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.
概览
- 阶段
- 1/2 期
- 状态
- 进行中（未招募）
- 入组人数
- 34
- 试验地点
- 19
- 主要终点
- Phase 1: Occurrence of dose-limiting toxicities (DLTs).
概览
简要总结
Phase 1 The objectives for Phase 1 of this study apply to all arms unless otherwise stated in the objective. • To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with relapsed/refractory (R/R) acute leukemia in each of the arms studied. • To characterize the pharmacokinetics (PK) parameters of SNDX-5613 and relevant metabolites in each of the arms studied. Phase 2 • To evaluate short- and long-term safety and tolerability of SNDX-5613. • To assess the complete remission (CR)+ complete remission with partial hematologic recovery (CRh) rate.
入排标准
- 年龄范围
- 0 years 至 65+ years（0-17 Years, 18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Diagnosis: Patients in Phase 1 Arm A and Arm B must have active acute leukemia harboring Lysine (K) methyltransferase 2A (KMT2A) rearrangement or Nucleophosmin 1 mutation (NPM1) mutation as defined by the National Comprehensive Cancer Network (NCCN) Guidelines stated in the protocol. Patients in Phase 1 Arm C, Arm D, Arm E and Arm F must meet one of the following 2 criteria: •active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts inperipheral blood) as defined by the NCCN Guidelines stated in the protocol. •acute leukemia harboring an KMT2A rearrangement, Nucleoporin 98 (NUP98) rearrangement, or NPM1 mutation that have detectable disease in the bone marrow not meeting criterion for active leukemia as described above.
- •Prior Therapy: Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines, and at least 21days since receipt of chimeric antigen receptor therapy or other modified T or Natural KIller (NK) cell therapy.
- •Prior Therapy: Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy with the exceptions as defined in the protocol.
- •Prior 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. See protocol for additional inclusion criteria.
- •Phase 1: • Arm A: Patients must not be receiving any strong CYP3A4 inhibitor/inducers or fluconazole. Patients who were receiving a strong CYP3A4 inhibitor/inducer or fluconazole must have discontinued the medication at least 7days prior to enrollment. • Arm B: Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole for antifungal prophylaxis for at least 7days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other strong CYP3A4 inhibitors/inducers. • Arm C: Patients must weigh ≥35 kg and be willing to receive daily cobicistat from C1D2 for at least 28 days. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers. Patients who were receiving a moderate/strong CYP3A4 inhibitor/inducer must have discontinued the medication at least 7days prior to enrollment. •Arm D: Patients must be receiving fluconazole for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate or strong CYP3A4 inhibitors/inducers. •Arms E: Patients must not be receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers for at least 7 days prior to enrollment and while on SNDX5613 treatment. • Arm F: Patients must be receiving isavuconazole for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers.
- •Phase 2: Documented R/R active acute leukemia. • Cohort 2A: Documented R/R ALL/MPAL with a KMT2A rearrangement. • Cohort 2B: Documented R/R AML with a KMT2A rearrangement. • Cohort 2C: Documented R/R AML with NPM1m. Mutational status is to be reviewed locally to determine patient eligibility in Phase 2 and confirmed centrally.
- •Disease Status: Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria after standard of care therapy, including but not limited to one or two cycles of intensive chemotherapy, or venetoclax combinations. Patients with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment are eligible. Refractory or relapsed leukemia is defined by presence of ≥5% blasts in the bone marrow and/or persistence or reappearance of peripheral blasts. Patients who have <5% blasts in the bone marrow at baseline may be replaced to ensure a sufficient number of patients for the efficacy analyses.
- •Age/Weight: Male or female patient aged ≥6 months. Patients intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kg. See Protocol Section 10.11.3.1 for age of inclusion criteria in Germany.
- •Performance Level: Eastern Cooperative Oncology Group (ECOG) performance status score 0–2 (if aged ≥18 years); Karnofsky Performance Scale of ≥50 (if aged ≥ 16 years and <18 years); Lansky Performance Score of ≥50 (if aged ≥12 years and <16 years). See Protocol Section 10.11.3.1 for ECOG performance status criteria in Germany.
- •Prior Therapy: Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
排除标准
- •Diagnosis: Diagnosis of active acute promyelocytic leukemia.
- •Concurrent Conditions: Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Patients may be on physiological doses of steroids.
- •Concurrent Conditions: 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 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 patient is not receiving any systemic therapy or radiation.
- •Concurrent Conditions: Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
- •Concurrent Conditions: History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.
- •Concomitant Medications and Interventions:
- •Any commercially available or investigational antileukemic therapy other than SNDX-5613, with exceptions as defined in the protocol.
- •Concomitant Medications and Interventions: Please refer to the protocol for the list of exclusion that apply to related to concomitant use of CYP3A4 inhibitors or inducers (Phase 1 and Phase 2).
- •Concomitant Medications and Interventions: Phase 1 and Phase 2: Patients 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 and the azoles permitted in the relevant arms of Phase 1 and in Phase
- •Please see Appendix 10.7 of the protocol for examples of medications that may be appropriate substitutes for such medications. Please refer to the protocol for additional exclusion criteria.
结局指标
主要结局
Phase 1: Occurrence of dose-limiting toxicities (DLTs).
Phase 1: Occurrence of dose-limiting toxicities (DLTs).
Phase 1: Frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related TEAEs (TRAEs), and serious adverse events (SAEs).
Phase 1: Frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related TEAEs (TRAEs), and serious adverse events (SAEs).
Phase 1: Incidence and shifts of clinically significant clinical laboratory abnormalities.
Phase 1: Incidence and shifts of clinically significant clinical laboratory abnormalities.
Phase 1: Change from baseline in other observations related to safety, including electrocardiograms (ECGs), vital signs, ophthalmologic examination findings, and performance status.
Phase 1: Change from baseline in other observations related to safety, including electrocardiograms (ECGs), vital signs, ophthalmologic examination findings, and performance status.
Phase 1: Pharmacokinetic (PK) parameters: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration versus time curve (AUC) from time 0 to t (AUC0–t), AUC from time 0 to 24 hours (AUC0–24), apparent oral clearance (CL/F), apparent volume of distribution (Vz/F), and half-life (t1/2).
Phase 1: Pharmacokinetic (PK) parameters: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration versus time curve (AUC) from time 0 to t (AUC0–t), AUC from time 0 to 24 hours (AUC0–24), apparent oral clearance (CL/F), apparent volume of distribution (Vz/F), and half-life (t1/2).
In Phase 1, the study endpoints will be assessed by dose cohort and overall. and will apply to all arms unless otherwise stated in the endpoint.
In Phase 1, the study endpoints will be assessed by dose cohort and overall. and will apply to all arms unless otherwise stated in the endpoint.
Phase 2: • CR+CRh rate. • Frequency, duration, and severity of TEAEs, TRAEs, and SAEs. • Incidence and shifts of clinically significant clinical laboratory abnormalities.
Phase 2: • CR+CRh rate. • Frequency, duration, and severity of TEAEs, TRAEs, and SAEs. • Incidence and shifts of clinically significant clinical laboratory abnormalities.
Phase 2: Change from baseline in other observations related to safety, including ECGs, vital signs, ophthalmologic examination findings, and performance status. For Phase 2, endpoints will be assessed by disease cohort (2A, 2B, and 2C separately) and pooled MLLr population.
Phase 2: Change from baseline in other observations related to safety, including ECGs, vital signs, ophthalmologic examination findings, and performance status. For Phase 2, endpoints will be assessed by disease cohort (2A, 2B, and 2C separately) and pooled MLLr population.
次要结局
- Phase 1: PK parameters for tablet vs. capsule evaluation: Cmax, Tmax, AUC0–t, AUC0–24, CL/F, Vz/F, t1/2.
- Phase 2: Transfusion independence, defined as any transfusion-free period lasting for at least 56 consecutive days, during which the patient is either on SNDX-5613 therapy or after cessation of SNDX-5613 therapy but prior to the start of new therapy.
- Phase 2: • CRc rate (ie, CR+CRh+CRi+CRp). • ORR (CRc+MLFS+PR). • Time to response. • Duration of response. • Event free survival. • Overall survival. • PK parameters: Cmax, Tmax, AUC0–t, AUC0–24, CL/F, Vz/F, and t1/2.
研究者
Angie Smith
Scientific
Syndax Pharmaceuticals Inc.