Ph 1/2 Study of ORIC-114 in Patients With Advanced Solid Tumors Harboring an EGFR or HER2 Alteration

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: ORIC-114
* Drug: Chemotherapy drug


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Previously received and progressed on or after available standard therapies and for whom additional standard therapy is considered unsuitable or intolerable In Parts I and II NSCLC patients must have received platinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy is contraindicated Part II Dose Optimization Cohort IIA: patients must either be naïve to an EGFR exon 20 targeted agent or only have received prior amivantamab, Cohort IIB: patients must be naïve to a HER2 targeted TKI, Cohort IIC: patients may have received a prior EGFR TKI In Part III, patients may have received any number of prior treatments 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Interval 3+3 dose escalation design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation and Dose Optimization<br>ORIC-114 dosed orally on a continuous daily dosing regimen in 28-day cycles. | Drug: ORIC-114<br>* ORIC-114 oral daily<br>|
| Experimental: Combination Dose Escalation<br>ORIC-114 dosed orally on a continuous dosing regimen in 21-day cycles. | Drug: ORIC-114<br>* ORIC-114 oral daily<br>Drug: Chemotherapy drug<br>* 21 days for up to 4 cycles<br>* Other names: carboplatin and pemetrexed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) | RP2D as determined by interval 3+3 dose escalation design | 12 months | 
| Maximum plasma concentration (Cmax) | PK of ORIC-114 | 28 Days | 
| Time of maximum observed concentration (Tmax) | PK of ORIC-114 | 28 Days | 
| Area under the curve (AUC) | PK of ORIC-114 | 28 Days | 
| Apparent plasma terminal elimination half-life (t1/2) | PK of ORIC-114 | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Duration of response (DOR) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Clinical benefit rate (CBR) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Progression-free survival (PFS) | Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Intracranial response rate (CR and/or PR) | Modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 
| Intracranial progression-free survival (PFS) | Modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR exon 20 insertion mutation, Atypical EGFR mutation, HER2 exon 20 insertion mutation, HER2 amplification/overexpression, NSCLC