A Phase I/II Trial of Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Phase 1: Recommended Phase 2 Dose (RP2D) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Adult Participants With Higher-Myelodysplastic Syndromes (MDS)
研究概览
简要总结
Background:
Myelodysplastic syndromes (MDS) are diseases that affect the bone marrow. They can inhibit the blood formation process and reduce blood cell counts. High-risk MDS can lead to leukemia. People with high-risk MDS have a low survival rate. Better treatments are needed.
Objective:
To test a study drug Eltanexor (KPT-8602), combined with another drug (Inqovi), in people with MDS.
Eligibility:
Adults aged 18 years and older with high-risk MDS that did not respond to treatment.
Design:
Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They may have a bone marrow biopsy: Their hip will be numbed; then a needle will be inserted to draw out a sample of soft tissue from inside the bone. They will answer questions about their quality of life. Genetic tests may be performed.
KPT-8602 and Inqovi are both tablets taken by mouth. Participants will take these drugs at home on a 28-day cycle. They will take Inqovi once a day on days 1 to 5. They will take KPT-8602 on a schedule assigned by the researcher. Participants will be given a drug diary to record each dose.
Participants will visit the clinic for an exam at least once in each cycle. Some tests, including the bone marrow biopsy, may be repeated.
Participants will continue treatment for at least 6 cycles. If their disease improves, they may continue taking the drugs after 6 cycles.
Participants will have follow-up visits at the clinic for about 8 years.
详细描述
Background:
- The myelodysplastic syndromes (MDS) are a group of clonal bone marrow neoplasms characterized by ineffective hematopoiesis, cytopenia, and high risk of transformation to acute myeloid leukemia (AML).
- The median survival of patients with newly diagnosed higher-risk MDS (HR-MDS) according to the Revised International Prognostic Scoring System (IPSS-R) is 1.5 years.
- Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the standard of care therapy for HR-MDS. However, less than half of patients respond to HMAs, and even the best responses are transient and non-curative.
- The only curative treatment for patients with MDS is allogeneic hematopoietic stem cell transplantation (HSCT); however, only a small portion are eligible for transplant.
- More effective therapies are needed for patients with HR-MDS.
- A promising approach for improving HMA efficacy in the treatment of MDS is by exploiting therapeutic synergism in combinatorial approaches.
- Inqovi (decitabine-cedazuridine) is an oral formulation of decitabine plus cytidine deaminase inhibitor that was recently Food and Drug Administration (FDA)-approved for MDS, based on a similar safety and efficacy profile to decitabine for injection.
- KPT-8602 (eltanexor) is an orally available, second-generation selective inhibitor of nuclear export (SINE) that covalently binds to exportin 1 (XPO1).
- XPO1 is a protein that mediates the nuclear export of molecules from the nucleus to the cytoplasm of the cell. Among affected molecules are tumor suppressor genes, messenger ribonucleic acid (mRNAs) encoding oncogenes (including cellular myelocytomatosis oncogene (c-MYC), and newly assembled ribosomal subunits.
- By interfering with c-MYC translation, KPT-8602 may diminish rebound methylation after decitabine cessation and improve treatment responses in patients with MDS.
- Preliminary reports from a Phase 1/2 trial of KPT-8602 monotherapy in patients with higher-risk MDS who have failed HMAs show anti-tumor activity and an acceptable toxicity profile.
- Sequential addition of KPT-8602 to Inqovi may improve treatment responses in patients with MDS by acting synergistically to inhibit further DNA methylation.
Objective:
- Phase I: To determine the recommended phase 2 dose (RP2D) of KPT-8602 in combination with Inqovi in adult participants with higher-risk MDS
- Phase II: To determine overall response rate (ORR) of KPT-8602 in combination with Inqovi in adult participants with higher- risk MDS
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase I- Dose escalation of Eltanexor (KPT-8602) for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by escalating doses of Eltanexor (KPT-8602)
干预措施: KPT-8602 (Drug)
Phase I- Dose escalation of Eltanexor (KPT-8602) for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by escalating doses of Eltanexor (KPT-8602)
干预措施: Inqovi (Drug)
Phase I- Dose escalation of Eltanexor (KPT-8602) for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by escalating doses of Eltanexor (KPT-8602)
干预措施: Bone marrow aspirate (Procedure)
Phase I- Dose escalation of Eltanexor (KPT-8602) for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by escalating doses of Eltanexor (KPT-8602)
干预措施: Bone marrow biopsy (Procedure)
Phase I- Dose escalation of Eltanexor (KPT-8602) for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by escalating doses of Eltanexor (KPT-8602)
干预措施: ECG (Diagnostic Test)
Phase II- Dose expansion for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by recommended phase 2 dose (RP2D)/Phase II dose of Eltanexor (KPT-8602)
干预措施: KPT-8602 (Drug)
Phase II- Dose expansion for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by recommended phase 2 dose (RP2D)/Phase II dose of Eltanexor (KPT-8602)
干预措施: Inqovi (Drug)
Phase II- Dose expansion for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by recommended phase 2 dose (RP2D)/Phase II dose of Eltanexor (KPT-8602)
干预措施: Bone marrow aspirate (Procedure)
Phase II- Dose expansion for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by recommended phase 2 dose (RP2D)/Phase II dose of Eltanexor (KPT-8602)
干预措施: Bone marrow biopsy (Procedure)
Phase II- Dose expansion for High-Risk Myelodysplastic Syndromes
Inqovi for 5 days, followed by recommended phase 2 dose (RP2D)/Phase II dose of Eltanexor (KPT-8602)
干预措施: ECG (Diagnostic Test)
结局指标
主要结局
Phase 1: Recommended Phase 2 Dose (RP2D) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Adult Participants With Higher-Myelodysplastic Syndromes (MDS)
时间窗: From day 1 of study drug through 28 days after the first dose
If no DLTs are observed at the highest planned dose level for evaluation (dose level 2), dose escalation will stop, and this will be considered the recommended phase 2 dose (RP2D) of Eltanexor (KPT-8602). A DLT is defined as a treatment-related toxicity based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Phase 1: Number of Participants Who Have Grades 3 and/or 4 Dose-limiting Toxicity (DLT) at the Recommended Phase 2 Dose (RP2D)
时间窗: First 28 days of study treatment
Participants enrolled in phase I will have the grades and types of toxicity reported at each dose level to determine the RP2D. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Phase 2: Overall Response Rate (ORR) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) Reported With a 95% Confidence Interval in Adult Participants With Higher-Myelodysplastic Syndromes (MDS)
时间窗: Each cycle (bloods), cycle 2 and 6 during treatment and every 3-6 months (bloods and bone marrow)
Participants evaluated in phase II will have the fraction with clinical responses reported, with a 95% confidence interval. ORR is defined as Complete Remission (CR)+Partial Remission (PR)+marrow (mCR) with hematologic improvement (HI) per each cohort and assessed by the 2006 International Working Group Response Criteria with Modified Definitions for Hematologic Improvement by the 2018 International Working Group Response Criteria. Complete Remission (CR) is bone marrow: ≤5% myeloblasts with normal maturation of all cell lines. Partial Remission (PR) is all CR criteria if abnormal before treatment except bone marrow blasts decreased by ≥50% over pretreatment but still \>5%; and cellularity and morphology not relevant. Marrow Complete Remission is bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment.
次要结局
- Phase 1: AUC Under the Concentration Time Curve (AUC 0-48h) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Participants With Myelodysplastic Syndromes (MDS)(1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one)
- Phase 1: Half-life of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Participants With Myelodysplastic Syndromes (MDS)(1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one)
- Phase 1: Calculating Steady State (Css) Concentration of Eltanexor (KPT-8602) When Given in Combination With Inqovi (Decitabine-Cedazuridine)(1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one)
- Phase 2: Number of Grades 1, 2, 3, 4, and/or 5 Toxicity of Eltanexor (KPT-8602) and Inqovi (Decitabine-Cedazuridine) at Each Dose Level in Participants With Myelodysplastic Syndromes (MDS)(At least weekly through cycle 3 and then at the start and every cycle after that)
- Phase 2: Number of Serious Adverse Events Leading to Discontinuation, Death, and Laboratory Abnormalities(At least weekly through cycle 3 and then at the start and every cycle after that)
研究者
Najla El Jurdi
Principal Investigator
National Cancer Institute (NCI)