A Phase 1, Open-Label, Multicenter Study of INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 290
- 试验地点
- 25
- 主要终点
- Number of participants with Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This study is being conducted to evaluate the safety, tolerability, dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) of INCA033989 administered as a Monotherapy or in Combination With Ruxolitinib in participants with myeloproliferative neoplasms.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Life expectancy > 6 months.
- •Willingness to undergo a pretreatment and regular on-study BM biopsies and aspirates (as appropriate to disease).
- •Existing documentation from a qualified local laboratory of CALR exon-9 mutation.
- •Participants with MF or ET as defined in the protocol.
排除标准
- •Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
- •Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
- •Participants with laboratory values exceeding the protocol defined thresholds.
- •Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
- •Active invasive malignancy over the previous 2 years.
- •History of clinically significant or uncontrolled cardiac disease.
- •Active or chronic HBV or active HCV or known history of HIV.
- •Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent used to treat the participant's disease, with the exception of ruxolitinib for TGBs only, within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
- •Participants undergoing treatment with G-CSF, GM-CSF, or TPO-R agonists at any time within 4 weeks before the first dose of study treatment.
- •Other protocol-defined Inclusion/Exclusion Criteria may apply.
研究组 & 干预措施
Part 1a Dose Escalation Cohort Disease Group A - with MF
INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) will enroll in this group.
干预措施: INCA033989 (Drug)
Part 1a Dose Escalation Cohort Disease Group A - with ET
INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with essential thrombocythemia (ET) will enroll in this group.
干预措施: INCA033989 (Drug)
Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R
INCA033989 will be administered at a protocol defined starting regimen in 28- day cycles and will allow for the evaluation of INCA033989 in combination with ruxolitinib to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) exhibiting suboptimal response (SubOpt R) will enroll in this group.
干预措施: INCA033989 (Drug)
Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R
INCA033989 will be administered at a protocol defined starting regimen in 28- day cycles and will allow for the evaluation of INCA033989 in combination with ruxolitinib to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) exhibiting suboptimal response (SubOpt R) will enroll in this group.
干预措施: Ruxolitinib (Drug)
Part 1b: Dose Expansion - with TGB-MF SubOpt R
INCA033989 will be administered as an add-on therapy in combination with ruxolitinibat at the RDE(s) identified during Part 1a. Participants with treatment Group B (TGB) MF SubOpt R will enroll in this group.
干预措施: INCA033989 (Drug)
Part 1b: Dose Expansion - with TGB-MF SubOpt R
INCA033989 will be administered as an add-on therapy in combination with ruxolitinibat at the RDE(s) identified during Part 1a. Participants with treatment Group B (TGB) MF SubOpt R will enroll in this group.
干预措施: Ruxolitinib (Drug)
Part 1b: Dose Expansion - with ET
INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) essential thrombocythemia (ET) will enroll in this group.
干预措施: INCA033989 (Drug)
Part 1c: Dose Expansion
INCA033989 will be administered at the dose level found to exhibit an overall positive benefit/risk as monotherapy or as combination therapy with Ruxolitinib. Participants with myelofibrosis (MF) will enroll in this group. The participants enrolled in the monotherapy arm will be offered the option to crossover to combination therapy with ruxolitinib if a suboptimal response to monotherapy is observed after 12 weeks.
干预措施: INCA033989 (Drug)
Part 1c: Dose Expansion
INCA033989 will be administered at the dose level found to exhibit an overall positive benefit/risk as monotherapy or as combination therapy with Ruxolitinib. Participants with myelofibrosis (MF) will enroll in this group. The participants enrolled in the monotherapy arm will be offered the option to crossover to combination therapy with ruxolitinib if a suboptimal response to monotherapy is observed after 12 weeks.
干预措施: Ruxolitinib (Drug)
Part 1b: Dose Expansion - with MF
INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) myelofibrosis MF will enroll in this group.
干预措施: INCA033989 (Drug)
结局指标
主要结局
Number of participants with Dose Limiting Toxicities (DLTs)
时间窗: Up to 28 days
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol.
Number of participants with Treatment-emergent Adverse Events (TEAEs)
时间窗: Up to 3 years and 60 days
Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug, including those leading to dose modification or discontinuation.
次要结局
- Pharmacokinetics Parameter: Cmax of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Cmin of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: AUC(0-t) of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: AUC 0-∞ of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: CL/F of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Vz/F of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: t1/2 of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Participants with MF: Response using the revised IWG-MRT and ELN response criteria for MF(Up to 3 years and 60 days)
- Participants With MF: Percentage of participants achieving spleen volume reduction as defined in the protocol(Up to 24 weeks)
- Participants with symptomatic anemia: Anemia Response as defined in the protocol(Up to 24 weeks)
- Participants with ET: Response using the revised IWG-MRT and ELN response criteria for ET(Up to 3 years and 60 days)
- Incidence of AEs, ECGs, vital signs, and clinical laboratory evaluation(Up to 3 years and 60 days)
- Percentage of participants achieving ≥ 50% reduction from baseline in total symptom score (TSS)(Week 12 and Week 24)
- Mean change from baseline in TSS(Week 12 and Week 24)
- Mean change in disease-related allele burden(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Cmax of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Tmax of INCA033989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Cmin of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: AUC(0-t) of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: AUC 0-∞ of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: CL/F of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Vz/F of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: t1/2 of INCA33989 alone or for the combination of INCA033989 with ruxolitinib(Up to 3 years and 60 days)