An Open-Label, Phase 1/2 Study of ORIC-114 as a Single Agent or in Combination With Chemotherapy, in Patients With Advanced Solid Tumors Harboring an EGFR or HER2 Alteration
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 350
- 试验地点
- 65
- 主要终点
- Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
The purpose of this study is to establish the recommended Phase 2 dose (RP2D) and/or maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of ORIC-114 as a Single Agent or in Combination with Chemotherapy when administered to patients with advanced solid tumors harboring an EGFR or HER2 alteration.
详细描述
ORIC-114 is a brain penetrant, selective, orally bioavailable, irreversible small molecule inhibitor designed to target EGFR and HER2 alterations, making it a promising therapeutic candidate for development in patients whose tumors harbor these alterations, including those with CNS metastases.
This is a first-in-human, open-label, single arm, multicenter, dose escalation study of ORIC-114 as a single agent (Part I), followed by dose optimization (Part II) to establish the recommended phase 2 dose (RP2D) and antitumor activity of ORIC-114 in patients with advanced solid tumors harboring an EGFR or HER2 alteration who have exhausted available treatment options. After the optimal RP2D has been determined, Phase 2 will be initiated via protocol amendment to add one or more expansion cohorts of patients with specific tumor types, treatment history, and/or expression of a specific biomarker to evaluate the antitumor activity of ORIC-114.
After completion of Part I dose escalation, Part III, a dose escalation study of ORIC-114 in combination with chemotherapy (carboplatin-pemetrexed) may be initiated to establish the RP2D and/or MTD and antitumor activity for the combination (US sites only).
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
- •Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented EGFR or HER2 exon 20 insertion mutation or atypical EGFR mutation as determined by any nucleic acid-based diagnostic testing method, or HER2 amplification/overexpression as determined by an immunohistochemistry (IHC) or an in situ hybridization (ISH) test
- •Part I Dose Escalation (CLOSED) Any solid tumor with
- •EGFR exon 20 insertion mutation
- •HER2 exon 20 insertion mutation
- •Atypical EGFR mutations (NSCLC only) (Appendix 8)
- •HER2 amplification or overexpression (HER2+)
- •Previously received and progressed on or after available standard therapies and for whom additional standard therapy is considered unsuitable or intolerable
- •Part I Extension (ONGOING)
- •Cohort IA: Patients with HER2+ breast cancer previously received and progressed on or after available standard therapies and for whom additional standard therapy is considered unsuitable or intolerable
- •Cohort IB: NSCLC patients with EGFR exon 20 insertion mutation previously treated with chemotherapy and amivantamab
- •Cohort IC: Treatment-naïve NSCLC patients with EGFR exon 20 insertion mutation
- •Cohort ID: Treatment-naïve NSCLC patients with EGFR atypical mutations
- •Part II Dose Optimization (ONGOING): NSCLC patients with
- •Cohort IIA: EGFR exon 20 insertion mutation, patients must have received platinum-based chemotherapy or other chemotherapy regimen if platinum- based chemotherapy was contraindicated. Additionally, patients must be naïve to an EGFR exon 20 targeted agent, ie, must have declined or be ineligible for all available exon 20 targeted therapies with proven benefit
- •Cohort IIB: HER2 exon 20 insertion mutation, patients must have received platinum-based chemotherapy or other chemotherapy regimen if platinum- based chemotherapy was contraindicated. Additionally, patients must be naïve to a HER2 exon 20 targeted TKI
- •Cohort IIC: Atypical EGFR mutation, patients may have received a prior EGFR TKI
- •Agreement and ability to undergo pretreatment biopsy
- •Measurable disease according to RECIST 1.1
- •CNS involvement, which is either previously treated and controlled, or untreated and asymptomatic
- •ECOG performance status of 0 or 1
- •Adequate organ function
排除标准
- •Known EGFR T790M mutation
- •Leptomeningeal disease and spinal cord compression
- •-- Except if LMD has been reported radiographically on baseline MRI, but is not suspected clinically by the Investigator; the subject must be free of neurological symptoms of LMD
- •History of class III or IV congestive heart failure or severe non-ischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months
- •Past medical history of interstitial lung disease (ILD), drug induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
- •Known, symptomatic human immunodeficiency virus (HIV) infection
- •Known active infection requiring treatment or history of hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients positive for HBsAg but normal HBV DNA level are allowed.
- •Active gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes
- •Any other concurrent serious uncontrolled medical, psychological, or addictive conditions
研究组 & 干预措施
Dose Escalation and Dose Optimization
ORIC-114 dosed orally on a continuous once daily dosing regimen in 28-day cycles.
干预措施: ORIC-114 (Drug)
Combination Dose Escalation
ORIC-114 dosed orally on a continuous once daily dosing regimen in 21-day cycles.
干预措施: Chemotherapy drug (Drug)
Combination Dose Escalation
ORIC-114 dosed orally on a continuous once daily dosing regimen in 21-day cycles.
干预措施: ORIC-114 (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D)
时间窗: 12 months
RP2D as determined by interval 3+3 dose escalation design
Maximum plasma concentration (Cmax)
时间窗: 28 Days
PK of ORIC-114
Time of maximum observed concentration (Tmax)
时间窗: 28 Days
PK of ORIC-114
Area under the curve (AUC)
时间窗: 28 Days
PK of ORIC-114
Apparent plasma terminal elimination half-life (t1/2)
时间窗: 28 Days
PK of ORIC-114
Part I: Provisional RP2Ds and/or MTD of ORIC-114.
Part I: Provisional RP2Ds and/or MTD of ORIC-114.
Part II: Optimal ORIC-114 RP2D.
Part II: Optimal ORIC-114 RP2D.
Part III: RP2D and/or MTD of ORIC-114 in combination with carboplatin-pemetrexed
Part III: RP2D and/or MTD of ORIC-114 in combination with carboplatin-pemetrexed
Incidence of adverse events, vital signs, evaluation of clinical laboratory results, 12-lead electrocardiogram (ECG), and other clinical assessments.
Incidence of adverse events, vital signs, evaluation of clinical laboratory results, 12-lead electrocardiogram (ECG), and other clinical assessments.
PK profile as measured by Tmax, Cmax, Clast, AUClast, AUCtau, AUCinf, Kel, t1/2, CL/F, Vz/F, Rac(Cmax), and Rac(AUC) as appropriate
PK profile as measured by Tmax, Cmax, Clast, AUClast, AUCtau, AUCinf, Kel, t1/2, CL/F, Vz/F, Rac(Cmax), and Rac(AUC) as appropriate
次要结局
- Objective response rate (ORR)(36 months)
- Duration of response (DOR)(36 months)
- Clinical benefit rate (CBR)(36 months)
- Progression-free survival (PFS)(36 months)
- Intracranial response rate (CR and/or PR)(36 months)
- Intracranial progression-free survival (PFS)(36 months)
- Assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 • Objective response rate (ORR) (complete response [CR] or partial response [PR]), measured as changes in target and non-target lesions relative to baseline every 8 weeks • Duration of response (DOR), defined as time of first response to first documentation of radiographic progression or death, whichever occurs first.
- • Clinical benefit rate (CBR) (CR, PR, or stable disease [SD] ≥6 months) • Progression-free survival (PFS), defined as time from first dose of ORIC-114 to first documentation of radiographic progression or death, whichever occurs first
- Intracranial response will be assessed according to modified RECIST 1.1 and/or RANO-BM • Intracranial response rate (CR or PR) measured as changes in target and non-target CNS lesions • Intracranial PFS, defined as time from first dose of ORIC-114 to first documentation of radiographic progression in the brain or death, whichever occurs first.