A Phase 1b, Open Label, Multi-center, Dose Optimization and Dose Expansion Study to Assess the Safety and Efficacy of DFV890 in Adult Patients With Myeloid Diseases
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 71
- 试验地点
- 33
- 主要终点
- Incidence of Dose-limiting Toxicities (DLTs)
研究概览
简要总结
Study CDFV890G12101 is an open-label, phase 1b, multicenter study with a randomized two-dose optimization part, and a dose expansion part consisting of three groups evaluating DFV890 in patients with myeloid diseases. The purpose of this study is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy and recommended dose for single agent DFV890 in patients with lower risk (LR: very low, low or intermediate risk) myelodysplastic syndromes (LR MDS), lower risk chronic myelomonocytic leukemia (LR CMML) and High-Risk Clonal Cytopenia of Undetermined Significance (HR CCUS).
详细描述
This research study is to find out if study treatment DFV890 is safe and tolerable, and can help patients who were diagnosed with a myeloid disease such as: very low, low or intermediate risk myelodysplastic syndromes (MDS), very low, low or intermediate risk chronic myelomonocytic leukemia (CMML) and High-Risk Clonal Cytopenia of Undetermined Significance (HR CCUS). The study seeks to determine the optimal dose of DFV890 that is safe and efficacious in patients with myeloid disease. The effectiveness and safety/tolerability of the study treatment is not yet confirmed in this disease setting.
Eligible patients meeting all study entry requirements will be required to provide a sample from their bone marrow at screening and at select study timepoints. All enrolled patients will be dosed for a minimum of twenty-four weeks (6 cycles of treatment) unless they experience side effects related to the study treatment requiring dose interruption/discontinuation, worsening of the disease, and/or if treatment is discontinued at the discretion of the investigator or the patient.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF)
- •The Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
- •Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions guidelines and must be willing to undergo a bone marrow aspirate.
- •4. Patients must have one of the following for eligibility into the study:
- •In dose optimization: IPSS-R defined very low, low or intermediate risk Myelodysplastic Syndrome (LR MDS) who failed to respond to or did not tolerate ESAs or luspatercept or HMAs and patients with del 5q who failed to respond to or did not tolerate lenalidomide; or
- •In dose optimization and expansion: IPSS-R defined very low, low or intermediate risk Chronic Myelomonocytic Leukemia (LR CMML) who failed to respond to or did not tolerate hydroxyurea or HMAs.
- •changes for dose expansion (applicable as of amendment 3):
- •LR MDS with ≤ 10% bone marrow blasts, IPSS-R score of ≤ 3.5, transfusion independent (TID) status as per IWG 2006 criteria (requiring <4U pRBC in 8 weeks), clinically meaningful cytopenia(s) and no or limited (<4 months) prior therapy for MDS.
- •LR CMML patients with symptomatic cytopenias and/or constitutional symptoms refractory, intolerant or unsuitable for standard first-line therapy.
- •HR-CCUS: Diagnosis of high-risk CCUS by clonal hematopoiesis risk score (CHRS) with clinically meaningful cytopenias and no prior therapy for a myeloid neoplasm.
排除标准
- •1. Systemic antineoplastic therapy (including cytotoxic chemotherapy, alpha-interferon, kinase inhibitors or other targeted small molecules, and toxin-immunoconjugates) or any experimental therapy within 28 days or 5 half-lives, whichever is longer, and recovered from the toxicities before the first dose of study treatment. For patients that received antibodies the washout period is 4 weeks prior to study treatment.
- •a. For TID LR MDS in Dose Expansion Phase only (applicable as of amendment 03):
- •Prior therapy for MDS administered for >4 months (ESA and luspatercept administered for ≤4 months will be allowed if washout period followed)
- •Concurrent malignancy requiring active systemic therapy
- •Prior or concurrent cytotoxic chemotherapy for MDS at any time
- •2. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
- •3. Patients who have previously been treated with agents that have the same mechanism of action as DFV890 as defined in Table 6-7, list of prohibited medications (e.g., drugs targeting the NLRP3 inflammasome pathway and the IL-1 pathway (canakinumab and anakinra)).
- •4. Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents anytime ≤ 1 week (or 5 half lives, whichever is longer) prior to start of study treatment.
- •5. Patients receiving:
- •a. concomitant medications that are known to be modulators of cytochrome P450 enzymes CYP2C9 and/or CYP3A (specifically strong or moderate inducers of CYP2C9, strong inducers of CYP3A enzymes, strong inhibitors of CYP2C9 and/or strong or moderate dual inhibitors of CYP2C9/CYP3A); and b. patients, who are poor CYP2C9 metabolizers receiving concomitant medications known to be strong or moderate inhibitors of CYP3A, whose concomitant medications cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to start of study treatment and for duration of the study. See Section 6.8 and list of prohibited drugs in Appendix 8 for more details.
- •6. Dose expansion only: Poor CYP2C9 metabolizers defined as genotype of the CYP2C9 *3/*3 or CYP2C9 *2/*3 allele combinations are excluded.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Dose escalation: DFV890 high dose
DFV890 given as single agent at a high dose
干预措施: DFV890 (Drug)
Dose escalation: DFV890 low dose
DFV890 given as single agent at a low dose
干预措施: DFV890 (Drug)
Dose expansion: DFV890 low dose
DFV890 given as single agent at a low dose
干预措施: DFV890 (Drug)
结局指标
主要结局
Incidence of Dose-limiting Toxicities (DLTs)
时间窗: 28 days
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as clinically relevant, occurring during the DLT monitoring period following the first administration of study treatment.
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: 36 months
Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs) and laboratory values qualifying and reported as AEs.
Incidence of dose interruptions, discontinuations and reductions
时间窗: 36 months
Number of patients with dose adjustments (interruptions, discontinuations and reductions) summarized by treatment group.
Incidence of Dose-limiting Toxicities (DLTs)
时间窗: 28 days
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as clinically relevant, occurring during the DLT monitoring period following the first administration of study treatment.
次要结局
- Reduction in red blood cell (RBC) / platelet transfusions from baseline for transfusion-dependent (TD) patients(Baseline, 36 months)
- Percentage of patients developing transfusion independence (TI) for ≥8 weeks, ≥12 weeks, ≥16 weeks or ≥24 weeks for TD patients(Baseline, 8 weeks, 12 weeks, 16 weeks and 24 weeks)
- Best overall response (BOR) per 2006 IWG criteria for MDS and CMML(Baseline, 36 months)
- Hematological improvement per 2006 IWG criteria for MDS and CMML.(36 months)
- Rate of hematological improvement per 2006 IWG criteria for CCUS(36 months)
- Time to onset of transfusion independence(36 months)
- Duration of response (DOR)(36 months)
- Change from baseline in hemoglobin (Hb)(Baseline, 36 months)
- Change from baseline in platelet count(Baseline, 36 months)
- Change from baseline in Absolute Neutrophil Count/White Blood Cells (ANC/WBC)(Baseline, 36 months)
- Overall response rate (ORR) for MDS and CMML(36 months)
- Time to progression to any type of myeloid malignancy (TTPM) for CCUS(36 months)
- Progression free survival (PFS)(36 months)
- Time to progression (TTP)(36 months)
- For CMML: reduction in spleen volume(Baseline, 36 months)
- For CMML: MPN-SAF total symptom score (TSS)(Baseline, 12 months)
- Maximum plasma concentration (Cmax) of DFV890(15 days)
- Area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of DFV890(15 days)
- Percentage of patients developing transfusion independence (TI) for ≥8 weeks, ≥12 weeks, ≥16 weeks or ≥24 weeks for TD patients(Baseline, 8 weeks, 12 weeks, 16 weeks and 24 weeks)
- Area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of DFV890(15 days)
- For CMML: MPN-SAF total symptom score (TSS)(Baseline, 12 months)
- Maximum plasma concentration (Cmax) of DFV890(15 days)