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

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

• Status: Active, not recruiting
• Conditions: NSCLC Harboring NRG1 Fusion; Solid Tumours Harboring NRG1 Fusion; Pancreatic Cancer Harboring NRG1 Fusion; NRG1 Fusion
• Intervention / Treatment: Drug: zenocutuzumab (MCLA-128)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria
    • Salzburger Universitätsklinikum
• Belgium
  • Leuven, Belgium
    • UZ Leuven
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G2M9
      • Princess MargaretCancer Centre
• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet
• France
  • Lyon, France
    • Centre Léon Bérard
  • Lyon, France
    • Hospital Louis Pradel, FR
  • Paris, France
    • Hopital Cochin
  • Paris, France, 94805
    • Institut Gustave Roussy
  • Paris, France
    • Hopital Curie
• Germany
  • Hamburg, Germany
    • Asklepios Kliniken Hamburg GmbH
  • Hamburg, Germany
    • Asklepios Klinik Altona
  • Heidelberg, Germany
    • Deutsches Krebsforschungszentrum
• Israel
  • Jerusalem, Israel
    • Shaare Zedek Medical Center
  • Tel Aviv, Israel
    • Sheba Medical Center
• Italy
  • Milan, Italy, 20162
    • Niguarda Cancer Centre
  • Milano, Italy
    • Ospedale San Raffaele
  • Roma, Italy
    • Istituti Fisioterapici Ospitalieri
• Japan
  • Chuo-Ku, Japan
    • National Cancer Center Hospital
  • Kawasaki, Japan
    • St. Marianna University School of Medicine Hospital
  • Osaka, Japan
    • Osaka International Cancer Institute
  • Tokyo, Japan
    • National Cancer Center East
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Seoul National University College of Medicine
  • Seoul, Korea, Republic of
    • Severance Hospital- Yonsei Cancer Center
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam Medical Center
  • Amsterdam, Netherlands, 1066 CX
    • NKI
  • Nijmegen, Netherlands
    • Radboud University Medical Center
• Norway
  • Oslo, Norway, 0379
    • university Hospital Oslo
• Singapore
  • Singapore, Singapore
    • National Cancer Centre of Singapore PTE LTD
• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron Institute of Oncology (VHIO)
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain, 28040
    • START Hospital Fundación Jiménez Diaz
  • Madrid, Spain, 28050
    • START Hospital Universitario Madrid Sanchinarro
  • Pamplona, Spain
    • Clinica Universidad de Navarra
  • Valencia, Spain
    • Instituto Valenciano Oncologia
• Sweden
  • Solna, Sweden
    • Karolinska Universitetssjukhuset
• Taiwan
  • Taipei, Taiwan
    • National Taiwan University Hospital 7
• United Kingdom
  • London, United Kingdom
    • Sarah Cannon Research Institute
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • Mayo Clinic
  • California
    • Cerritos, California, United States
      • The Oncology Institute of Hope and Innovation
    • Irvine, California, United States
      • University of California Irvine
    • Palo Alto, California, United States
      • Stanford University
    • San Diego, California, United States
      • Sharp Memorial Hospital
  • District of Columbia
    • District of columbia, District of Columbia, United States
      • Georgetown University
  • Florida
    • Hollywood, Florida, United States
      • Memorial Cancer Institute
    • Jacksonville, Florida, United States
      • Mayo Clinic
    • Jacksonville, Florida, United States
      • Cancer Specialists of North Florida
  • Georgia
    • Atlanta, Georgia, United States
      • Emory Winship Cancer Institute
  • Illinois
    • Rolling Meadows, Illinois, United States
      • Northwest Oncology & Hematology
  • Massachusetts
    • Boston, Massachusetts, United States
      • Dana Farber Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States
      • Mayo Clinic
  • Montana
    • Billings, Montana, United States
      • Billings Clinic Cancer Center
    • Butte, Montana, United States
      • St. James Healthcare
  • New York
    • New York, New York, United States
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • University of Pennsylvania
  • South Dakota
    • Sioux Falls, South Dakota, United States
      • Averra Medical Group
  • Texas
    • Houston, Texas, United States
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States
      • Utah Cancer Specialists
    • Salt Lake City, Utah, United States
      • Huntsman Cancer Institute
  • Virginia
    • Fredericksburg, Virginia, United States
      • Hematology-Oncology Specialist of Fredericksburg
  • Washington
    • Seattle, Washington, United States
      • Virginia Mason Hospital & Seattle Medical Center
    • Spokane, Washington, United States
      • Hematology Oncology Associates
    • Tacoma, Washington, United States
      • Northwest Medical Specialties

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / 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; Other Names: bispecific; MCLA-128
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; Other Names: bispecific; MCLA-128
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; Other Names: bispecific; MCLA-128

What is the study measuring?

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
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
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 centrally	36 months
Clinical Benefit Rate (CBR) of zenocutuzumab (MCLA-128) assessed locally and BICR	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 24 weeks) by RECIST v1.1 .	36 months
Duration of Response as per BICR	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 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 BICR	To assess time to onset of response in patients with NRG1 fusions as assessed centrally	36 months

Collaborators and Investigators

• Sponsor: Partner Therapeutics, Inc.
• Investigators: Principal Investigator: Alison Schram, MD, Memorial Sloan Kettering Medical Center

Publications and helpful links

Helpful Links

• For more information about MCLA-128 and the MCLA-128-CL01 study

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 16, 2016
• First Submitted That Met QC Criteria: September 22, 2016
• First Posted (Estimated): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): April 29, 2025
• Last Update Submitted That Met QC Criteria: April 25, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; Non-small cell lung cancer; Solid tumor; Pancreatic cancer; Immunologic Factors; PDAC; Bispecific Antibody IgG1, HER2, HER3; MCLA-128; Antibodies, Bispecific; NRG1 fusion; zenocutuzumab
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Antibodies, Bispecific; Immunoglobulin G
• Other Study ID Numbers: MCLA-128-CL01; 2014-003277-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No