Study Evaluating Zenocutuzumab in Patients With or Without Molecularly Defined Cancers

Who can take part

• Signed informed consent before initiation of any study procedures
• Age ≥ 18 years at signature of informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Estimated life expectancy of ≥ 12 weeks
• Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)
• Adequate organ function:; Absolute neutrophil count ≥ 1.5 × 109/L; Hemoglobin ≥ 9 g/dL; Platelets ≥ 100 × 109/L; Serum calcium within normal ranges (or corrected with supplements); Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN) (in case of liver involvement by malignancy, ALT/AST ≤ 5 × ULN will be allowed); Total bilirubin ≤ 1.5 × ULN (in case of Gilbert disease, total bilirubin ≤ 3 × ULN will be allowed); Estimated glomerular filtration rate of > 30 mL/min based on the Cockroft-Gault formula (Appendix D); Serum albumin > 3.0 g/dL
• Availability of a representative tumor specimen, either a formalin-fixed paraffin embedded (FFPE) de novo (ie, obtained up to 2 months before signing of the informed consent form [ICF]) or an FFPE archival tumor sample, preferably collected within 2 years of the start of study treatment. A fresh FFPE sample is preferred
• Sexually active male and female patients of childbearing potential must agree to use contraceptive measures
• A1. Have histologically confirmed locally advanced, unresectable, or metastatic NSCLC harboring an NRG1 gene fusion detected by DNA- or RNA-based next generation sequencing in a tumor sample or in plasma-cell free DNA. A2. Have received prior standard therapy appropriate for the tumor type and disease or must be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy in the opinion of the Investigator or have no satisfactory available treatment options. A3. Have at least 1 measurable lesion per RECIST v1.1. A4. Able to swallow oral medications and absence of gastrointestinal conditions (eg, malabsorption, resection) deemed to jeopardize intestinal absorption

Who cannot take part

• Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 14 days of study entry
• Previous exposure to anti-HER3-directed therapies
• Participation in another interventional clinical trial or treatment with any investigational drug within 4 weeks before study entry
• Chronic use of high-dose oral corticosteroid therapy (> 10 mg of prednisone- equivalent a day)
• History of prior or concomitant malignancies (other than excised nonmelanoma skin cancer, cured in situ cervical carcinoma, or low-grade Ta or T1 urothelial carcinoma of the bladder that has undergone potentially curative therapy) within 3 years of study entry
• Patients with the following known infectious diseases:; Known active hepatitis B infection (hepatitis B surface antigen [HBsAg] positive) without receiving antiviral treatment; Known positive test for hepatitis C virus (HCV) RNA
• B2. More than 2 lines of systemic chemotherapy for metastatic disease. B3. Patients with only nonmeasurable lesions other than bone metastasis (eg, pleural effusion, ascites, other visceral locations). B4. A history of seizure or any condition predisposing patient to seizure within 12 months before study treatment, including history of unexplained loss of consciousness or transient ischemic attack, for patients receiving enzalutamide
• Uncontrolled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) or unstable angina
• History of congestive heart failure Class II-IV by New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment (except atrial fibrillation, or paroxysmal supraventricular tachycardia)
• History of myocardial infarction within 6 months of study entry
• Current serious illness or medical conditions including, but not limited to uncontrolled active infection, and clinically significant pulmonary, metabolic, or psychiatric disorders
• Known human immunodeficiency virus (HIV)-positive patients unless the CD4+ count is ≥ 300/μL, viral load is undetectable, and the patient is currently receiving highly active antiretroviral therapy
• Known leptomeningeal involvement