NCT04176198招募中1 期
A Phase 1/2, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral Nuvisertib (TP-3654) in Patients With Intermediate or High-Risk Primary or Secondary Myelofibrosis
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 240
- 试验地点
- 127
- 主要终点
- Determine the incidence of treatment emergent adverse events
研究概览
简要总结
This study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of nuvisertib (TP-3654) in patients with intermediate or high-risk primary or secondary MF.
详细描述
Arm 1 will enroll patients who have been previously treated and failed on a JAK inhibitor or ineligible to receive treatment with a JAK inhibitor.
Arm 2 will enroll patients who are on a stable dose of ruxolitinib, but who have either lost response or had a suboptimal or plateau in response.
Arm 3 will enroll patients who have been previously treated with a JAK inhibitor (except momelotinib)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must meet all of the following inclusion criteria to be eligible:
- •Nuvisertib (TP-3654) Monotherapy Arm:
- •Confirmed pathological diagnosis of primary myelofibrosis (PMF) or post-PV-MF/post-ET- MF and intermediate or high-risk primary or secondary MF
- •Previously treated with JAK inhibitor(s) and is intolerant, resistant, refractory or has lost response to the JAK inhibitor(s) or is ineligible to be treated with JAK inhibitor
- •Fulfill the following clinical laboratory parameters:
- •Platelet count ≥ 25 x 10^9 /L, without assistance of growth factors or platelet transfusions
- •ANC ≥ 1 x 10^9/L without assistance of granulocyte growth factors
- •Peripheral blood blast count < 5%
- •ECOG performance status ≤ 1
- •Life expectancy ≥ 6 months
- •Adequate renal function
- •Adequate hepatic function
- •Adequate coagulation function
- •Splenomegaly (spleen volume of ≥ 450 cm3 by MRI or CT scan) within 2 weeks prior to Cycle 1 Day
- •Dose escalation: At least 2 symptoms measurable (score ≥ 1) using the MF-SAF
- •Dose expansion: At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF
- •Nuvisertib (TP-3654) + Ruxolitinib Arm:
- •Confirmed pathological diagnosis of PMF or post-PV-MF/post ET- MF and intermediate or high-risk primary or secondary MF
- •On ruxolitinib treatment for ≥ 6 months, and on a stable dose of ruxolitinib (5 to 25 mg BID) for ≥ 8 weeks prior to the first dose of nuvisertib, but has either lost response or had a suboptimal or plateau in response
- •Fulfills the following clinical laboratory parameters:
- •Platelet count ≥ 50 × 10^9/L (without assistance of growth factors or platelet transfusions)
- •ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
- •Peripheral blood blast count < 5% at screening
- •Adequate renal function
- •Adequate hepatic function
- •Adequate coagulation function
- •Splenomegaly (spleen volume of ≥ 450 cm3 by MRI/CT scan) within 2 weeks prior to Cycle 1 Day 1
- •At least 2 symptoms measurable with each score ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0
- •ECOG performance status ≤ 1
- •Life expectancy ≥ 6 months
- •Nuvisertib (TP-3654) + Momelotinib Arm
- •Confirmed pathological diagnosis of PMF or post-PV-MF/post ET-MF and intermediate or high-risk primary or secondary MF
- •Previously treated with an approved JAK inhibitor (except momelotinib) for PMF or Post-PV/ET MF for ≥ 12 weeks, or ≥ 4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥ 4 units of red blood cells in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma
- •Fulfills the following clinical laboratory parameters:
- •Anemic, defined as Hb <10 g/dL or requiring RBC transfusion at baseline
- •Platelet count ≥ 50 × 109/L (without assistance of growth factors or platelet transfusions)
- •ANC ≥ 1 × 109/L without assistance of granulocyte growth factors
- •Peripheral blood blast count < 5% at screening
- •Adequate renal function
- •Adequate hepatic function
- •Adequate coagulation function
- •Splenomegaly (spleen volume of ≥ 450 cm3 by MRI/CT scan) within 2 weeks prior to Cycle 1 Day 1
- •At least 2 symptoms measurable with each score of ≥ 3 or a total average score of ≥ 10 per MFSAF v4.0
- •ECOG performance status ≤ 1
- •Life expectancy ≥ 6 months
- •Patients meeting any one of these
排除标准
- •will be prohibited from participating in this study:
- •Nuvisertib (TP-3654) Monotherapy Arm:
- •Received previous systemic antineoplastic therapy or any experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day
- •Hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).
- •Major surgery within 4 weeks prior to Cycle 1 Day 1 and/or not recovered adequately from from surgery prior to first dose.
- •Splenic irradiation within 6 months prior to Screening or prior splenectomy.
- •Prior allogeneic stem cell transplant within the last 6 months.
- •Eligible for allogeneic bone marrow or stem cell transplantation.
- •Unresolved Grade ≥ 2 non-hematological toxicity related to prior treatment
- •History of symptomatic congestive heart failure, or myocardial infarction, or uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; left ventricular ejection fraction (LVEF) < 45% by echocardiogram within 4 weeks prior to Cycle 1 Day
- •Corrected QT interval > 480msec.
- •Prior or concurrent malignancy that could interfere with the investigational regime.
- •Known history of chronic liver disease, e.g. portal hypertension or any of its complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin deficiency, Wilson's disease, etc.
- •Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic antimicrobial within 1 week prior to Cycle 1 Day
- •Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required)
- •Exhibited allergic reactions or sensitivity to nuvisertib, or similar compound.
- •Medical condition or GI tract surgery that could impair absorption or result in short bowel syndrome with diarrhea.
- •Systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior to the first dose of study treatment (note: topical, inhaled, nasal, and ophthalmic steroids are not prohibited).
- •Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding.
- •Pregnant or breastfeeding
- •Currently receiving any other investigational agent.
- •Nuvisertib (TP-3654) + Ruxolitinib Arm:
- •Received previous systemic antineoplastic therapy (other than ruxolitinib) or any other experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1 (Note: Prior treatment with nuvisertib is not allowed. Hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).
- •Received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior to Cycle 1 Day 1 (Note: Topical, inhaled, nasal, and ophthalmic steroids are not prohibited)
- •Known allergic reactions or sensitivity to nuvisertib, or similar compound.
- •Splenic irradiation within 6 months prior to Screening or prior splenectomy
- •Prior allogeneic stem cell transplant within the last 6 months (Note: Patients who have relapsed after 6 months post-transplant and do not have active GVHD are eligible).
- •Eligible for allogeneic bone marrow or stem cell transplantation (Note: Patients who are not willing to undergo transplantation or for whom a suitable donor is not available are considered as transplant ineligible.)
- •Major surgery within 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately prior to first dose.
- •Active, uncontrolled bacterial, viral, or fungal infections, requiring parenteral antimicrobial within 1 week prior to Cycle 1 Day 1
- •Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required)
- •Known history of chronic liver disease (eg, portal hypertension or any of its complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin deficiency, Wilson's disease, etc) (Note: Abnormal liver morphology at baseline imaging may require additional testing, as needed).
- •Unresolved Grade ≥ 2 non-hematological adverse events related to prior treatment (stable Grade 2 conditions may be permitted in consultation with the Sponsor)
- •History of myocardial infarction or symptomatic congestive heart failure or uncontrolled arrhythmia within 6 months prior to Cycle 1 Day 1; LVEF <45% by echocardiogram within 4 weeks prior to Cycle 1 Day 1
- •Corrected QTcF of > 480 msec
- •Prior or concurrent malignancy that could interfere with the safety or efficacy assessment of the study intervention
- •History of a medical condition or GI tract surgery that could impair absorption or could result in short bowel syndrome with diarrhea
- •Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or thalassemia, or severe GI bleeding
- •Pregnant or breastfeeding
- •Nuvisertib (TP-3654) + Momelotinib Arm:
- •Received previous systemic antineoplastic therapy or any experimental therapy within 2 weeks or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1 (Notes: Prior treatment with momelotinib or nuvisertib is not allowed; in patients with ongoing JAK inhibitor therapy, ie, ruxolitinib, at screening, JAK inhibitor therapy must be tapered over a period of at least 1 week. Patients on a low dose of ruxolitinib (eg, 5 mg QD) may have a reduced taper period or no taper; hydroxyurea or anagrelide are allowed up to 24 hours prior to Cycle 1 Day 1).
- •Received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 1 week prior to Cycle 1 Day 1 (Note: Topical, inhaled, nasal, and ophthalmic steroids are not prohibited).
- •Known allergic reactions or sensitivity to nuvisertib, momelotinib, or any structurally similar drug, or to any component of the formulations of either study intervention
- •Splenic irradiation within 6 months prior to screening or prior splenectomy
- •Prior allogenic stem cell transplant within the last 6 months (Note: Patients who have relapsed after 6 months post-transplant and do not have active GVHD are eligible).
- •Eligible for allogeneic bone marrow or stem cell transplantation (Note: Patients who are not willing to undergo transplantation or for whom a suitable donor is not available are considered as transplant ineligible).
- •Major surgery within 4 weeks prior to Cycle 1 Day 1 and/or have not recovered adequately from surgery prior to first dose.
- •Active, uncontrolled bacterial, viral, or fungal infections, requiring parenteral antimicrobial within 1 week prior to Cycle 1 Day 1
- •Chronic active or acute viral hepatitis A, B, or C infection (testing for hepatitis B and C are required)
- •Known history of chronic liver disease (eg, portal hypertension or any of its complications, cirrhosis, Child-Pugh C, auto-immune hepatitis, alpha-1 anti-trypsin deficiency, Wilson's disease, etc) (Note: Abnormal liver morphology at baseline imaging may require additional testing, as needed)
- 另有 8 项未显示
研究组 & 干预措施
Arm 3: nuvisertib (TP-3654) in combination with momelotinib
Experimental
干预措施: Momelotinib (Drug)
Arm 2: nuvisertib (TP-3654) added on to ruxolitinib
Experimental
干预措施: Nusivertib (Drug)
Arm 1: nuvisertib (TP-3654)
Experimental
干预措施: Nusivertib (Drug)
Arm 3: nuvisertib (TP-3654) in combination with momelotinib
Experimental
干预措施: Nusivertib (Drug)
Arm 2: nuvisertib (TP-3654) added on to ruxolitinib
Experimental
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Determine the incidence of treatment emergent adverse events
时间窗: From start of treatment to end of study
Number of participants with Treatment Emergent Adverse Events and Serious Adverse Events
Determine the incidence of dose-limiting toxicities (DLTs)
时间窗: 28 days
Number of participants with DLTs
Assess patients for any evidence of preliminary activity by determining the number of patients with ≥ 35% spleen volume reduction (SVR35)
时间窗: From start of treatment to end of study
Number of participants with ≥ 35% spleen volume reduction (SVR35)
次要结局
- Number of participants achieving objective response by IWG-MRT response criteria(From start of treatment to end of study)
- Number of participants who have ≥ 25% spleen volume reduction(Every 12 weeks from cycle 1 day 1 through cycle 19 day 1, and then every 24 weeks therafter during treatment.)
- Number of participants with ≥ 50% improvement in total symptom score (TSS50) at week 24(24 weeks)
- Determine the change in Patient Global Impression of Change (PGIC) at week 24 through end of study.(After 24 weeks of treatment to end of study)
- Determine the incidence of QT interval changes(25 hours)
- Establish the half-life (t½) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib(24 hours)
- Establish the Area under the plasma concentration versus time curve (AUC) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib(24 hours)
- Establish the Peak Plasma Concentration (Cmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib(24 hours)
- Establish the Time of Maximum concentration observed (tmax) of nuvisertib monotherapy, in combination with ruxolitinib, and in combination with momelotinib(24 hours)
研究者
研究点 (127)
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