A Phase 1 Study of KTX-1001, an Oral, First-In-Class, Selective, and Potent MMSET Catalytic Inhibitor That Suppresses H3K36me2 in Patients With Relapsed and Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 165
- 试验地点
- 43
- 主要终点
- Dose Escalation: Determination of Recommended Phase 2 Dose (RP2D) and/or Maximum Tolerated Dose (MTD) Dose Expansion: Provide preliminary efficacy data on the antitumor effects of KTX-1001 in combination with other anti-myeloma therapy
研究概览
简要总结
A Phase I study to evaluate the safety of a novel, orally available, selective, and potent small molecule inhibitor of the histone lysine methyl transferase MMSET (also known as NSD2/WHSC1) to prevent the dimethylation of H3K36 in adult patients with relapsed or refractory multiple myeloma (RRMM).
详细描述
This is a Phase I, open-label, dose-escalation and expansion study in adult patients with RRMM.
In the dose escalation phase (Part A), patients will be evaluated for DLTs during Cycle 1 (28 days). The KTX-1001 MTD, RP2D, and schedule will be determined.
In the dose expansion phase (Part B), patients with t(4;14) will receive KTX-1001 at the RP2D alone and in combination with investigational therapy Mezigdomide or SOC therapy (dexamethasone, carfilzomib or pomalidomide) to further define safety and tolerability and provide preliminary efficacy information.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for Dose-Expansion:
- •≥ 18 years of age
- •ECOG score ≤ 1
- •Multiple myeloma (as per IMWG)
- •Prior therapy for MM: Participants must have received at least 1 and up to 3 prior lines of therapy as defined by IMWG, and the following drug classes: PI, IMiD, and anti-CD38 antibody. For mezigdomide combination Cohorts B1 and B2, participants must have received at least 2 prior lines of therapy
- •Participants must have a confirmed diagnosis of progressive MM (per IMWG), t(4;14) confirmed by fluorescence in situ hybridization (FISH) testing performed in a centralized Clinical Laboratory Improvement Amendments (CLIA) accredited laboratory via fresh tumor biopsy.
- •Measurable disease, including at least 1 of the following criteria:
- •Serum M protein ≥ 0.50 g/dL (by SPEP)
- •Serum IgA ≥ 0.50 g/dL (IgA myeloma patients)
- •Urine M protein ≥ 200 mg/24 h (by UPEP)
- •sFLC involved light chain ≥ 10 mg/dL (100 mg/L) (patients with abnormal sFLC ratio)
- •Bone marrow plasma cells ≥ 30% (if only criterion for measurability)
- •Agreement to enroll into the REMS program (Cohort D- pomalidomide cohort only)
排除标准
- •for Dose-Expansion:
- •Treatment with the following therapies in the specified time period prior to first dose:
- •Patients in Cohorts B1 and B2 must not have received prior mezigdomide treatment
- •Carfilzomib in the immediate last prior line of therapy for patients enrolled in Cohorts C1 and C2
- •Pomalidomide in the immediate last prior line of therapy for patients enrolled in cohort D
- •Radiation, chemotherapy, immunotherapy, or any other anticancer therapy ≤ 2 weeks
- •Cellular therapies ≤ 8 weeks
- •Autologous transplant < 100 days
- •Allogenic transplant ≤ 6 months, or > 6 months with active GVHD
- •Major surgery ≤ 4 weeks
- •Current plasma cell leukemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, and skin changes) syndrome, solitary bone lesion or bone lesions as the only evidence for plasma cell dyscrasia, myelodysplastic syndrome or a myeloproliferative neoplasm or light chain amyloidosis
- •Active CNS disease: participants with previously treated stable CNS disease are eligible, except for Cohorts B1 and B2 for which known CNS myeloma involvement is completely excluded.
- •Inadequate bone marrow function
- •Inadequate renal, hepatic, pulmonary, and cardiac function
- •Active, ongoing, or uncontrolled systemic viral, bacterial, or fungal infection. Permitted prophylactic medications, antimicrobials or antiretroviral therapies defined in protocol.
- •Use of acid reducing agents and strong inhibitors or inducers of CYP3A4 within 7 days or 5 half-lives (whichever is longer) prior to first dose
- •Strong CYP1A2 inhibitors for patients receiving pomalidomide (Cohort D)
- •Active malignancy not related to myeloma requiring therapy within < 2 years prior to enrollment, or not in complete remission, with exceptions defined in protocol.
研究组 & 干预措施
Cohort C (carfilzomib/KYPROLIS®): KTX-1001 + carfilzomib + dex
Cohort C1 (carfilzomib/KYPROLIS®): KTX-1001 at RP2D1 + carfilzomib + dex Cohort C2 (carfilzomib/KYPROLIS®): KTX-1001 at RP2D2 + carfilzomib + dex
干预措施: Cohort C1 & C2: KTX-1001 + Carfilzomib (KYPROLIS®) (Drug)
Cohort B (Mezigdomide): KTX-1001 + Mezigdomide + dex
Cohort B1 (Mezigdomide): KTX-1001 at RP2D1 + Mezigdomide + dex Cohort B2 (Mezigdomide):: KTX-1001 at RP2D2 + Mezigdomide + dex
干预措施: Cohort B1 & B2: KTX-1001+Mezigdomide (Drug)
Cohort D (pomalidomide): KTX-1001 + pomalidomide + dex
Cohort D (pomalidomide): KTX-1001 at RP2D2 + pomalidomide + dex
干预措施: Cohort D: KTX-1001+ pomalidomide (Pomalyst, Imnovid) (Drug)
Cohort A (Single agent): KTX-1001 + dexamethasone
Cohort A1 (single agent): KTX-1001 at RP2D1 + dex Cohort A2 (single agent): KTX-1001 at RP2D2 + dex
干预措施: Cohort A1 & A2: KTX-1001 (Drug)
结局指标
主要结局
Dose Escalation: Determination of Recommended Phase 2 Dose (RP2D) and/or Maximum Tolerated Dose (MTD) Dose Expansion: Provide preliminary efficacy data on the antitumor effects of KTX-1001 in combination with other anti-myeloma therapy
时间窗: Cycle 1 (28 days)
Incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (TEAEs), treatment-related AEs, and clinically significant changes in laboratory test results
次要结局
- Disease Specific Response to KTX-1001± Combination Therapy(Duration of Study)
- Pharmacokinetics & Pharmacodynamics KTX-1001± Combination Therapy(Duration of Study)
- Safety profile of KTX-1001± Combination Therapy(Duration of Study)
- Disease Specific Response to KTX-1001± Combination Therapy(Duration of Study)
- Safety profile of KTX-1001± Combination Therapy(Duration of Study)