NSCLC Harboring NRG1 Fusion, Metastatic Castration-resistant Prostate Cancer
Conditions
Brief summary
This is a Phase II, open-label, 2-arm, multicenter, international study designed to evaluate the efficacy of zenocutuzumab alone or in combination in patients with the following diagnoses: Group A: NRG1+ NSCLC Group B: mCRPC
Detailed description
Study Design: This is an open label (all participants know the identity of the study drug), multicenter (more than one study site), study consisting of 2 parts: Group A (NRG1+ NSCLC): Approximately 50 NRG1+NSCLC patients will be enrolled and will receive zenocutuzumab in combination with afatinib 40 mg orally once daily. Group B (mCRPC): Up to 40 mCRPC patients will be enrolled and will receive zenocutuzumab in combination with the AR targeting agent enzalutamide or abiraterone on which they experienced disease progression immediately before study entry. For the administration of zenocutuzumab in combination in Groups A and B, the Treatment Period will include 2 phases, an initial safety run-in phase, and an expansion phase with an interim efficacy analysis. The study will consist of 4 periods: Screening, Treatment, Safety Follow-up, and Long-term Follow up.
Interventions
anti epidermal growth factor receptor (EGFR)/HER2 agent
second-generation androgen receptor antagonist
androgen synthesis inhibitor
BIOLOGICALMCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Sponsors
Merus N.V.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(Groups A, B) 1. Signed informed consent before initiation of any study procedures. 2. Age ≥ 18 years at signature of informed consent. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Estimated life expectancy of ≥ 12 weeks. 5. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA). 6. 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. 7. 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. 8. Sexually active male and female patients of childbearing potential must agree to use contraceptive measures. Inclusion Criteria: (Group A Only) 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. Inclusion Criteria: (Group B Only) B1. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features. B2. Metastatic disease documented by at least 2 bone lesions on whole body bone scintigraphy, or soft tissue disease documented by computed tomography (CT) scan/magnetic resonance imaging (MRI). B3. Ongoing androgen deprivation with a serum testosterone level ≤ 1.73 nmol/L (≤ 50 ng/dL) at Screening. B4. Current ongoing therapy with a next-generation AR signaling inhibitor (enzalutamide or abiraterone) started at least 90 days before Screening. B5. Progressive disease by PCWG3 criteria B6. Able to swallow oral medications and absence of gastrointestinal conditions (eg, malabsorption, resection) deemed to jeopardize intestinal absorption.
Exclusion criteria
(Groups A, B) 1. 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. 2. Previous exposure to anti-HER3-directed therapies. 3. Known leptomeningeal involvement. 4. Participation in another interventional clinical trial or treatment with any investigational drug within 4 weeks before study entry. 5. Chronic use of high-dose oral corticosteroid therapy (\> 10 mg of prednisone- equivalent a day). 6. Uncontrolled hypertension (systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg) or unstable angina. 7. 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). 8. History of myocardial infarction within 6 months of study entry. 9. 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. 10. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, and clinically significant pulmonary, metabolic, or psychiatric disorders. 11. 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. 12. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of response. | Every 8 weeks until study ends, approximately 2 years | Objective Response Rate (ORR) by local assessment per RECIST v1.1 |
| Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of Prostate-Specific antigen level ≥ 50% (PSA50) response. | Every 4 weeks until study ends, approximately 2 years | PSA50 response rate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by independent central review | Every 8 weeks until study ends, approximately 2 years | Objective Response Rate (ORR) per RECIST v1.1 |
| Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of survival | Continuous through study completion, up to 2 years | Overall Survival (OS) |
| Group A: Evaluate safety and tolerability of zenocutuzumab in combination with afatinib | continuous through study completion, an average of 9 months | Frequency and nature of adverse events (AEs) that are related to treatment as assessed by Common Terminology Criteria for AEs (CTCAE) version 5.0 |
| Group A: Maximum plasma concentration [Cmax] of zenocutuzumab when given in combination with afatinib | 12 months | Cmax |
| Group A: Characterize immunogenicity of zenocutuzumab. | 12 months | Incidence of antidrug antibodies against zenocutuzumab |
| Group A: Area under the concentration versus time curve from time zero to time t [AUC0-t] of zenocutuzumab when given in combination with afatinib | 12 months | AUC0-t |
| Group A: Area under the concentration versus time curve from time zero to time t [AUC0-t] afatinib when given in combination with zenocutuzumab | 12 months | AUC0-t |
| Group A: Area under the concentration versus time curve [AUC0-∞] of afatinib when given in combination with zenocutuzumab | 12 months | AUC0-∞ |
| Group A: Maximum plasma concentration [Cmax] afatinib when given in combination with zenocutuzumab | 12 months | Cmax |
| Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of antitumor activity as assessed by local investigator. | Every 8 weeks until study ends, approximately 2 years | Objective Response Rate (ORR) per RECIST v1.1 |
| Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of Prostate-specific antigen level ≥ 30% (PSA30) response. | Every 4 weeks until study ends, approximately 2 years | PSA30 response rate |
| Group B: Evaluate efficacy zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of survival parameters | Continuous through study completion, up to 2 years | Radiographic Progression Free Survival (rPFS) by local investigator per Prostate Cancer Clinical Trials Working Group 3 Modified Response Evaluation Criteria in Solid Tumors (PCWG3-modified RECIST) v1.1 and Overall Survival (OS) |
| Group B: Evaluate safety and tolerability of zenocutuzumab in combination with enzalutamide or abiraterone acetate. | continuous through study completion, an average of 6 months | Frequency and nature of adverse events (AEs) that are related to treatment as assessed by Common Terminology Criteria for AEs (CTCAE) version 5.0 |
| Group A: Area under the concentration versus time curve [AUC0-∞] of zenocutuzumab when given in combination with afatinib | 12 months | AUC0-∞ |
| Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by local investigator | Every 8 weeks until study ends, approximately 2 years | Objective Response Rate (ORR) per RECIST v1.1 |
Countries
United States
Outcome results
None listed