraception from the time of enrollment through 120 days following the last study drug dose.
排除标准
- •Participants meeting any of the following criteria are not eligible for study participation:
- •Diagnosis of active acute promyelocytic leukemia.
- •Isolated extramedullary relapse (Phase 2 Cohorts 2A-2C only).
- •Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic).
- •Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Participants with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
- •Hepatitis B or C.
- •Pregnant or nursing women.
- •Cardiac Disease:
- •Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
- •Corrected QT interval (QTc) >450 milliseconds.
- •Gastrointestinal Disease:
- •any gastrointestinal issue of the upper GI tract that might affect oral drug absorption or ingestion (that is, gastric bypass and gastroparesis).
- •Cirrhosis with a Child-Pugh score of B or C.
- •Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant participants must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Participants may be on physiological doses of steroids.
- •Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (for example, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the participant is not receiving any systemic therapy or radiation.
- •In Phase 1 and Phase 2: Participants requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (for example, diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the relevant arms of Phase 1 and in Phase
- •Note: Other protocol defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Revumenib
Experimental
Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib. Participants will be enrolled in 1 of 6 dose-escalation arms:
- Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole
- Arm B: Participants receiving any strong CYP3A4 inhibitors for antifungal prophylaxis
- Arm C: Participants receiving revumenib and cobicistat
- Arm D: Participants receiving fluconazole for antifungal prophylaxis
- Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers
- Arm F: Participants receiving isavuconazole for antifungal prophylaxis
Phase 2: Oral revumenib; 4 indication-specific expansion cohorts will be enrolled:
- Cohort 2A: Participants with KMT2Ar ALL/MPAL
- Cohort 2B: Participants with KMT2Ar AML
- Cohort 2C: Participants with NPM1m AML
- Cohort 2D: Participants with acute leukemia (including KMT2Ar, NPM1m, NUP98r and other acute leukemias expected to have HOX/MEIS upregulation)
干预措施: revumenib (Drug)
Revumenib
Experimental
Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib. Participants will be enrolled in 1 of 6 dose-escalation arms:
- Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole
- Arm B: Participants receiving any strong CYP3A4 inhibitors for antifungal prophylaxis
- Arm C: Participants receiving revumenib and cobicistat
- Arm D: Participants receiving fluconazole for antifungal prophylaxis
- Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers
- Arm F: Participants receiving isavuconazole for antifungal prophylaxis
Phase 2: Oral revumenib; 4 indication-specific expansion cohorts will be enrolled:
- Cohort 2A: Participants with KMT2Ar ALL/MPAL
- Cohort 2B: Participants with KMT2Ar AML
- Cohort 2C: Participants with NPM1m AML
- Cohort 2D: Participants with acute leukemia (including KMT2Ar, NPM1m, NUP98r and other acute leukemias expected to have HOX/MEIS upregulation)
干预措施: cobicistat (Drug)
结局指标
主要结局
Cmax (Phase 1)
时间窗: Approximately 1 year
Maximum plasma concentration (Cmax) of revumenib and relevant metabolites (Phase 1)
Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)
时间窗: Approximately 1 year
Assessed by the NCI CTCAE version 5.0 (Phase 1)
Tmax (Phase 1)
时间窗: Approximately 1 year
Time to observed maximum plasma concentration of revumenib and relevant metabolites (Phase 1)
AUC0-t (Phase 1)
时间窗: Approximately 1 year
Area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of revumenib and relevant metabolites (Phase 1)
Number of participants with dose-limiting toxicities (DLTs) (Phase 1)
时间窗: Approximately 1 year
Assessed by the NCI CTCAE version 5.0 (Phase 1)
CR+CRh rate (Phase 2 [Cohorts 2A-2C])
时间窗: Approximately 3 years
To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2 \[Cohorts 2A-2C\])
Number of participants with TEAEs (Phase 2 [Cohorts 2A-2C])
时间窗: Approximately 3 years
Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohorts 2A-2C\])
Cmax (Phase 2 [Cohort 2D])
时间窗: Approximately 3 years
Cmax of revumenib (Phase 2 \[Cohort 2D\])
AUC0-tau (Phase 2 [Cohort 2D])
时间窗: Approximately 3 years
Area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) of revumenib (Phase 2 \[Cohort 2D\])
次要结局
- Transfusion independence (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- CRc rate (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- TTR (Phase 2 [Cohorts 2A-2C])(Approximately 34 months)
- DOR (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- EFS (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- OS (Phase 2 [Cohorts 2A-2C])(Approximately 5 years)
- Cmax (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- Tmax (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- AUC0-t (Phase 2 [Cohorts 2A-2C])(Approximately 3 years)
- Number of participants with TEAEs (Phase 2 [Cohort 2D])(Approximately 3 years)
研究者
研究点 (98)
Loading locations...
相似试验
撤回
1 期
Pharmacokinetics, Safety, and Efficacy of Brigatinib Monotherapy in Pediatric and Young Adult Participants With ALK+ Anaplastic Large Cell Lymphoma, Inflammatory Myofibroblastic Tumors or Other Solid TumorsAnaplastic Lymphoma Kinase Positive (ALK +) Anaplastic Large Cell LymphomaInflammatory Myofibroblastic TumorsSolid TumorsNCT04260009Takeda
终止
1 期
Phase 1/2 Study of OBI-999 in Patients With Advanced Solid TumorsLocally Advanced Solid TumorNCT04084366OBI Pharma, Inc44
终止
1 期
A Study of NKT2152, a HIF2α Inhibitor, in Patients With Advanced Clear Cell Renal Cell CarcinomaClear Cell Renal Cell CarcinomaccRCCRenal Cell CarcinomaNCT05119335NiKang Therapeutics, Inc.120
Unknown
1 期
Phase 1 Study of HLX10, a Monoclonal Antibody Targeting Programmed Death-1 (PD-1) in Patients With Advanced Solid TumorsSolid TumorNCT03468751Henlix, Inc30
招募中
1 期
Study of LM-299 in Subjects Advanced Malignant TumorsMalignant TumorsNCT06650566LaNova Medicines Limited108
相关资讯
FDA Updates: Approvals and Designations in Leukemia, Prostate Cancer, and Melanoma• Capivasertib plus abiraterone and ADT shows improved radiographic progression-free survival in PTEN-deficient metastatic hormone-sensitive prostate cancer.
• LBS-007 receives FDA fast track designation for acute myeloid leukemia treatment based on promising early response data from a phase 1/2 trial.
• BLA submitted for RP1 with nivolumab for advanced melanoma patients who progressed on prior PD-1 inhibitor therapy.
• Revumenib receives FDA approval for relapsed/refractory KMT2A-rearranged acute leukemia based on phase 1/2 AUGMENT-101 trial data.last yearFDA Approves Revumenib for Relapsed/Refractory KMT2A-Rearranged Acute Leukemia- The FDA has approved revumenib (Revuforj; Syndax Pharmaceuticals) as a first-in-class therapy for relapsed or refractory acute leukemia with KMT2A rearrangements.
- Revumenib, a menin inhibitor, targets the interaction between menin and KMT2A protein, which is crucial for the leukemogenic process in KMT2Ar leukemia.
- Clinical trials showed revumenib significantly improved remission rates compared to historical controls, with a complete remission rate of 22.8% in the AUGMENT-101 trial.
- Pharmacists play a vital role in optimizing dosing, monitoring for adverse events like QTc prolongation and differentiation syndrome, and ensuring patient safety.last yearRevumenib Shows Promise in Relapsed/Refractory NPM1-Mutated AML- Revumenib demonstrated a 23% complete remission rate with or without partial hematological recovery (CR/CRh) in relapsed/refractory NPM1-mutated AML patients.
- A significant 64% of evaluable patients achieving CR/CRh with revumenib had negative minimal residual disease (MRD) status.
- The overall response rate (ORR) was 47% in this heavily pre-treated population, with a manageable safety profile.
- Syndax Pharmaceuticals plans to file a supplemental NDA for revumenib in NPM1-mutated AML in the first half of 2025.last yearFDA Approves Revumenib for Relapsed/Refractory Acute Leukemia with KMT2A Translocation- The FDA has approved revumenib (Revuforj) for relapsed or refractory acute leukemia with a lysine methyltransferase 2A (KMT2A) translocation in patients aged one year and older.
- Revumenib's approval was based on the AUGMENT-101 trial, which demonstrated a complete remission (CR) plus CR with partial hematologic recovery (CRh) rate of 21.2%.
- The median duration of CR+CRh was 6.4 months, and the median time to CR or CRh was 1.9 months in patients treated with revumenib in the clinical trial.
- Common adverse reactions included hemorrhage, nausea, and increased phosphate, with the recommended dose varying by patient weight and CYP3A4 inhibitor use.last yearFDA Approves Revumenib for Relapsed/Refractory KMT2A-Translocated Acute Leukemia- The FDA has granted accelerated approval to revumenib for adult and pediatric patients (1 year and older) with relapsed or refractory acute leukemia harboring a KMT2A translocation.
- The approval was based on the AUGMENT-101 trial, a single-arm, multicenter study that demonstrated a complete remission (CR) plus CR with partial hematologic recovery (CRh) rate of 21.2%.
- Among patients who achieved CR or CRh, the median time to response was 1.9 months, with a median duration of 6.4 months, showcasing the drug's rapid and durable effect.
- Revumenib offers a new treatment option for a high-risk leukemia subtype, addressing a critical unmet need for patients with limited therapeutic alternatives.last year
7 articles
1 / 2