PIKture-01: First-in-Human Study of the PI3KαH1047R Mutant-Selective Inhibitor OKI-219 as Monotherapy in Participants With Advanced Solid Tumors and as Part of Combination Therapy in Participants With Advanced Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- OnKure, Inc.
- 入组人数
- 200
- 试验地点
- 67
- 主要终点
- Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of SAEs
研究概览
简要总结
OKI-219-101 is a Phase 1a/1b, open-label, multicenter, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and efficacy of OKI-219 as monotherapy and in combination with other anti-cancer drugs. Phase 1a (Part A) will investigate escalating doses of OKI-219 monotherapy, and Phase 1b will investigate OKI-219 (at a tolerated dose determined in Part A) in combination with fulvestrant (Part B), trastuzumab and tucatinib (Part C), atirmociclib (Part D), and ribociclib and fulvestrant (Part E). Participants will continue to receive study treatment until disease progression, intolerable toxicity, or other study treatment withdrawal criteria are met.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Participants with advanced solid tumors with documented evidence of a PI3KαH1047R mutation in tumor tissue and/or blood (ie, ctDNA).
- •Eastern Cooperative Oncology Group (ECOG) Performance status score of to
- •Life expectancy > 12 weeks for Part A and > 6 months for Parts B, C, D, and E in the opinion of the Investigator.
- •Adequate organ and bone marrow function
- •Have adequate archival tumor tissue sample available or be approved by the Sponsor for enrollment if no tumor sample is available.
- •At least 1 measurable lesion based on RECIST version 1.
- •Additional Cohort-specific key inclusion criteria:
- •Participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer, must have received at least 1 prior line of hormonal therapy and at least 1 prior line of CDK4/6-inhibitor in the advanced or metastatic setting.
- •Participants with HER2+ locally advanced, unresectable or metastatic breast cancer, must have received prior taxane, trastuzumab, pertuzumab, and tucatinib. Prior trastuzumab deruxtecan is allowed but not required.
- •Participants with HER2-low breast cancer must have received prior trastuzumab deruxtecan.
- •Participants with colorectal cancer must have KRAS wild-type disease.
- •Participants with locally advanced, unresectable or metastatic HR+/HER2- breast cancer must have received at least 1 prior line of hormonal therapy in the advanced or metastatic setting and at least 1 prior CDK4/6-inhibitor.
- •Participants with HER2-low breast cancer should have received prior trastuzumab deruxtecan
- •Part C ● Participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer must have received prior taxane, trastuzumab, and pertuzumab unless unavailable in the region or contraindicated. Prior trastuzumab deruxtecan is allowed but not required.
- •● Participants must have HR+/HER2- locally advanced, unresectable or metastatic breast cancer
- •Part E ● Participants must have HR+/HER2- locally advanced, unresectable or metastatic breast cancer.
排除标准
- •Treatment with any investigational product or other anticancer therapy within 28 days or 5 half-lives, whichever is shorter, of the start of treatment
- •Participants with a known KRAS mutation.
- •Participants with a known deleterious mutation in phosphatase and tensin homolog (PTEN) or negative for PTEN protein expression by IHC.
- •Major surgery or wide-field radiation within 28 days or limited field palliative radiation within 7 days prior to the first dose of study drug.
- •Known active central nervous system metastasis, including leptomeningeal disease.
- •Uncontrolled Type 1 or Type 2 diabetes as defined by HbA1C ≥ 8%.
- •Concomitant active malignancy or previous malignancy within 2 years of the time of enrollment.
- •Impaired cardiovascular function or clinically significant cardiovascular disease,
- •History of symptomatic drug-induced pneumonitis.
- •Participants with active HIV, Hepatitis B, and Hepatitis C viral infections
- •Additional Cohort-specific key exclusion criteria:
- •Grade 2 or higher diarrhea at study entry.
- •History of chronic liver disease.
- •● History of interstitial lung disease.
研究组 & 干预措施
Phase 1b: Part D Dose Expansion
OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part E Dose Expansion
OKI-219 + Fulvestrant + Ribociclib Dose Expansion in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Ribociclib (Drug)
Phase 1b: Part B Dose Escalation
OKI-219 + Fulvestrant Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part B Dose Escalation
OKI-219 + Fulvestrant Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Fulvestrant (Drug)
Phase 1b: Part B Dose Optimization
OKI-219 + Fulvestrant Dose Optimization in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1a: Part A Dose Escalation
OKI-219 Monotherapy Dose Escalation in participants with advanced solid tumors with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part B Dose Optimization
OKI-219 + Fulvestrant Dose Optimization in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Fulvestrant (Drug)
Phase 1b: Part C Dose Escalation
OKI-219 + Tucatinib + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part C Dose Escalation
OKI-219 + Tucatinib + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Trastuzumab (Drug)
Phase 1b: Part C Dose Escalation
OKI-219 + Tucatinib + Trastuzumab Dose Escalation in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Tucatinib (Drug)
Phase 1b: Part C Dose Expansion
OKI-219 + Tucatinib + Trastuzumab Dose Expansion in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part C Dose Expansion
OKI-219 + Tucatinib + Trastuzumab Dose Expansion in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Trastuzumab (Drug)
Phase 1b: Part C Dose Expansion
OKI-219 + Tucatinib + Trastuzumab Dose Expansion in participants with HR±/HER2+ locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Tucatinib (Drug)
Phase 1b: Part D Dose Escalation
OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part D Dose Escalation
OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Fulvestrant (Drug)
Phase 1b: Part D Dose Escalation
OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Atirmociclib (Drug)
Phase 1b: Part D Dose Expansion
OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Fulvestrant (Drug)
Phase 1b: Part E Dose Escalation
OKI-219 + Fulvestrant + Ribociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Ribociclib (Drug)
Phase 1b: Part E Dose Expansion
OKI-219 + Fulvestrant + Ribociclib Dose Expansion in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
Phase 1b: Part E Dose Escalation
OKI-219 + Fulvestrant + Ribociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Fulvestrant (Drug)
Phase 1b: Part E Dose Expansion
OKI-219 + Fulvestrant + Ribociclib Dose Expansion in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Fulvestrant (Drug)
Phase 1b: Part D Dose Expansion
OKI-219 + Fulvestrant + Atirmociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: Atirmociclib (Drug)
Phase 1b: Part E Dose Escalation
OKI-219 + Fulvestrant + Ribociclib Dose Escalation in participants with HR+/HER2- locally advanced, unresectable or metastatic breast cancer with the PI3KαH1047R mutation
干预措施: OKI-219 (Drug)
结局指标
主要结局
Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of SAEs
时间窗: Through 30 days after last dose, an average of 1 year
Number and type of SAEs experienced by participants during treatment and follow-up
Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of Grade 2 or greater treatment emergent adverse events
时间窗: Through 30 days after last dose, an average of 1 year
Number of treatment-emergent adverse events (TEAEs) equal or greater than Grade 2 experienced during treatment and follow-up
Assess rate of dose modifications during treatment with OKI-219 as monotherapy or in combination with other anti-cancer therapies
时间窗: Through last study dose, an average of 1 year
rate of dose modifications
Identify maximum tolerated dose (MTD) of OKI-219 in monotherapy
时间窗: Cycle 1 (First 28 days on treatment)
Frequency of participants experiencing dose-limiting toxicities during the first 28-day cycle
Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of SAEs
时间窗: Through 30 days after last dose, an average of 1 year
Number and type of SAEs experienced by participants during treatment and follow-up
Assess safety of OKI-219 as monotherapy or in combination with other anti-cancer therapies: incidence of Grade 2 or greater treatment emergent adverse events
时间窗: Through 30 days after last dose, an average of 1 year
Number of treatment-emergent adverse events (TEAEs) equal or greater than Grade 2 experienced during treatment and follow-up
Assess rate of dose modifications during treatment with OKI-219 as monotherapy or in combination with other anti-cancer therapies
时间窗: Through last study dose, an average of 1 year
rate of dose modifications
次要结局
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: terminal elimination half-life time (t1/2)(Through cycle 6 of treatment (up to 28 weeks))
- To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: objective response rate (ORR)(Up to approximately 36 months)
- To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: clinical benefit rate (CBR)(Up to approximately 36 months)
- Dose optimization only: to estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: progression free survival (PFS)(Up to approximately 36 months)
- To assess the dose-response impact of OKI-219 as monotherapy and in combination with other anti-cancer therapies on PI3KαH1047R ctDNA levels(Through last study dose, an average of 1 year)
- To determine the impact of OKI-219 dosing as monotherapy and in combination with other anti-cancer therapies on blood glucose and insulin(Through last study dose, an average of 1 year)
- To assess the PDx activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies(Through last study dose, an average of 1 year)
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: maximum plasma concentration (Cmax)(Through cycle 6 of treatment (up to 28 weeks))
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: time of maximum plasma concentration (Tmax)(Through cycle 6 of treatment (up to 28 weeks))
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: area under the plasma concentration-time curve (AUC)(Through cycle 6 of treatment (up to 28 weeks))
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: maximum plasma concentration (Cmax)(Through cycle 6 of treatment (up to 28 weeks))
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: time of maximum plasma concentration (Tmax)(Through cycle 6 of treatment (up to 28 weeks))
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: area under the plasma concentration-time curve (AUC)(Through cycle 6 of treatment (up to 28 weeks))
- Assess the plasma PK of OKI-219 following single and multiple doses as monotherapy or in combination with other anti-cancer therapies: terminal elimination half-life time (t1/2)(Through cycle 6 of treatment (up to 28 weeks))
- To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: objective response rate (ORR)(Up to approximately 36 months)
- To estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: clinical benefit rate (CBR)(Up to approximately 36 months)
- Dose optimization only: to estimate the preliminary antitumor activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies: progression free survival (PFS)(Up to approximately 36 months)
- To assess the dose-response impact of OKI-219 as monotherapy and in combination with other anti-cancer therapies on PI3KαH1047R ctDNA levels(Through last study dose, an average of 1 year)
- To determine the impact of OKI-219 dosing as monotherapy and in combination with other anti-cancer therapies on blood glucose and insulin(Through last study dose, an average of 1 year)
- To assess the PDx activity of OKI-219 as monotherapy and in combination with other anti-cancer therapies(Through last study dose, an average of 1 year)