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

2015-01

2026-12-31

2026-12-31

250

Study Overview

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

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)

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 examine: * Group F: Patients with NSCLC with documented NRG1 fusion * Group G: Patients with pancreatic adenocarcinoma 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 24 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.

  • Solid Tumours Harboring NRG1 Fusion
  • NSCLC Harboring NRG1 Fusion
  • Pancreatic Cancer Harboring NRG1 Fusion
  • NRG1 Fusion
  • DRUG: zenocutuzumab (MCLA-128)
  • MCLA-128-CL01
  • 2014-003277-42 (EUDRACT_NUMBER Identifier) (EUDRACT_NUMBER: )

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates Results Reporting Dates Study Record Updates

2016-08-16  

N/A  

2025-04-25  

2016-09-22  

N/A  

2025-04-29  

2016-09-23  

N/A  

2025-04  

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/ArmIntervention/Treatment
EXPERIMENTAL: Part 2 Pancreatic adenocarcinoma harboring NRG1 fusion

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)

  • full length IgG1 bispecific antibody targeting HER2 and HER3
EXPERIMENTAL: Part 2 NSCLC cancer harboring NRG1 fusion

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)

  • full length IgG1 bispecific antibody targeting HER2 and HER3
EXPERIMENTAL: Part 2 Solid tumour (basket) harboring NRG1 fusion

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)

  • full length IgG1 bispecific antibody targeting HER2 and HER3
Primary Outcome MeasuresMeasure DescriptionTime Frame
Objective overall response rate (ORR) as per local investigator's assessmentEvaluation 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 locally36 Months
Secondary Outcome MeasuresMeasure DescriptionTime Frame
Overall response rate as per Blinded Independent Central Review (BICR)Assess the anti-tumor response of zenocutuzumab (MCLA-128) by RECIST v1.1 as assessed centrally36 months
Clinical Benefit Rate (CBR) of zenocutuzumab (MCLA-128) assessed locally and BICRCBR 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 24 weeks) by RECIST v1.1 .36 months
Duration of Response as per BICRTo assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed centrally36 months
Time to response per RECIST v1.1. as per local investigator assessmentTo assess time to onset of response in patients with NRG1 fusions as assessed locally36 months
Time to response per RECIST v1.1. as per BICRTo assess time to onset of response in patients with NRG1 fusions as assessed centrally36 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
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 state36 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
half-life [t1/2]Assess the half-life 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 antibodiesAssess serum titers of anti-drug antibodies36 months
Evaluation of progression free survival (PFS)36 months
Evaluation of overall survival (OS)12 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

    Inclusion Criteria:

  • At least one measurable lesion according to RECIST v1.1 OR evaluable disease for a limited number of patients (up to 15) 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:

    • 1. more than 14 days or more than 5 half-lives prior to study entry, whichever is shorter. 2. more than 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 ≥75 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 more than 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 LVEF below 50% on the screening echocardiogram; or history or presence of any significant cardiovascular disease, including unstable angina or myocardial infarction within 12 months prior to screening, congestive heart failure (NYHA Class III or IV), 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 ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

    • PRINCIPAL_INVESTIGATOR: Alison Schram, MD, Memorial Sloan Kettering Medical Center

    Publications

    The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

    General Publications

    • Schram AM, Goto K, Kim DW, Macarulla T, Hollebecque A, O'Reilly EM, Ou SI, Rodon J, Rha SY, Nishino K, Duruisseaux M, Park JO, Neuzillet C, Liu SV, Weinberg BA, Cleary JM, Calvo E, Umemoto K, Nagasaka M, Springfeld C, Bekaii-Saab T, O'Kane GM, Opdam F, Reiss KA, Joe AK, Wasserman E, Stalbovskaya V, Ford J, Adeyemi S, Jain L, Jauhari S, Drilon A; eNRGy Investigators. Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer. N Engl J Med. 2025 Feb 6;392(6):566-576. doi: 10.1056/NEJMoa2405008.
    • Kim DW, Schram AM, Hollebecque A, Nishino K, Macarulla T, Rha SY, Duruisseaux M, Liu SV, Al Hallak MN, Umemoto K, Wesseler C, Cleary JM, Springfeld C, Neuzillet C, Joe A, Jauhari S, Ford J, Goto K. The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions. Future Oncol. 2024;20(16):1057-1067. doi: 10.2217/fon-2023-0824. Epub 2024 Feb 13.
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