Recruiting
Phase 1
Phase 2

MCLA-158

Sponsor:

Merus B.V.

Code:

NCT03526835

Conditions

Advanced/Metastatic Solid Tumors

Colorectal Cancer

Gastric Cancer

Gastroesophageal-junction Cancer

NSCLC

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

MCLA-158

MCLA-158 + Pembrolizumab

MCLA-158 + FOLFIRI

MCLA-158 + FOLFOX

Study Details

Brief summary:

This is a Phase 1/2 open-label, multi-center, multi-national study with an initial dose escalation part to determine the recommended Phase II dose (RP2D) of MCLA-158 single agent in patients with mCRC.

The dose escalation part has been completed and the RP2D will be further evaluated in an expansion part of the study. Cohorts of selected solid tumor indications for which there is evidence of EGFR dependency and potential sensitivity to EGFR inhibition will be evaluated including head and neck cancer and metastatic colorectal cancer (mCRC).

The study will further assess the safety, tolerability, PK, PD, immunogenicity, and anti-tumor activity of MCLA-158 in monotherapy or in combination with other therapies.

Conditions

Advanced/Metastatic Solid Tumors

Colorectal Cancer

Gastric Cancer

Gastroesophageal-junction Cancer

NSCLC

Study ID

NCT03526835

Start date

May 2, 2018

Status verified date

Jul, 2026

Completion date

Nov, 2028

Anticipated

Primary completion date

May, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent.
  • A baseline fresh tumor sample (FFPE) from a metastatic or primary site (if safe/feasible).
  • Amenable for biopsy (if safe/feasible).
  • Measurable disease as defined by RECIST version 1.1 by radiologic methods.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Life expectancy ≥ 12 weeks, as per investigator.
  • Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA).
  • Adequate organ function
  • Expansion cohorts: patients with locally advanced unresectable or metastatic disease for the following indications:

SINGLE AGENT:

  • SECOND-/THIRD-LINE HNSCC PATIENTS (cohort closed to enrolment): patients who have progressed on or after, or are intolerant to, anti-PD-(L)1 therapy and platinum therapy as monotherapy or in combination with other agents and no previous exposure to EGFR inhibitors. Patients treated with platinum-containing therapy only in the adjuvant setting, or in the context of multimodal therapy for locally advanced disease should have disease progression within 6 months of the last dose of platinum containing therapy. Patients with no more than 2 prior lines of treatment in recurrent or metastatic disease. • Human papilloma virus (HPV) status determined by p16 immunohistochemistry (IHC) or molecular HPV test for all oropharyngeal tumors should be reported when available.
  • The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
  • 3L+ mCRC (cohort open to enrolment) patients must have:
  • No oncogenic missense mutations in KRAS, NRAS, BRAF, or EGFR ectodomain, and no HER2 (ERBB2) or KRAS amplification, as detected in plasma by ctDNA NGS central testing performed during screening.
  • A microsatellite stable (MSS) tumor.
  • Received ≥2 and no more than 4 lines of prior therapy in the metastatic setting including:

1. Chemotherapy with oxaliplatin, irinotecan, and a fluoropyrimidine,
2. Targeted therapy with an anti-VEGF therapy

COMBINATION:

  • FIRST-LINE HNSCC (cohort closed to enrolment): patients eligible to receive pembrolizumab as first-line monotherapy with tumors expressing programmed cell death protein ligand 1 (PD-L1), combined positive score (CPS) ≥1, as determined by a Food and Drug Administration (FDA) approved test in the US, or by an approved equivalent test in other countries; patients should not have previous systemic therapy administered in the recurrent or metastatic setting, although previous systemic therapy as part of multimodal treatment for locally advanced disease is allowed if ended ≥6 months prior to signing the ICF. The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Previous treatments with anti PD-(L)1 or anti-EGFR therapies are not allowed.
  • mCRC (cohorts open to enrolment): Patients should have been previously diagnosed with histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the colon or rectum. Patients must be RAS/ RAF WT as determined using tumor tissue (primary or metastatic) by an appropriate tumor tissue based assay, to be confirmed by the sponsor, and must have an MSS tumor. Patients must be naive to prior anti-EGFR therapy.

i. Cohort to be treated with petosemtamab and FOLFIRI: patients may have received up to 1 prior chemotherapy regimen for the metastatic setting, consisting of 1L fluoropyrimidine-oxaliplatin-based chemotherapy ± bevacizumab.

ii. Cohort to be treated with petosemtamab and FOLFOX: patients may have received up to 1 prior chemotherapy regimen in the metastatic setting consisting of 1L fluoropyrimidine-irinotecan-based chemotherapy ± bevacizumab

Exclusion Criteria:

  • 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.
  • Known leptomeningeal involvement.
  • Participation in another clinical study or treatment with any investigational drug within 4 weeks prior to study entry.
  • Any systemic anticancer therapy within 4 weeks or 5 half-lives whichever is shorter of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity ( e.g. mitomycin C,nitrosoureas), or anticancer immunotherapies, a washout period of 6 weeks is required.
  • Requirement for immunosuppressive medication (e.g. methotrexate, cyclophosphamide)
  • Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible, irrespective of when it was received.
  • Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 NCI-CTCAE v4.03 is allowed.
  • History of hypersensitivity reaction to any of the excipients of petosemtamab, human proteins or any non-IMP treatment required for this study.
  • Uncontrolled hypertension (systolic blood pressure \[BP\] > 150 mmHg and/or diastolic BP > 100 mmHg) with appropriate treatment or unstable angina. History of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia). History of myocardial infarction within 6 months of study entry.
  • History of prior malignancies with the exception of excised cervical intraepithelial neoplasia or nonmelanoma skin cancer, or curatively treated cancer deemed at low risk for recurrence with no evidence of disease for 3 years.
  • Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. Patients with a history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of ILD on baseline chest computerized tomography (CT) scan.
  • Current serious illness or medical conditions including, but not limited to uncontrolled active infection,clinically significant pulmonary, metabolic or psychiatric disorders.
  • Patients with known infectious diseases:

i. Active hepatitis B infection (hepatitis B surface antigen \[HBsAg\] positive) without receiving antiviral treatment.

ii. Positive test for hepatitis C ribonucleic acid (HCV) RNA).

• Pregnant or breastfeeding patients; patients of childbearing potential must use highly effective contraception methods prior to study entry, for the duration of study participation, and for 6 months after the last dose of MCLA-158.

Study Design

Enrollment

560 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: MCLA-158 (Single-Agent)

In Part 1, the dose escalation phase, patients with metastatic CRC will receive escalating doses of MCLA-158 (every 2 weeks) until MTD or RP2D is reached. Each Cycle is 28 days. Single agent treatment. In Part 2, the expansion phase, participants with metastatic CRC and certain other solid tumors will receive intravenous infusion (i.v.) of MCLA-158 at the recommended Phase II dose (RP2D) every 2 weeks, at Day 1 and Day 15. The duration of each treatment cycle is 28 days. In addition, in the expansion phase, one randomized cohort will evaluate 2 doses (1100 mg and 1500 mg) of MCLA-158 in head and neck squamous cell carcinoma patients. Also in the expansion phase, a subcutaneous formulation of MCLA-158 will be evaluated.

experimental: MCLA-158 + Pembrolizumab

MCLA-158 in combination with pembrolizumab will be explored first in head and neck squamous cell carcinoma patients eligible to receive pembrolizumab as first-line monotherapy.

experimental: MCLA-158 + FOLFIRI combination chemotherapy

MCLA-158 in combination with FOLFIRI will be explored in mCRC patients with up to 1 line of prior regimen.

experimental: MCLA-158 + FOLFOX combination chemotherapy

MCLA-158 in combination with FOLFOX will be explored in mCRC patients with up to 1 line of prior regimen.

Interventions

MCLA-158

full-length IgG1 bispecific antibody targeting EGFR and LGR5

MCLA-158 + Pembrolizumab

MCLA-158 in combination with pembrolizumab will be explored first in HNSCC patients eligible to receive pembrolizumab as first-line monotherapy.

MCLA-158 + FOLFIRI

MCLA-158 in combination with FOLFIRI will be explored in mCRC patients with up to 1 line of prior regimen.

MCLA-158 + FOLFOX

MCLA-158 in combination with FOLFOX will be explored in mCRC patients with up to 1 line of prior regimen.

Primary outcome measure

  • Escalation: Number of patients with Dose Limiting Toxicities (DLTs) during Cycle 1 [ Time Frame: 4 weeks ]
  • Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer, and combination cohorts): Safety and tolerability: AEs and SAEs [ Time Frame: 6-12 months ]
  • Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer): Treatment discontinuations and dose modifications due to AEs [ Time Frame: 6-12 months ]
  • Expansion (single agent - randomized expansion in 2/3L Head and Neck cancer): Best overall response (BOR) [ Time Frame: 36 months ]
  • Expansion (Single agent - non-randomized, and combination cohorts): Objective response rate (ORR) [ Time Frame: 36 months ]
  • Expansion (single agent - randomized expansion in 2/3L Head and Neck cancer): exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg: TEAEs [ Time Frame: 8 weeks ]
  • Expansion: (mCRC subcutaneous cohort): Bioavailability of subcutaneous vs intravenous administration [ Time Frame: 6 weeks ]
  • Expansion: (mCRC subcutaneous cohort): Area under the concentration versus time curve from time zero to time t [AUC0-t] [ Time Frame: 6 weeks ]
  • Expansion: (mCRC subcutaneous cohort): Maximum plasma concentration [Cmax] [ Time Frame: 8 weeks ]
  • Expansion: (mCRC subcutaneous cohort): Minimum plasma drug concentration [Ctrough] [ Time Frame: 6 weeks ]

Central Contacts and Locations

Central contacts

Silke Thiele, MD

+31 85 016 2500enquiries-merus@genmab.com

Eduardo Pennella, MD

+1 617 401 4499USenquiries-merus@genmab.com

Locations

UCSD

Recruiting

La Jolla, California, United States, 92093

Sharp Healthcare

Recruiting

San Diego, California, United States, 92123

Rocky Mountain Cancer Centers

Recruiting

Lone Tree, Colorado, United States, 80124

University of Florida

Recruiting

Gainesville, Florida, United States, 32610

Sarah Cannon Research Institute (Lake Nona)

Recruiting

Orlando, Florida, United States, 32827

Emory University

Recruiting

Atlanta, Georgia, United States, 30322

Massachusetts General Hospital - Dana Farber

Recruiting

Boston, Massachusetts, United States, 02114

Washington University School of Medicine at St Louis

Recruiting

St Louis, Missouri, United States, 63110

Cayuga Medical Center

Recruiting

Ithaca, New York, United States, 14850

Mt. Sinai

Recruiting

New York, New York, United States, 10029

Memorial Sloan Kettering Cancer Center

Recruiting

New York, New York, United States, 10065

Hematology-Oncology Associates of Central New York

Recruiting

Syracuse, New York, United States, 13057

Cleveland Clinic

Recruiting

Cleveland, Ohio, United States, 44195

Ohio State University

Recruiting

Columbus, Ohio, United States, 43221

Taylor Cancer Research Center

Recruiting

Maumee, Ohio, United States, 43537

SSM OKC Hightower Clinical

Recruiting

Oklahoma City, Oklahoma, United States, 73102

University of Pennsylvania

Recruiting

Philadelphia, Pennsylvania, United States, 19104

The University Of Tennessee Health Science Center

Recruiting

Memphis, Tennessee, United States, 38103

Texas Oncology

Recruiting

Dallas, Texas, United States, 75246

Oncology Consultants

Recruiting

Houston, Texas, United States, 77030

Texas Oncology

Recruiting

Tyler, Texas, United States, 75702

Utah Cancer Specialists

Recruiting

Salt Lake City, Utah, United States, 84106

University of Utah Health Huntsman Cancer Hospital

Recruiting

Salt Lake City, Utah, United States, 84112

Oncology & Hematology Associates of Southwest Virginia

Recruiting

Roanoke, Virginia, United States, 24014

Georgetown University Medical Center

Recruiting

Georgetown, Washington, United States, 20007

Cancer Care Northwest

Recruiting

Spokane, Washington, United States, 99202

More Information

Sponsor

Merus B.V.

Last update posted

Jul 29, 2026

Last verified

Jul, 2026

Keywords

  • Bispecific antibody
  • First-in-human
  • MCLA-158
  • Antibodies
  • Bispecific
  • immunologic factors
  • Cytokines
  • EGFR
  • LGR5

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by Merus B.V. on 2026-07-29.