A 2-tiered, Phase 2, Rule-based, Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib (TEW-7197) in the Treatment of Anemic Patients With Philadelphia Chromosome-negative MPNs (Ph-neg MPNs)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Number of Tier 2 Patients Who Have Achieved Erythropoietic Response as Defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
研究概览
简要总结
This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood cell formation in these diseases. The study design allows all patients to receive the study drug, vactosertib. The dose of vactosertib is individualized within a pre-set range based upon its effectiveness and tolerability. A total of up to 37 patients will be treated.
详细描述
This is a two-tiered multi arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs. The first tier of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of vactosertib for all patients. Treatment dose is escalated according to prospectively-defined rules, and a toxicity and treatment effect algorithm during the period of 16 weeks (4 treatment cycles). If pre-established efficacy and safety endpoints are met, then Tier 1 of the study will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 treatment cycles).
Vactosertib will be administered concurrently with the patient's current treatment (if any). Prior to enrollment, patients must be on a stable dose of their current therapy for 3 months prior to entering the study. Supportive care measures including packed red blood cell (PRBC) transfusions for HGB <7g/dL, or symptomatic anemia, will be permitted. Administration of erythropoiesis stimulating agents (ESAs), however, will not be permitted on the trial (patients recruited would have serum EPO >125 U/L above which the benefit of ESAs is not supported).
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
- •Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).
- •Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET).
- •For patients receiving cytoreductive therapy, they should be on a stable dose of current cytoreductive therapy for at least 3 months prior to C1D
- •Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) unit within the past 4 weeks with HGB ≤8.5g/dL.
- •Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following:
- •Serum erythropoietin (EPO) >125 U/L.
- •Proven ESA unsuitability is defined by history of any of the following:
- •Loss of erythroid hematologic improvement while receiving stable or increased ESA dose; or
- •ESA-attributed toxicity that, in the treating physician's opinion, makes ESA therapy unsuitable for subject.
- •ESA refractoriness defined by lack of erythroid hematologic improvement to ESA:27
- •Less than 1.5 g/dL increase in hemoglobin after at least 6 weeks of ESA therapy; or
- •Ongoing transfusion dependence that has not been reduced by > 4U over an 8-week period compared to ESA pre-treatment 8 weeks.
- •Acceptable Cardiovascular status
排除标准
- •Any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study.
- •Patients with history of TIA or stroke within the past 12 months are excluded.
- •Female subjects who are breastfeeding, or intend to breastfeed, during the study or in the 30 days following the last dose of study drug are excluded.
研究组 & 干预措施
Tier 1: Vactosertib 50 mg BID
Vactosertib intra-patient dose finding cohort.
干预措施: Vactosertib (Drug)
Tier 1: Vactosertib 100 mg BID
干预措施: Vactosertib (Drug)
Tier 1: Vactosertib 150 mg BID
干预措施: Vactosertib (Drug)
Tier 1: Vactosertib 200mg BID
干预措施: Vactosertib (Drug)
Tier 2: Vactosertib
干预措施: Vactosertib (Drug)
结局指标
主要结局
Number of Tier 2 Patients Who Have Achieved Erythropoietic Response as Defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
时间窗: baseline to week 16
Number of patients who achieve an erythropoietic response defined by: 1. HGB increase of 1.5g/dL compared to baseline hemoglobin; 2. Reduction in PRBC transfusion rate to ≤ 50% of pre-treatment transfusion rate; or 3. Reduction in PRBC transfusions by ≥ 4 Units over an 8-week period.
Number of Tier 2 Patients Who Have Achieved Splenic Response in Symptoms as Defined by International Working Group (IWG) Criteria
时间窗: baseline to week 16
Number of patients who have achieved splenic response defined by: 1. Non-palpable spleen when baseline spleen size was 5-10 cm below left costal margin; 2. At least 50% reduction in spleen size when baseline spleen is \> 10 cm below left costal margin 3. At least 35% reduction in spleen size as assessed by US, CT or MRI.
Identify the Safest, Minimally Effective Starting Dose Level for Patients on Tier 1
时间窗: Baseline to week 16
The safest minimally effective dose is defined as the lowest dose level for which no dose limiting toxicity (DLT) was observed in Tier 1 AND the lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 meet Criteria for Clinical Benefit
Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 1
时间窗: Baseline to week 12
Identify the incidence of dose limiting toxicity (DLT) within the first 12 weeks which are defined as: 1. Any non-hematologic grade ≥3 toxicity except for nausea, vomiting or diarrhea lasting 3 days or less 2. Any grade 4 neutropenia of any duration 3. Any grade ≥3 neutropenia that has not recovered to grade ≥2 within 7 days of onset 4. Any grade ≥3 febrile neutropenia 5. Any grade ≥3 thrombocytopenia associated with clinically significant bleeding or requiring platelet transfusion
Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 1
时间窗: Baseline to week 12
Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 1 stopping rule. The tier 1 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study.
Number of Tier 2 Patients Who Have Achieved Clinical Response in Symptoms as Defined by International Working Group (IWG) Criteria
时间窗: baseline to week 16
Number of patients who have achieved clinical response defined by a reduction in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score by ≥ 50% compared to pretreatment score
Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 2
时间窗: baseline to week 12
Identify the number of dose limiting toxicities (DLT) within the first 12 weeks which are defined as: 1. Any non-hematologic grade ≥3 toxicity except for nausea, vomiting or diarrhea lasting 3 days or less 2. Any grade 4 neutropenia of any duration 3. Any grade ≥3 neutropenia that has not recovered to grade ≥2 within 7 days of onset 4. Any grade ≥3 febrile neutropenia 5. Any grade ≥3 thrombocytopenia associated with clinically significant bleeding or requiring platelet transfusion
Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 2
时间窗: baseline to week 12
Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 2 stopping rule. The tier 2 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study.
次要结局
- Progression Free Survival Defined as the Duration of Time From Start of Treatment to Time of Progression(Week 1 Day 1 to 6 months post treatment discontinuation)
- Number of Patients in Which a Histological Response is Seen(16 weeks)
- Number of Patients in Which a Molecular Response is Seen(16 weeks)
- Number of Patients Who Have Experienced Any of the Following: Hematologic Toxicities, Infections, Disease Progression, and Thrombosis Events(baseline to 16 weeks)
- Overall Survival Defined as the Amount of Time a Patient is Alive After Starting Study Treatment(Week 1 Day 1 to 6 months post treatment discontinuation. This collection period for both subjects on study was over an average duration of 54 weeks.)
- Number of Patients in Which a Pharmacodynamic Response is Seen(16 weeks)