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

Phase 1

Recruiting

• Conditions: Solid Tumors
• Interventions: Drug: ORIC-114; Drug: Chemotherapy drug

• Registration Number: NCT05315700
• Lead Sponsor: ORIC Pharmaceuticals

Brief Summary

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

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: 2024-10
• Last Update Submitted: 2024-10-16
• Last Update Posted: 2024-10-18
• Primary Completion: 2025-03
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 350

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

  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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Combination Dose Escalation	Chemotherapy drug	ORIC-114 dosed orally on a continuous once daily dosing regimen in 21-day cycles.
Dose Escalation and Dose Optimization	ORIC-114	ORIC-114 dosed orally on a continuous once daily dosing regimen in 28-day cycles.
Combination Dose Escalation	ORIC-114	ORIC-114 dosed orally on a continuous once daily dosing regimen in 21-day cycles.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (30)

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

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Spartanburg Regional Healthcare System; 🇺🇸 Spartanburg, South Carolina, United States

Next Oncology; 🇺🇸 Fairfax, Virginia, United States

Chris O'Brien Lifehouse; 🇦🇺 Camperdown, Australia

Peter MacCallum Cancer Centre; 🇦🇺 Melbourne, Australia

One Clinical Research, Hollywood Medical Centre; 🇦🇺 Nedlands, Australia

Sydney Adventist Health; 🇦🇺 Sydney, Australia

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

The Chinese University of Hong Kong; 🇭🇰 Shatin, Hong Kong

Chungbuk University Hospital; 🇰🇷 Cheongju-si, Korea, Republic of

National Cancer Center; 🇰🇷 Goyang-si, Korea, Republic of

Catholic University of Korea, St, Vincent Hospital; 🇰🇷 Gyeonggi-do, Korea, Republic of

Gachon University Hospital; 🇰🇷 Incheon, Korea, Republic of

Seoul National Bundang Hospital; 🇰🇷 Seongnam-si, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Medical University of Gdańsk; 🇵🇱 Gdańsk, Poland

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

The Christie NHS Foundation Trust; 🇬🇧 Manchester, England, United Kingdom