A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy)

Study Overview
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Brief Summary
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This is a Phase I/II, open-label, multi-center, multi-national, dose escalation, single agent study to assess the safety, tolerability, PK, PD, immunogenicity and anti-tumor activity of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy)

Detailed Description
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Study Design : This open label (all participants know the identity of the study drug), multicenter (more than one study site), first-in-human study consisting of 2 parts. Part 1 is a dose escalation and Part 2 is a dose expansion cohort. Part 1 has been completed. Part 2 new patient populations examined: Group F: Patients with NSCLC with documented NRG1 fusion Group G: Patients with pancreatic adenocarcinoma with documented NRG1 fusion Group H: Patients with any other solid tumor with documented NRG1 fusion For these new patient populations, Part 2 will further characterize the safety and tolerability of the selected dose level of zenocutuzumab (MCLA-128), as well as assessment of CBR, defined as the proportion of patients with a CR, PR or durable SD (SD for at least 12 weeks in duration). For the new patient populations, overall response rate (ORR) and duration of response (DOR) will be described. The study consists of 3 periods: Screening period (up to 28 days prior to the first dose of study drug); Treatment period (treatment cycles of 28 days); and Follow Up period (through 30 days after the last dose and quarterly checks for survival data for up to 2 years). Participants' safety will be monitored throughout the study.

Official Title
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A Phase I/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients With Solid Tumors (eNRGy)

Conditions
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NRG1 Fusion, Solid Tumours Harboring NRG1 Fusion, NSCLC Harboring NRG1 Fusion, Pancreatic Cancer Harboring NRG1 Fusion

Intervention / Treatment
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* Drug: zenocutuzumab (MCLA-128)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least one measurable lesion according to RECIST v1.1 OR evaluable disease for a limited number of patients (up to 10) in Group H; Performance status of ECOG 0 - 2; Estimated life expectancy of at least 12 weeks; Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤Grade 1; Treatment with anti-cancer medication or investigational drugs within the following intervals before the first dose of MCLA-128: >14 days or >5 half-lives prior to study entry, whichever is shorter. >14 days for radiotherapy. Recovery from major surgery or other complication to ≤ Grade 2 or baseline ; Absolute neutrophil count ≥1.5 x 109/L without colony stimulating factor support for at least 7 days prior to screening; Platelets ≥100 x 109/L without transfusion support for at least 7 days prior to screening; Hemoglobin ≥8 g/dL or ≥5 mmol/L; Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN; in cases of metastatic liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed; in cases of antecedents of Gilbert's syndrome when total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN will be allowed; Estimated glomerular filtration rate (GFR) of >30 mL/min Able to provide a tumor biopsy sample (fresh strongly preferred or else archival); Not pregnant or nursing Fertile patients must use effective contraception during and for 6 month after completion of study therapy; Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy or no satisfactory alternative treatment options are available; Locally-advanced unresectable or metastatic solid tumor malignancy with documented NRG1 gene fusion, identified through molecular assays such as next generation sequencing-based assays [DNA or RNA], as routinely performed at CLIA or other similarly-certified laboratories. Exclusion Criteria: Pregnant or lactating; Presence of an active uncontrolled infection or an unexplained fever; Known hypersensitivity to any of the components of MCLA-128; Known HIV, active Hepatitis B without receiving antiviral treatment, or Hepatitis C; patients treated for Hepatitis C and have undetectable viral loads are eligible Known symptomatic or unstable brain metastases; Patients with leptomeningeal metastases Presence of congestive heart failure or Left Ventricular Ejection Fraction<50% or history of significant cardiac disease, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication. Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative intent more than 2 years prior to study entry; Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 2 Pancreatic adenocarcinoma harboring NRG1 fusion<br>Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks. | Drug: zenocutuzumab (MCLA-128)<br>* full length IgG1 bispecific antibody targeting HER2 and HER3<br>* Other names: MCLA-128;|
| Experimental: Part 2 NSCLC cancer harboring NRG1 fusion<br>Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks. | Drug: zenocutuzumab (MCLA-128)<br>* full length IgG1 bispecific antibody targeting HER2 and HER3<br>* Other names: MCLA-128;|
| Experimental: Part 2 Solid tumour (basket) harboring NRG1 fusion<br>Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks. | Drug: zenocutuzumab (MCLA-128)<br>* full length IgG1 bispecific antibody targeting HER2 and HER3<br>* Other names: MCLA-128;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective overall response rate (ORR) as per local investigator's assessment | Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR) | 36 months | 
| Duration of response per RECIST v1.1 as per local Investigator's assessment. | To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed locally | 36 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration [Cmax] | Assess the Cmax of zenocutuzumab (MCLA-128) | 36 months | 
| Volume of distribution [V] | Assess the volume of distribution of zenocutuzumab (MCLA-128) | 36 months | 
| Volume of distribution at steady state [Vss] | Assess the volume of distribution of zenocutuzumab (MCLA-128) at steady state | 36 months | 
| half-life [t1/2] | Assess the half-life of zenocutuzumab (MCLA-128) | 36 months | 
| Area under the concentration versus time curve from time zero to time t [AUC0-t] | Assess the Area under the concentration versus time curve from time zero to time t [AUC0-t] of zenocutuzumab (MCLA-128) | 36 months | 
| area under the concentration versus time curve [AUC0-∞] | Assess the area under the concentration versus time curve [AUC0-∞] of zenocutuzumab (MCLA-128) | 36 months | 
| time to reach maximum concentration [tmax] | Assess the time to reach maximum concentration [tmax] of zenocutuzumab (MCLA-128) | 36 months | 
| Incidence of anti-drug antibodies against zenocutuzumab (MCLA-128) | Assess the Incidence of anti-drug antibodies against zenocutuzumab (MCLA-128) | 36 months | 
| serum titers of anti-drug antibodies | Assess serum titers of anti-drug antibodies | 36 months | 
| Overall response rate as per central review | Assess the anti-tumor response of zenocutuzumab (MCLA-128) by RECIST v1.1 as assessed centrally | 36 months | 
| Clinical Benefit Rate (CBR) of zenocutuzumab (MCLA-128) assessed locally and centrally | CBR assessed as the proportion of patients in whom a complete response (CR) or partial response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 12 weeks) by RECIST v1.1 . | 36 months | 
| Duration of Response as per central review | To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed centrally | 36 months | 
| Time to response per RECIST v1.1. as per local Investigator's assessment. | To assess time to onset of response in patients with NRG1 fusions as assessed locally | 36 months | 
| Time to response per RECIST v1.1. as per central review | To assess time to onset of response in patients with NRG1 fusions as assessed centrally | 36 months | 
| Characterize the safety and tolerability of zenocutuzumab (MCLA-128) | Number of participants with Adverse Events (AE) and Serious Adverse Events (SAE) | 6-12 months | 
| Evaluation of progression free survival (PFS) |  | 36 months | 
| Evaluation of overall survival (OS) |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bispecific Antibody IgG1, HER2, HER3, MCLA-128, Antibodies, Bispecific, Immunologic Factors, NRG1 fusion, NRG1, Solid tumor, Pancreatic cancer, PDAC, Non-small cell lung cancer, NSCLC, zenocutuzumab