A Phase 1 Open-Label Study Evaluating the Safety and Tolerability, and Pharmacokinetics of Navitoclax Monotherapy and in Combination with Ruxolitinib in Myeloproliferative Neoplasm Subjects, Incorporating Extension Part 6 – Continued Access for Navitoclax to Roll Over Subjects in France and Bulgaria from Studies M16-191 and M20-178
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 16
- 主要终点
- Part 3: To evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe.
研究概览
简要总结
The objectives of this study are to evaluate safety and tolerability, preliminary efficacy, and pharmacokinetics of navitoclax when administered as monotherapy and in combination with ruxolitinib in Japanese and/or Taiwanese subjects with MPN (Parts 1 and 2) and to evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe (Part 3).
The primary objective in Part 4 is to evaluate the effect of navitoclax, a CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML.
The primary objective in Part 5 is to evaluate the effect of navitoclax on the PK, safety, and tolerability of ruxolitinib in subjects with first-line and relapsed/refractory MF in the US and Europe
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Treatment
- 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
- •Part 1 and Part 2 of the study are not being conducted within the EEA.
- •Part 3: Subject must be requiring treatment and have failed or are intolerant to at least one prior therapy and be ineligible for allogeneic stem cell transplantation. Subjects who refuse standard therapy may only be enrolled in regions where permitted by local regulations
- •Part 3: Subject must have an ECOG performance status ≤
- •Part 3: Subject must meet laboratory parameters for bone marrow reserves, platelet count, neutrophil count, renal function, hepatic function and enzymes, AST and ALT, Billirubin, coagulation, serum potassium and hypocalcemia.
- •Part 4: Subjects with a documented diagnosis of primary or secondary MF, ET, PV or chronic myelomonocytic leukemia (CMML) as defined by the WHO classification.
- •Part 4: Subject must be requiring treatment and have failed or are intolerant to at least one prior therapy and be ineligible for allogeneic stem cell transplantation. Subjects who refuse standard therapy may only be enrolled in regions where permitted by local regulations.
- •Part 6: Subject must currently be receiving navitoclax in France or Bulgaria in a navitoclax clinical trial (M16-191, M19-753, or M20-178) and, in the opinion of the treating investigator, deriving clinical benefit from ongoing navitoclax treatment.
- •Part 6: Subject must have completed assessments through the End of Treatment Visit / Treatment Completion Visit in their parent protocol prior to starting navitoclax under Extension Part
- •Part 4: Subject must have an ECOG performance status ≤
- •Part 4: Subject must meet laboratory parameters for bone marrow reserves, platelet count, neutrophil count, renal function, hepatic function and enzymes, AST and ALT, Billirubin, coagulation and serum potassium.
- •Part 5: Subjects with a documented diagnosis of primary MF as defined by the WHO classification, post-PV MF, or post-ET MF.
- •Part 5: Subject must be requiring treatment for MF and must either have no prior treatment with a JAK2 inhibitor or have received treatment with ruxolitinib meeting at least one of the following criteria listed in protocol eligibility criteria
- •Part 5: Subject must have an ECOG performance status ≤
- •Subjects ≥ 18 years old
- •Part 3: At screening or baseline (pre-dose on Day 1), subject has QTc interval by Fridericia's correction (QTcF) ≤ 450 msec.
- •Part 3: Subjects with a documented diagnosis of primary or secondary MF, ET, PV or chronic myelomonocytic leukemia (CMML) as defined by the WHO classification.
排除标准
- •Part 1 and Part 2 of the study are not being conducted within the EEA.
- •Part 5: Subject must not have received CYP2C9 inducers within 10 days prior to the first dose of study drugs.
- •Part 3: Subject must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).
- •Part 3: Subject must not be currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.
- •Part 3: Subject must not have had prior therapy with a BH3 mimetic compound.
- •Part 3: Subject must not have received strong or moderate CYP3A inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of navitoclax.
- •Part 3: Subject must not have received strong CYP3A inducers within 10 days prior to the first dose of navitoclax.
- •Part 4: Subject must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy)."
- •Part 4: Subject must not be currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.
- •Part 4: Subject must not have had prior therapy with a BH3 mimetic compound.
- •Part 4:Subject must not have received strong or moderate CYP3A inhibitors or CYP2C9 within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.
- •Part 4: Subject must not have received strong or moderate CYP2C9 inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.
- •Part 4: Subject must not have received strong CYP3A or CYP2C9 inducers within 10 days prior to the first dose of study drugs.
- •Part 5: Subject must not have a history of an active malignancy other than MF within the past 2 years prior to study entry, except for: - Adequately treated in situ carcinoma of the cervix uteri - Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin - Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy.
- •Part 5: Subject must not be currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.
- •Part 5: Subject must not have received strong CYP3A inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.
- •Part 5: Subject must not have received CYP2C9 inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.
- •Part 5: Subject must not have received strong CYP3A inducers within 10 days prior to the first dose of study drugs.
结局指标
主要结局
Part 3: To evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe.
Part 3: To evaluate the effect of navitoclax on corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with MPN or CMML in the US and Europe.
Part 4: To evaluate the effect of navitoclax, a potential CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML.
Part 4: To evaluate the effect of navitoclax, a potential CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML.
Part 5: To evaluate the effect of navitoclax on the PK, safety, and tolerability of ruxolitinib in subjects with MF in the US and Europe.
Part 5: To evaluate the effect of navitoclax on the PK, safety, and tolerability of ruxolitinib in subjects with MF in the US and Europe.
次要结局
- Safety Endpoint: Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing (hematology, chemistry, coagulation, and urinalysis) as a measure of safety and tolerability
- Pharmacodynamic Endpoint: Part 3 only- ECG variables will include QTcF, heart rate, PR interval (time from the onset of the P wave to the start of the QRS complex), QRS duration, and waveform composition.
- Pharmacokinetic Endpoint: Pharmacokinetic (PK) samples will be collected at specified time points and analyzed for navitoclax
- Efficacy Endpoint: Preliminary efficacy will be evaluated.
研究者
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