2024-519275-26-00招募中2 期
A phase I-II, multicentre, open label clinical trial to assess the safety and tolerability of the combination of low-dose cytarabine or azacitidine, plus Venetoclax and Quizartinib in newly diagnosed acute myeloid leukemia patients aged equal or more than 60 years old ineligible for standard induction chemotherapy
Fundacion PETHEMA5 个研究点 分布在 1 个国家目标入组 84 人开始时间: 2024年11月15日最近更新:
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 84
- 试验地点
- 5
- 主要终点
- Phase I: Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules -Phase II: CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules
研究概览
简要总结
-For the phase I: to establish the RP2D of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules. -For the phase II: to assess and to compare the CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules.
研究设计
- 分配方式
- Randomized
- 主要目的
- Ven-a-qui
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed AML.
- •Morphological diagnosis of AML (WHO criteria 2008).
- •Patient must be considered be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.
- •≥ 71 years of age; 3.
- •≥ 60 to 70 years of age with at least one of the following co-morbidities: ECOG Performance Status of 2 or 3; Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronic stable angina; DLCO ≤ 65% or FEV1 ≤ 65% or significant history of chronic pulmonary obstructive; Creatinine clearance ≥ 30 mL/min to < 50 ml/min Moderate hepatic impairment with total bilirubin, SGPT or SGOT > 1.5 to ≤ 3.0 × ULN Non active/controlled prior neoplastic disease Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Trial Coordinators before study enrollment (e.g, prior MDS or MPS, high-risk cytogenetics)
- •ECOG performance status ≤
- •Male subjects who are sexually active, must agree, from Study Day 1 through at least 120 days after the last dose of study drug, to practice the protocol specified contraception.
- •Female subjects must be either postmenopausal for at least 1 year before screening OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding
- •Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC) prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
排除标准
- •Age <60 years.
- •Prior treatment with any investigational drug or device within 30 days prior to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational procedures
- •Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
- •Known uncontrolled or significant cardiovascular disease, including any of the following: a) Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker; b) QTcF interval >450 msec; c) Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome); d) Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg; e) History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes); f) History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker); g) History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening; h) History of New York Heart Association Class 3 or 4 heart failure; i) Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal; j) Complete left bundle branch block;
- •Prior therapy for AML (except hydroxiurea).
- •Subject enrolling into a dose-escalation cohort must not have received a known strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before the first Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohort must not have received a known strong or moderate inducer or strong inhibitor of CYP3A within 7 days before the first Quizartinib or Venetoclax dose.
- •Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days before anticipated first dose of Venetoclax and must consent not to consume through the last dose of Venetoclax.
- •Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion;
- •Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
- •Known history of human immunodeficiency virus (HIV).
- •History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or other study medication.
- •Genetic diagnosis of acute promyelocytic leukemia.
- •Non mutated FLT3-ITD subjects will be considered ineligible during the randomized Phase II after 48 non mutated FLT3-ITD subjects have been randomized.
- •Treated (excluding surgery or hormone-therapy) for another malignancy within 6 months before randomization or previously diagnosed with another malignancy and have any evidence of disease which may compromise the administration of investigational treatment schedule.
- •Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.
- •Serum creatinine ≥ 2.5 mg/dL or creatinine clearance < 30 mL/min (unless it is attributable to AML activity).
- •Bilirubin, SGPT or SGOT > 3 times the upper normal limit (unless it is attributable to AML activity).
- •WBC> 50 x 109/L. Subject should have white blood cell count <50 × 109/L before starting therapy. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
- •Contraindications for Quizartinib or Venetoclax.
- •History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
结局指标
主要结局
Phase I: Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules -Phase II: CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules
Phase I: Recommended phase 2 dose (RP2D) of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules -Phase II: CR/CRi rate of AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules
次要结局
- CR/CRi rate after 1, and 4 cycles
- Overall survival (OS)
- Safety and tolerability of the AZA based and LDAC based triple combination with Quizartinib and Venetoclax schedules (overall hematologic and non-hematologic toxicity)
- Event-free survival (EFS)
- Disease-free survival (DFS)
- Relapse-free survival (RFS)
- Quality of life (from the EuroQoL Group EQ-5D-5L and the EORTC QLQ-C30 instruments)
- Medical resources during treatment phase
- Minimal residual disease (MRD)
- CRh rate (Bone marrow blasts <5% with partial hematologic recovery defined as ANC ≥0.5 × 109/L and platelet count ≥50 × 109/L, with no evidence of extramedullary leukemia and cannot be classified as CR)
- Early mortality (first 30 and 60 days)
- Separate analyses in secondary AML, CBF, FLT3-ITD, NPM1, P53, and IDH1/IDH2 subsets.
- Exploration of biomarkers predictive of drug activity and duration of response. Potential analyses may include: o To evaluate the MRD negativity rate in the BM using MPFC and NGS o Immune recovery o Exhaustive biomarker plan including baseline and relapse molecular characterization by NGS
研究者
Dr. Juan José Lahuerta
Scientific
Fundacion PETHEMA
研究点 (5)
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