Study Evaluating Zenocutuzumab in Patients With or Without Molecularly Defined Cancers

• ClinicalTrials.gov Identifier: NCT05588609
• Recruitment Status: Recruiting
• First Posted: October 20, 2022
• Last Update Posted: May 15, 2023
• Sponsor: Merus N.V.
• Information provided by (Responsible Party): Merus N.V.

Study Description

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

Condition or disease	Intervention/treatment	Phase
NSCLC Harboring NRG1 Fusion; Metastatic Castration-resistant Prostate Cancer	Drug: Afatinib Oral Tablet; Drug: Enzalutamide Pill; Drug: Abiraterone acetate tablets; Biological: MCLA-128	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study Evaluating Activity of Zenocutuzumab (MCLA-128) in Patients With or Without Molecularly Defined Cancers
• Actual Study Start Date: November 17, 2022
• Estimated Primary Completion Date: October 2025
• Estimated Study Completion Date: March 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: NSCLC harboring NRG1+ fusion; Participants will receive intravenous infusion of 750 mg of zenocutuzumab once every 2 weeks in combination with afatinib 40 mg orally once daily.	Drug: Afatinib Oral Tablet; anti epidermal growth factor receptor (EGFR)/HER2 agent; Other Names: GILOTRIF®; GIOTRIF®; Biological: MCLA-128; full length IgG1 bispecific antibody targeting HER2 and HER3; Other Name: Zenocutuzumab
Experimental: Part 1: mCRPC; Participants will receive intravenous infusion of 750 mg of zenocutuzumab once every 2 weeks in combination with the AR targeting agent they experienced disease progression on prior to study entry: enzalutamide 160 mg orally once daily or abiraterone 1000 mg orally once daily with prednisone 5 mg orally twice daily.	Drug: Enzalutamide Pill; second-generation androgen receptor antagonist; Other Name: XTANDI®; Drug: Abiraterone acetate tablets; androgen synthesis inhibitor; Other Name: ZYTIGA®; Biological: MCLA-128; full length IgG1 bispecific antibody targeting HER2 and HER3; Other Name: Zenocutuzumab
Experimental: Part 2: NSCLC harboring NRG1+ fusion; Participants will receive intravenous infusion of 750 mg of zenocutuzumab once every 2 weeks in combination with afatinib 40 mg orally once daily.	Drug: Afatinib Oral Tablet; anti epidermal growth factor receptor (EGFR)/HER2 agent; Other Names: GILOTRIF®; GIOTRIF®; Biological: MCLA-128; full length IgG1 bispecific antibody targeting HER2 and HER3; Other Name: Zenocutuzumab
Experimental: Part 2: mCRPC; Participants will receive intravenous infusion of 750 mg of zenocutuzumab once every 2 weeks in combination with the AR targeting agent they experienced disease progression on prior to study entry: enzalutamide 160 mg orally once daily or abiraterone 1000 mg orally once daily with prednisone 5 mg orally twice daily	Drug: Enzalutamide Pill; second-generation androgen receptor antagonist; Other Name: XTANDI®; Drug: Abiraterone acetate tablets; androgen synthesis inhibitor; Other Name: ZYTIGA®; Biological: MCLA-128; full length IgG1 bispecific antibody targeting HER2 and HER3; Other Name: Zenocutuzumab

Outcome Measures

Primary Outcome Measures :

1. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of response. [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Objective Response Rate (ORR) by local assessment per RECIST v1.1
2. Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of Prostate-Specific antigen level ≥ 50% (PSA50) response. [ Time Frame: Every 4 weeks until study ends, approximately 2 years ]
   PSA50 response rate

Secondary Outcome Measures :

1. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by local investigator [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Objective Response Rate (ORR) per RECIST v1.1
2. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by local investigator [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Duration of Response (DOR) per RECIST v1.1
3. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by local investigator [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Time to Response (TTR) per RECIST v1.1
4. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by independent central review [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Objective Response Rate (ORR) per RECIST v1.1
5. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by independent central review [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Duration of Response (DOR) per RECIST v1.1
6. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by independent central review [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Time to Response (TTR) per RECIST v1.1
7. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by independent central review [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Progression-free Survival (PFS) per RECIST v1.1
8. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of antitumor activity as assessed by local investigator [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
   Progression-free Survival (PFS) per RECIST v1.1
9. Group A: Evaluate efficacy of zenocutuzumab in combination with afatinib in terms of survival [ Time Frame: Continuous through study completion, up to 2 years ]
   Overall Survival (OS)
10. Group A: Evaluate safety and tolerability of zenocutuzumab in combination with afatinib [ Time Frame: 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
11. Group A: Maximum plasma concentration [Cmax] of zenocutuzumab when given in combination with afatinib [ Time Frame: 12 months ]
    Cmax
12. Group A: Characterize immunogenicity of zenocutuzumab. [ Time Frame: 12 months ]
    Incidence of antidrug antibodies against zenocutuzumab
13. 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 [ Time Frame: 12 months ]
    AUC0-t
14. Group A: Area under the concentration versus time curve [AUC0-∞] of zenocutuzumab when given in combination with afatinib [ Time Frame: 12 months ]
    AUC0-∞
15. Group A: Area under the concentration versus time curve [AUC0-∞] of afatinib when given in combination with zenocutuzumab [ Time Frame: 12 months ]
    AUC0-∞
16. Group A: Area under the concentration versus time curve from time zero to time t [AUC0-t] afatinib when given in combination with zenocutuzumab [ Time Frame: 12 months ]
    AUC0-t
17. Group A: Maximum plasma concentration [Cmax] afatinib when given in combination with zenocutuzumab [ Time Frame: 12 months ]
    Cmax
18. Group A: Characterize immunogenicity of zenocutuzumab. [ Time Frame: 12 months ]
    Serum titers of antidrug antibodies against zenocutuzumab
19. Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of antitumor activity as assessed by local investigator. [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
    Objective Response Rate (ORR) per RECIST v1.1
20. Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of Prostate-specific antigen level ≥ 30% (PSA30) response. [ Time Frame: Every 4 weeks until study ends, approximately 2 years ]
    PSA30 response rate
21. Group B: Evaluate efficacy zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of survival parameters [ Time Frame: 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)
22. Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of antitumor activity as assessed by local investigator. [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
    Duration of Response (DOR) per PCWG3-modified RECIST v1.1
23. Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of antitumor activity as assessed by local investigator. [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
    Time to Response (TTR) per PCWG3-modified RECIST v1.1
24. Group B: Evaluate efficacy of zenocutuzumab in combination with enzalutamide or abiraterone acetate in terms of Prostate-specific antigen level ≥ 30% (PSA30) response. [ Time Frame: Every 8 weeks until study ends, approximately 2 years ]
    time to Prostate-specific antigen (PSA) progression per PCWG3-modified RECIST v1.1
25. Group B: Evaluate safety and tolerability of zenocutuzumab in combination with enzalutamide or abiraterone acetate. [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Exclusion Criteria: (Group A) A1. Patients previously exposed to afatinib. A2. History of interstitial lung disease (ILD), ILD-like adverse reactions (such as lung infiltration, pneumonitis, acute respiratory distress syndrome, allergic alveolitis), or radiation pneumonia requiring steroid therapy.

Exclusion Criteria: (Group B) B1. More than 2 lines of a second-generation hormonal agent for metastatic disease.

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.

Contacts and Locations

Contacts

Contact: Shekeab Jauhari, MD; 617-401-4499; USenquiries@merus.nl

Locations

United States, California

The Oncology Institute of Hope & Innovation; Recruiting

Whittier, California, United States, 90603

Contact: Study Coordinator 562-693-4777

Principal Investigator: Paul La Porte, MD

United States, Florida

Florida Cancer Specialists; Recruiting

Lake Mary, Florida, United States, 32746

Contact: Study Coordinator 407-804-6133

Principal Investigator: Alexander Philipovskiy, MD, PhD

United States, Maryland

The Center for Cancer and Blood Disorders; Recruiting

Bethesda, Maryland, United States, 20817

Contact: Study Coordinator

Contact 301-571-2016

Principal Investigator: Mark Goldstein, MD

United States, Ohio

TriHealth Cancer Institute; Recruiting

Cincinnati, Ohio, United States, 45220

Contact: Study Coordinator 513-479-3402

Principal Investigator: Benjamin Kuritzky, MD

University Hospitals - Seidman Cancer Center; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Study Coordinator 216-844-5393

Principal Investigator: Pedro Barata, MD

United States, Utah

Utah Cancer Specialists; Recruiting

Salt Lake City, Utah, United States, 84106

Contact: Study Coordinator

Contact 801-281-6864

Principal Investigator: Stephan D Kendall, MD

United States, Washington

Northwest Medical Specialties; Recruiting

Tacoma, Washington, United States, 98405

Contact: Study Coordinator 253-428-8700

Principal Investigator: Li Zhang, MD

Sponsors and Collaborators

Merus N.V.

More Information

• Responsible Party: Merus N.V.
• ClinicalTrials.gov Identifier: NCT05588609
• Other Study ID Numbers: MCLA-128-CL03
• First Posted: October 20, 2022
• Last Update Posted: May 15, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Abiraterone Acetate; Afatinib; Antineoplastic Agents; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 Enzyme Inhibitors; Protein Kinase Inhibitors