A Phase 1 Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 260
- 试验地点
- 38
- 主要终点
- To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)
研究概览
简要总结
This is an open-label, multi-center Phase 1 study of LY3410738, an oral, covalent isocitrate dehydrogenase (IDH) inhibitor, in patients with IDH1 and/or IDH2-mutant advanced hematologic malignancies who may have received standard therapy
详细描述
This study includes 2 parts: dose escalation and dose expansion. The dose escalation will enroll eligible patients with select IDH-mutant advanced hematologic malignancies. Once the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of LY3410738 is established, the dose expansion will begin and enroll into 5 cohorts to further evaluate safety and clinical activity
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 65+ years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Advanced IDH mutant hematologic malignancy including:
- •-- For Dose Escalation Arm C and Dose Expansion Cohort 5:
- •Patients with newly diagnosed AML who are 75 years or older or have comorbidities that preclude the use of intensive chemotherapy
- •Patients with R/R AML (US only)
- •Patients must have received prior therapy
- •Blasts at least 5% in bone marrow.
- •Patients must have a qualifying IDH1 R132, IDH2 R140 or IDH2 R172 mutation
- •Eastern Cooperative Oncology Group (ECOG) 0 to 2
- •Adequate organ function
- •Ability to swallow capsules or tablets
- •Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
- •Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.
排除标准
- •Investigational agent or anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter; or investigational monoclonal antibody within 4 weeks prior to planned start of LY3410738
- •For Dose Escalation Arm C and Dose Expansion Cohort 5:
- •Prior venetoclax treatment is not allowed.
- •Patients are allowed to receive up to 1 cycle of single agent azacitidine or azacitidine plus venetoclax while waiting for results of locally obtained molecular profiling, including IDH1/IDH2 mutational status, prior to starting on study.
- •Major surgery within 4 weeks prior to planned start of LY
- •Active, uncontrolled clinically significant systemic bacterial, viral, fungal or parasitic infection or an unexplained fever > 38.5ºC during Screening or on the first day of study drug administration.
- •Another concurrent malignancy requiring active therapy.
- •Active central nervous system involvement
- •Any unresolved toxicities from prior therapy greater than CTCAE v5.0 Grade 2 at the time of starting study treatment except for alopecia.
- •History of hematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy within 60 days of the first dose of LY
- •Clinically significant cardiovascular disease
- •Active hepatitis B virus (HBV)
- •Active hepatitis C virus (HCV)
- •Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug
- •Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or P- glycoprotein (P-gp) inhibitor, with the exception of patients being treated with allowed antifungal inhibitors of CYP3A4
- •Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738
- •Any serious underlying medical or psychiatric condition (e.g. alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand informed consent or that in the opinion of the Investigator would contraindicate the patient's participation in the study or confound the results of the study
- •Known human immunodeficiency virus (HIV), excluded due to potential drug-drug interactions between antiretroviral medications and LY3410738
- •Pregnancy, lactation or plan to breastfeeding during the study or within 90 days of the last dose of study intervention
- •Known hypersensitivity to any of the components of LY3410738 or its formulation
研究组 & 干预措施
Cohort 1
Patients with relapsed/refractory (R/R) AML harboring an IDH1 R132 mutation who have received a prior IDH inhibitor.
干预措施: LY3410738 (Drug)
Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine)
Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738.
干预措施: LY3410738 (Drug)
Dose Escalation Arm B (Monotherapy)
Patients requiring a strong CYP3A4 inhibitor for active management or prevention of a lifethreatening condition, such as an azole administered to prevent invasive fungal infection.
干预措施: LY3410738 (Drug)
Dose Escalation Arm A (Monotherapy)
Patients not requiring a strong cytochrome P450 3A4 (CYP3A4) inhibitor.
干预措施: LY3410738 (Drug)
Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine)
Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738.
干预措施: Venetoclax (Drug)
Dose Escalation Arm C (LY3410738, Venetoclax, and Azacitidine)
Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for active treatment within 7 days of starting LY3410738.
干预措施: Azacitidine (Drug)
Cohort 4
Patients with R/R AML, MDS, CMML or other advanced hematologic malignancy harboring IDH2 mutations.
干预措施: LY3410738 (Drug)
Cohort 2
Patients with R/R AML harboring an IDH1 R132 mutation who have not received a prior IDH inhibitor.
干预措施: LY3410738 (Drug)
Cohort 3
Patients with R/R MDS, chronic myelomonocytic leukemia (CMML) or other advanced hematologic malignancy harboring an IDH1 R132 mutation.
干预措施: LY3410738 (Drug)
Cohort 5
Patients with newly diagnosed AML, R/R AML, or other advanced hematologic malignancy harboring IDH1 and/or IDH2 mutations with no prior venetoclax therapy. Strong CYP3A4 inhibitor allowed but not required.
干预措施: Venetoclax (Drug)
Cohort 5
Patients with newly diagnosed AML, R/R AML, or other advanced hematologic malignancy harboring IDH1 and/or IDH2 mutations with no prior venetoclax therapy. Strong CYP3A4 inhibitor allowed but not required.
干预措施: LY3410738 (Drug)
Cohort 5
Patients with newly diagnosed AML, R/R AML, or other advanced hematologic malignancy harboring IDH1 and/or IDH2 mutations with no prior venetoclax therapy. Strong CYP3A4 inhibitor allowed but not required.
干预措施: Azacitidine (Drug)
结局指标
主要结局
To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)
时间窗: Up to 30 months
For Dose Escalation
To assess the activity of LY3410738 as measured by the overall response rate (ORR) per the Investigator assessment
时间窗: Up to 30 months
For Dose Expansion
次要结局
- To assess the activity of LY3410738 as measured by the overall response rate (ORR) per Investigator assessment(Up to 30 months)
- To assess the activity of LY3410738 by Complete Remission (CR) Rate (CRR) plus partial hematologic recovery (AML patients)(Up to 30 months)
- To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma(Up to 30 months)
- To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points(Up to 30 months)
- To determine the safety profile and tolerability of LY3410738 including acute and chronic toxicities by collecting and evaluating adverse events and treatment emergent adverse events(Up to 30 months)
- To assess the activity of LY3410738 as measured by Best Overall Response (BOR) per Investigator assessment(Up to 30 months)
- To assess the activity of LY3410738 by Duration of Response(Up to 30 months)
- To assess the activity of LY3410738 by Hematologic improvement in patients with MDS(Up to 30 months)
- To determine the safety profile and tolerability of LY3410738 including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events(Up to 30 months)
- To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma.(Up to 30 months)