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

• ClinicalTrials.gov Identifier: NCT02912949
• Recruitment Status: Recruiting
• First Posted: September 23, 2016
• Last Update Posted: July 1, 2020
• Sponsor: Merus N.V.
• Information provided by (Responsible Party): Merus N.V.

Tracking Information

• First Submitted Date: August 16, 2016
• First Posted Date: September 23, 2016
• Last Update Posted Date: July 1, 2020
• Actual Study Start Date: January 2015
• Estimated Primary Completion Date: September 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 21, 2019)

• Characterize the safety and tolerability of zenocutuzumab (MCLA-128) [ Time Frame: 6-12 months ]
  Number of participants with Adverse Events (AE) and Serious Adverse Events (SAE)
• Objective overall response rate (ORR) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)
• Duration of response (DOR) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)
• Correlation of anti-tumor activity and biomarkers [ Time Frame: 36 months ]
  Evaluate the correlation between the anti-tumor activity of zenocutuzumab (MCLA-128) and HER2
• Correlation of anti-tumor activity and biomarkers [ Time Frame: 36 months ]
  Evaluate the correlation between the anti-tumor activity of zenocutuzumab (MCLA-128) and HER3
• Correlation of anti-tumor activity and biomarkers [ Time Frame: 36 months ]
  Evaluate the correlation between the anti-tumor activity of zenocutuzumab (MCLA-128) and Heregulin
• Correlation of anti-tumor activity and biomarkers [ Time Frame: 36 months ]
  Evaluate the correlation between the anti-tumor activity of zenocutuzumab (MCLA-128) and disease related biomarkers (i.e. CA19-9)

Original Primary Outcome Measures (submitted: September 22, 2016)

• Number of participants with Dose Limiting Toxicities (DLT) [ Time Frame: 6-12 months ]
  Evaluation of number of participants with treatment related toxicities observed during a step in the dose escalation.
• Number of participants with Treatment-Related Adverse Events (AE) [ Time Frame: 6-12 months ]
  Evaluation of number of participants with abnormal laboratory values and/or AE that are related to treatment as assessed by CTCAE version 4.03

Current Secondary Outcome Measures (submitted: October 21, 2019)

• Incidence of AE [safety and tolerability] [ Time Frame: 36 months ]
  Evaluate severity, frequency and duration of Adverse events
• Maximum plasma concentration [Cmax] [ Time Frame: 36 months ]
  Assess the Cmax of zenocutuzumab (MCLA-128)
• Volume of distribution [V] [ Time Frame: 36 months ]
  Assess the volume of distribution of zenocutuzumab (MCLA-128)
• Volume of distribution at steady state [Vss] [ Time Frame: 36 months ]
  Assess the volume of distribution of zenocutuzumab (MCLA-128) at steady state
• half-life [t1/2] [ Time Frame: 36 months ]
  Assess the half-life of zenocutuzumab (MCLA-128)
• Area under the concentration versus time curve from time zero to time t [AUC0-t] [ Time Frame: 36 months ]
  Assess the Area under the concentration versus time curve from time zero to time t [AUC0-t] of zenocutuzumab (MCLA-128)
• area under the concentration versus time curve [AUC0-∞] [ Time Frame: 36 months ]
  Assess the area under the concentration versus time curve [AUC0-∞] of zenocutuzumab (MCLA-128)
• time to reach maximum concentration [tmax] [ Time Frame: 36 months ]
  Assess the time to reach maximum concentration [tmax] of zenocutuzumab (MCLA-128)
• Incidence of anti-drug antibodies against zenocutuzumab (MCLA-128) [ Time Frame: 36 months ]
  Assess the Incidence of anti-drug antibodies against zenocutuzumab (MCLA-128)
• serum titers of anti-drug antibodies [ Time Frame: 36 months ]
  Assess serum titers of anti-drug antibodies
• Anti-tumor response of zenocutuzumab (MCLA-128) by RECIST v1.1 [ Time Frame: 36 months ]
  Assess the anti-tumor response of zenocutuzumab (MCLA-128) by RECIST v1.1
• Clinical Benefit Rate (CBR) of zenocutuzumab (MCLA-128) [ Time Frame: 36 months ]
  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 .
• Progression Free Survival (PFS) and survival [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining objective progression-free survival (PFS) and/or survival

Original Secondary Outcome Measures (submitted: September 22, 2016)

• Incidence of Treatment Related AE [safety and tolerability] [ Time Frame: 36 months ]
  Frequency of Treatment Related AEs or SAEs
• Maximum plasma concentration [Cmax] [ Time Frame: 36 months ]
  Maximum plasma concentration [Cmax] as measured from all individual plasma concentrations
• Volume of distribution [V] [ Time Frame: 36 months ]
  volume of distribution [V]
• Volume of distribution at steady state [Vss] [ Time Frame: 36 months ]
  volume of distribution at steady state [Vss]
• half-life [t1/2] [ Time Frame: 36 months ]
  half-life [t1/2]
• Area under the concentration versus time curve from time zero to time t [AUC0-t] [ Time Frame: 36 months ]
  area under the concentration versus time curve from time zero to time t [AUC0-t]
• area under the concentration versus time curve [AUC0-∞] [ Time Frame: 36 months ]
  area under the concentration versus time curve [AUC0-∞]
• time to reach maximum concentration [tmax] [ Time Frame: 36 months ]
  time to reach maximum concentration [tmax]
• Incidence of anti-drug antibodies against MCLA-128 [ Time Frame: 36 months ]
  Number of participants with anti-drug antibodies against MCLA-128
• serum titers of anti-drug antibodies [ Time Frame: 36 months ]
  serum titers of anti-drug antibodies against MCLA-128
• Anti-tumor response of MCLA-128 by RECIST v1.1 [ Time Frame: 36 months ]
  Anti-tumor response as measured by RECIST v1.1
• Clinical benefit rate of MCLA-128 [ Time Frame: 36 months ]
  Clinical benefit rate 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 .
• Objective overall response rate (ORR) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)
• Duration of response (DOR) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)
• Progression Free Survival (PFS) and survival [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining objective progression-free survival (PFS) and/or survival

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion
• Official Title: A Phase I/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients With Solid Tumors
• Brief Summary: 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.

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 examined:

• Group F: Patients with NSCLC with documented NRG1 fusion
• Group G: Patients with pancreatic cancer 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.

Number of Sites:

Up to 40 sites are estimated to be involved during Parts 1 and 2 of the study. Additional sites may be added to ensure there is an acceptable enrollment rate or to replace non-enrolling/withdrawn sites.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumours Harboring NRG1 Fusion
• NSCLC Harboring NRG1 Fusion
• Pancreatic Cancer Harboring NRG1 Fusion
• NRG1 Fusion

Intervention

Drug: zenocutuzumab (MCLA-128)

full length IgG1 bispecific antibody targeting HER2 and HER3

Other Name: bispecific

Study Arms

• Experimental: Part 2 Pancreatic 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.
  Intervention: Drug: zenocutuzumab (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.
  Intervention: Drug: zenocutuzumab (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.
  Intervention: Drug: zenocutuzumab (MCLA-128)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 13, 2019): 250
• Original Estimated Enrollment (submitted: September 22, 2016): 120
• Estimated Study Completion Date: September 2022
• Estimated Primary Completion Date: September 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 or 1;
• 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. >14 days or >5 half-lives prior to study entry, whichever is shorter.
  2. >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;
• Platelets ≥100 x 109/L;
• Hemoglobin ≥8 g/dL or ≥2.2 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;
• Locally-advanced unresectable or metastatic solid tumor malignancy with documented NRG1 gene fusion, identified through molecular assays such as PCR, next generation sequencing-based assays [DNA or RNA], or FISH 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Merus Inquiries; 1-833-NRG-1234

• Listed Location Countries: Canada, France, Italy, Korea, Republic of, Netherlands, Norway, Singapore, Spain, Taiwan, United States
• Removed Location Countries: Israel, Portugal

Administrative Information

• NCT Number: NCT02912949
• Other Study ID Numbers: MCLA-128-CL01; 2014-003277-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Merus N.V.
• Study Sponsor: Merus N.V.
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alison Schram, MD; Memorial Sloan Kettering Medical Center

• PRS Account: Merus N.V.
• Verification Date: May 2020