Phase I Study With Dose-escalation and Expansion Evaluating the Safety and Efficacy of Oral Arsenic (ATO) in Low-risk Myelodysplastic Syndromes Failing Erythropoiesis Stimulating Agents and Luspatercept (or Ineligible for the Latter)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 6
- 主要终点
- To determine the dose-limiting toxicity (DLT) of oral Arsenic (ATO)
研究概览
简要总结
Phase I study with dose-escalation and expansion evaluating the safety and efficacy of oral Arsenic (ATO) in low-risk Myelodysplastic Syndromes having failed to Erythropoiesis Stimulating Agents and Luspatercept (or ineligible for the latter).
详细描述
Dose escalation cohort to determine the dose limiting toxicity according to a BOIN (Bayesian optimal interval) scheme.
Patients will receive one dose of study treatment (oral Arsenic (ATO)) 5d/7 for 21 days over a 28-day cycle.
Three doses of ATO will be tested (0.10 mg/kg, 0.15 mg/kg and 0.20 mg/kg), and 9 patients will be treated at each dose.
An expansion cohort at the selected dose based on DSMB recommendations will be conducted with 6 patients, for a maximum of 15 patients included at this dose level.
Tolerability will be assessed after one treatment cycle. Response will be assessed after 3 cycles of treatment. Responders may continue study treatment until progression or limiting toxicity. Limiting toxicity is defined as any grade III/IV extra-hematological toxicity or grade IV hematological toxicity lasting more than 25 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Patients must meet all the following criteria to participate in the study:
- •Myelodysplastic syndrome according to WHO (World Health Organization) 2022 classification
- •Age ≥ 18 years
- •Patient with low-risk Myelodysplastic Syndromes according to Revised International Prognostic Scoring System (IPSS-R) classification (very low, low, intermediate):
- •non-sideroblastic who failed to achieved a response or who subsequently relapse after Erythropoiesis Stimulating Agents (ESA) (at Epoetin alfa 60000UI or equivalent over at least 12 weeks) without disease progression or ineligible to ESA (defined by Erythopoietine (EPO) > 500UI/L)
- •sideroblastic who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000UI or equivalent over at least 12 weeks) or ineligible for ESA (defined by EPO >500UI/L) and who failed to achieved a response or who subsequently relapse after Luspatercept
- •del (5q) who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000IU or equivalent over at least 12 weeks) and who failed to achieved a response or who subsequently relapse after Lenalidomide
- •Transfusion dependence (at least 3 RBC (Red Blood Cell) within a 16-week period and at least 2 transfusion episodes during this period)
- •Patient not eligible for another clinical trial
- •Adequate renal function defined by creatinine level less than 1.5 times the upper limit of normal and creatinine clearance ≥ 40mL/min (according to MDRD (Modification of Diet in Renal Disease) formula)
- •Adequate liver function defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal
- •Patient not refractory to platelet transfusions
- •Written consent
- •Patient must understand and voluntarily sign informed consent form
- •Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements
- •Performance status 0-2 at the time of screening
- •A FCBP (female of childbearing potential) for this study was defined as a sexually mature woman who: (1) had not undergone a hysterectomy or bilateral oophorectomy; or (2) had not been naturally postmenopausal (amenorrhea following cancer therapy did not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
- •A FCBP participating in the study must:
- •Have had 2 negative pregnancy tests as verified by the investigator prior to starting IP (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing a monthly pregnancy testing during the course of the study and after end of treatment.
- •If sexually active, agreed to have used, and been able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting treatment, during treatment (including dose interruptions), and for 24 weeks after discontinuation of treatment.
- •Highly effective contraception was defined in this protocol as the following (information also appeared in the Informed Consent Form): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy.
- •Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 24 weeks following treatment discontinuation, even if he had undergone a successful vasectomy.
排除标准
- •Any patient meeting one of the following criteria cannot be included in the study:
- •Severe infection or any uncontrolled severe condition
- •Uncontrolled hypertension
- •Significant cardiac disease - NYHA (New York Heart Association) Class III or IV or having suffered a myocardial infarction in the last 6 months
- •QTcF (Fridericia's corrected QT interval) > 460ms
- •Use of investigational agents within 30 days or any anticancer therapy (including IMiD (Immunomodulatory treatments)) within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered at least a grade 1 from all acute toxicity from any previous therapy. However, patients may have received Lenalidomide, hypomethylating agent, or anti-lymphocytic serum (ALS) (but not within 4 weeks before the study entry and, for ALS, within 16 weeks before the study entry).
- •Use of EPO within 4 weeks before the study entry
- •Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast
- •Patient already enrolled in another therapeutic trial of an investigational drug
- •Known Human Immunodeficiency Virus infection or active hepatitis B or C
- •Women who are or could become pregnant or who are currently breastfeeding
- •Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form
- •Patient eligible for allogeneic stem cell transplantation
- •No affiliation to a health insurance system
研究组 & 干预措施
ATO
Oral Arsenic treatment
干预措施: Arsenic Trioxide (ATO) (Drug)
结局指标
主要结局
To determine the dose-limiting toxicity (DLT) of oral Arsenic (ATO)
时间窗: At the end of cycle 1 (each cycle is 28 days)
Dose-limiting toxicity will be defined by the occurrence during the first treatment cycle of any of the following toxicities related to the trial drug (oral ATO): * Non-hematological toxicity of grade ≥ 3 * Hematological toxicity of grade ≥ 4 corresponding to a decrease of 50% or more of absolute neutrophil count (ANC) or platelet count from baseline or lower limit (if baseline was above normal), without recovery at D42 of the first cycle.
Part 1 (Phase I study): Dose-limiting toxicity (DLT) of oral ATO over an observation period from day 28 to day 42 following the start of cycle 1
Part 1 (Phase I study): Dose-limiting toxicity (DLT) of oral ATO over an observation period from day 28 to day 42 following the start of cycle 1
Part II (Expansion Phase): Erythroid response rate (HI-E) after 12 weeks oral ATO treatment
Part II (Expansion Phase): Erythroid response rate (HI-E) after 12 weeks oral ATO treatment
次要结局
- To determine safety profile(Through study completion, an average of 2 years)
- Pharmacokinetics(At the end of cycle 1 (each cycle is 28 days))
- Efficacy(At the end of cycle 3 (each cycle is 28 days))
- Response duration(Through study completion, an average of 2 years)
- Progression-free survival(Through study completion, an average of 2 years)
- Overall survival(Through study completion, an average of 2 years)
- Safety profile and tolerability measured according to CTCAE (latest version)
- Bioequivalence compared to IV ATO in terms of PK/PD
- Response to treatment will be assessed after cycle 3 according to IWG 2018 criteria
- Response duration measured from date of objective response to date of relapse or progression (or date of last news in absence of event)
- Rate and time to transformation to high-risk MDS or AML
- Progression-free survival
- Overall survival from date of inclusion to death or date of last news
- Exploratory criteria: factors associated with survival and response, including IPSS-R, karyotype and somatic mutations (IPSS-M)