An Open-Label, Phase 1/1b, Study of ORIC-114 in Patients With Advanced Solid Tumors Harboring an EGFR or HER2 Alteration

ORIC-114 is a brain penetrant, selective, orally bioavailable, irreversible small molecule inhibitor of EGFR and HER2 alterations, including exon 20 insertion mutations.

This is a first-in-human, open-label, single arm, multicenter, dose escalation followed by dose expansion study to establish the recommended phase 2 dose (RP2D) and preliminary antitumor activity of ORIC-114 in patients with advanced solid tumors harboring an EGFR or HER2 alteration who have exhausted available treatment options

The study will begin with dose finding in patients with various solid tumors (Dose Escalation); additional dose expansion cohorts in specific tumor types (Dose Expansion), treatment history, and/or expression of a specific biomarker may be initiated via protocol amendment.

The study will evaluate escalating dose levels of ORIC-114 administered orally, daily in 28-day cycles following an accelerated titration design used for Dose Level 1, after which, escalating doses of ORIC-114 will be administered following an interval 3+3 design.

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented EGFR or HER2 exon 20 insertion 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

  -- NSCLC patients must have received platinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy is contraindicated

• Agreement and ability to undergo pretreatment biopsy
• Measurable disease according to RECIST 1.1
• CNS involvement which is either previously treated and controlled, or 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