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
- 进行中（未招募）
- 入组人数
- 160
- 试验地点
- 58
- 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, and 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 and ET as defined in the protocol.
排除标准
- •Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
- •Active invasive malignancy over the previous 2 years.
- •Active HBV/HCV, HIV.
- •History of clinically significant or uncontrolled cardiac disease.
- •Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
- •Laboratory values outside the Protocol-defined ranges.
- •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.
- •Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
- •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 within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
- •For TGBs only: Undergoing treatment with a potent/strong inhibitor or inducer of CYP 3A4/5 within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment, or expected to receive such treatment during the study.
- •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 as monotherapy 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 as monotherapy to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with with essential thrombocythemia (ET) will enroll in this group.
干预措施: INCA033989 (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)
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 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 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 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 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 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 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)
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 TEAEs leading to dose modification or discontinuation
时间窗: Up to 3 years and 60 days
Number of participants with TEAEs leading to dose modification or discontinuation.
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 monotherapy and in combination with ruxolitinib
次要结局
- Participants With MF: Percentage of participants achieving spleen volume reduction as defined in the protocol(Up to 3 years and 60 days)
- Participants with MF with symptomatic anemia: Anemia Response(Up to 3 years and 60 days)
- Participants With ET: Response Rate(Up to 3 years and 60 days)
- Mean change in disease-related allele burden(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Cmin of INCA33989(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: AUC(0-t) of INCA33989(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Vz/F of INCA33989(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: t1/2 of INCA33989(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Cmax of INCA33989(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: Tmax of INCA033989(Up to 3 years and 60 days)
- Pharmacokinetics Parameter: AUC 0-∞ of INCA33989(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)
- Pharmacokinetics Parameter: CL/F of INCA33989(Up to 3 years and 60 days)
- Participants With ET: Mean change from baseline of total symptom score (TSS)(Up to 3 years and 60 days)