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

Phase 1/2

Recruiting

• Conditions: Solid Tumors

• Registration Number: 2024-512264-66-00
• Lead Sponsor: ORIC Pharmaceuticals Inc.

Brief Summary

Part I: To assess the safety and tolerability of ORIC-114 as a single agent

Part II: To select the optimal ORIC-114 RP2D for Phase 2 expansion cohorts

Part III: To assess the safety and tolerability of ORIC-114 in combination with carboplatin-pemetrexed

Parts I, II, & III: To assess the pharmacokinetics (PK) of ORIC-114

Detailed Description

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).

Study Timeline

• Study Start: 2022-03-10
• Study First Submitted: 2022-03-24
• Study First Submitted QC: 2022-04-06
• Study First Posted: 2022-04-07
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-31
• Last Update Posted: 2025-08-05
• Primary Completion: 2026-09
• Study Completion: 2027-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

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

  1. 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

  2. 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

  3. 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

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Primary Outcome Measures

Name	Time	Method
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

Secondary Outcome Measures

Name	Time	Method
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.		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		• 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.		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.

Trial Locations

Locations (38)

City of Hope; 🇺🇸 Long Beach, California, United States

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Yale Cancer Center; 🇺🇸 New Haven, Connecticut, United States

Georgetown University; 🇺🇸 Washington, District of Columbia, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

NYU Langone Health Perlmutter Cancer Center; 🇺🇸 New York, New York, United States

Duke Cancer Institute; 🇺🇸 Durham, North Carolina, United States

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