A Study of Bispecific Antibody MCLA-158 in Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT03526835
• Recruitment Status: Recruiting
• First Posted: May 16, 2018
• Last Update Posted: March 5, 2024
• Sponsor: Merus N.V.
• Information provided by (Responsible Party): Merus N.V.

Tracking Information

• First Submitted Date: April 4, 2018
• First Posted Date: May 16, 2018
• Last Update Posted Date: March 5, 2024
• Actual Study Start Date: May 2, 2018
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 1, 2024)

• Escalation: Number of patients with Dose Limiting Toxicities (DLTs) [ Time Frame: 6-12 months ]
  Evaluation of number of participants with treatment related toxicities observed during the dose escalation.
• Escalation: Severity of Dose Limiting Toxicities (DLT) [ Time Frame: 6-12 months ]
  Evaluation of the severity of treatment related toxicities observed during the dose escalation.
• Escalation and Expansion: Safety and tolerability: laboratory values [ Time Frame: 6-12 months ]
  Number of participants with abnormal laboratory tests results
• Dose Expansion (Combination): Safety and tolerability: AEs and SAEs [ Time Frame: 6-12 months ]
  Incidence, severity, and relationship of AEs and SAEs, in combination with pembrolizumab in HNSCC
• Escalation and Expansion: Safety and tolerability: (ECG) [ Time Frame: 6-12 months ]
  Number of participants with abnormal ECG readings
• Escalation and Expansion: Safety and tolerability: vital signs [ Time Frame: 6-12 months ]
  Number of participants with abnormal vital signs
• Escalation and Expansion: Safety and tolerability [ Time Frame: 6-12 months ]
  Treatment discontinuations due to AEs and dose modifications due to AEs
• Expansion (single agent - non-randomized): Objective overall response rate (ORR) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)
• Escalation: RP2D [ Time Frame: 36 months ]
  To determine the preliminary RP2D of single agent petosemtamab in mCRC patients who have progressed on chemotherapy, with or without an anti-vascular endothelial growth factor (VEGF) therapy, and with an anti-EGFR therapy (if RASwt)
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Incidence and severity and relationship of AEs and SAEs [ Time Frame: 12 months ]
  To descriptively characterize all relevant clinical safety and efficacy data within the study
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Treatment discontinuations due to AEs and dose modifications due to AEs [ Time Frame: 12 months ]
  To descriptively characterize all relevant clinical safety and efficacy data within the study
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Best overall response [ Time Frame: 12 months ]
  To descriptively characterize all relevant clinical safety and efficacy data within the study
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Incidence of AEs and SAEs [ Time Frame: 12 months ]
  To characterize the exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg Q2W in terms of TEAEs
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Incidence of TEAEs [ Time Frame: 8 weeks ]
  To characterize the incidence of TEAEs at Week 8

Original Primary Outcome Measures (submitted: May 15, 2018)

• Number of patients with Dose Limiting Toxicities (DLTs) [ Time Frame: 6-12 months ]
  Evaluation of number of participants with treatment related toxicities observed during the dose escalation.
• Severity of Dose Limiting Toxicities (DLT) [ Time Frame: 6-12 months ]
  Evaluation of the severity of treatment related toxicities observed during the dose escalation.
• Expansion: Frequency of Treatment-Related Adverse Events (AE) [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the number of participants with AEs or SAEs that are related to treatment as assessed by CTCAE version 4.03
• Expansion: Severity of Treatment-Related Adverse Events (AE) [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the severity of abnormal laboratory values and/or AEs that are related to treatment as assessed by CTCAE version 4.03
• Expansion: Changes in laboratory values [ Time Frame: up to 30 days post last dose ]
  Evaluation of the changes between baseline and post-baseline laboratory parameters.
• Expansion: Changes in vital signs [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the changes between baseline and post-baseline vital sign values
• Expansion: Frequency of dose interruptions and reductions [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the number of dose interruptions and reductions

Current Secondary Outcome Measures (submitted: March 1, 2024)

• Escalation & Expansion: Incidence of anti-drug antibodies against MCLA-158 [ Time Frame: 36 months ]
  Number of participants with anti-drug antibodies against MCLA-158
• Escalation & Expansion: Serum titers of anti-drug antibodies [ Time Frame: 36 months ]
  Serum titers of anti-drug antibodies against MCLA-158
• Escalation & Expansion (non-randomized cohort): Cytokine Panel Expression Profile [ Time Frame: 36 months ]
  Evaluation of the cytokine expression profile
• Escalation & Expansion: Biomarkers for EGFR activation and signaling [ Time Frame: 36 months ]
  Evaluation of biomarker results for EGFR activation and signaling
• Escalation & Expansion: EGFR expression [ Time Frame: 36 months ]
  Biomarkers in tumor samples relevant to EGFR expression in relation to early tumor response profile of MCLA-158
• Escalation & Expansion: LGR5 expression [ Time Frame: 36 months ]
  Biomarkers in tumor samples relevant to LGR5 expression in relation to early tumor response profile of MCLA-158
• Escalation & Expansion: Duration of response (DOR) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)
• Escalation & Expansion: 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
• Escalation & Expansion: End of infusion (EOI) plasma concentration [Ceoi] [ Time Frame: 36 months ]
  End of infusion (EOI) plasma concentration [Ceoi] as measured from all individual plasma concentrations
• Escalation & Expansion: Maximum plasma concentration [Cmax] [ Time Frame: 36 months ]
  Maximum plasma concentration as measured from all individual plasma concentrations
• Escalation & Expansion: Plasma concentration at 0 hours [C0h] [ Time Frame: 36 months ]
  Plasma concentration at 0 hours [C0h] as measured from all individual plasma concentrations
• Escalation & Expansion: 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]
• Escalation & Expansion: Area under the concentration versus time curve [AUC0-∞] [ Time Frame: 36 months ]
  Area under the concentration versus time curve [AUC0-∞]
• Escalation & Expansion: Clearance of plasma [CL] [ Time Frame: 36 months ]
  Clearance of plasma [CL]
• Escalation & Expansion: Volume of distribution at steady state [Vss] [ Time Frame: 36 months ]
  Volume of distribution at steady state [Vss]
• Escalation & Expansion: Time to reach maximum concentration [tmax] [ Time Frame: 36 months ]
  Time to reach maximum concentration [tmax]
• Escalation & Expansion: Half-life [t1/2] [ Time Frame: 36 months ]
  Half-life [t1/2]
• Expansion: Frequency of Treatment-Related Adverse Events (AE) [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the number of participants with AEs or SAEs that are related to treatment as assessed by CTCAE version 4.03
• Expansion: Severity of Treatment-Related Adverse Events (AE) [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the severity of AEs that are related to treatment as assessed by CTCAE version 4.03
• Expansion: Frequency of dose interruptions and reductions [ Time Frame: up to 30 days post-last dose ]
  Evaluation of the number of dose interruptions and reductions
• Escalation & Expansion: Overall survival (OS) [ Time Frame: 36 months ]
  Evaluation of clinical benefit assessed by RECIST v1.1 determining overall survival (OS)
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer): exposure-efficacy relationship of petosemtamab administered at 1100 mg and 1500 mg: Target Lesions [ Time Frame: 8 weeks ]
  Percentage change from baseline in sum of the diameters of target lesions at Week 8
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer): exposure-efficacy relationship of petosemtamab administered at 1100 mg and 1500 mg: TEAEs [ Time Frame: 8 weeks ]
  Incidence of Grade 3-4 TEAEs at Week 8
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer): exposure-efficacy relationship of petosemtamab administered at 1100 mg and 1500 mg: IRR TEAEs [ Time Frame: 8 weeks ]
  Incidence of IRR TEAEs at Week 8
• Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer): exposure-efficacy relationship of petosemtamab administered at 1100 mg and 1500 mg : non-IRR TEAEs [ Time Frame: 8 weeks ]
  Incidence of non-IRR TEAEs at Week 8

Original Secondary Outcome Measures (submitted: May 15, 2018)

• Incidence of anti-drug antibodies against MCLA-158 [ Time Frame: 36 months ]
  Number of participants with anti-drug antibodies against MCLA-158
• Serum titers of anti-drug antibodies [ Time Frame: 36 months ]
  Serum titers of anti-drug antibodies against MCLA-158
• Cytokine Panel Expression Profile [ Time Frame: 36 months ]
  Evaluation of the cytokine expression profile
• Biomarkers for EGFR activation and signaling [ Time Frame: 36 months ]
  Evaluation of biomarker results for EGFR activation and signaling
• Biomarkers for resistance to EGFR therapies [ Time Frame: 36 months ]
  Evaluation of biomarker results for resistance to EGFR therapies
• Biomarkers for Wnt signaling in CTCs, proteins, ctDNA, and miRNA [ Time Frame: 36 months ]
  Evaluation of biomarker results for Wnt signaling in CTCs, proteins, ctDNA, and miRNA
• 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
• End of infusion (EOI) plasma concentration [Ceoi] [ Time Frame: 36 months ]
  End of infusion (EOI) plasma concentration [Ceoi] as measured from all individual plasma concentrations
• Maximum plasma concentration [Cmax] [ Time Frame: 36 months ]
  Maximum plasma concentration as measured from all individual plasma concentrations
• Plasma concentration at 0 hours [C0h] [ Time Frame: 36 months ]
  Plasma concentration at 0 hours [C0h] as measured from all individual plasma concentrations
• 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-∞]
• Clearance of plasma [CL] [ Time Frame: 36 months ]
  Clearance of plasma [CL]
• Volume of distribution at steady state [Vss] [ Time Frame: 36 months ]
  Volume of distribution at steady state [Vss]
• Time to reach maximum concentration [tmax] [ Time Frame: 36 months ]
  Time to reach maximum concentration [tmax]
• Half-life [t1/2] [ Time Frame: 36 months ]
  Half-life [t1/2]

Current Other Pre-specified Outcome Measures (submitted: February 15, 2023)

• Escalation & Expansion: Biomarkers for Wnt signaling proteins [ Time Frame: 36 months ]
  Evaluation of biomarker results for Wnt signaling proteins
• Escalation & Expansion: Biomarkers for genetic aberrations in ctDNA [ Time Frame: 36 months ]
  Evaluation of biomarker results in genetic aberrations in ctDNA
• Escalation & Expansion: Biomarkers for differential expression of miRNA [ Time Frame: 36 months ]
  Evaluation of biomarker results for differential expression of miRNA
• Escalation & Expansion: Biomarkers for differential expression of mRNA [ Time Frame: 36 months ]
  Evaluation of biomarker results for differential expression of mRNA

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Bispecific Antibody MCLA-158 in Patients With Advanced Solid Tumors
• Official Title: Phase 1/2 Dose Escalation and Cohort Expansion Study Evaluating MCLA-158 (Petosemtamab) as Single Agent or in Combination in Advanced Solid Tumors

Brief Summary

This is a Phase 1/2 open-label, multi-center, multi-national study with an initial dose escalation part to determine the 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.

The study will further assess the safety, tolerability, PK, PD, immunogenicity, and anti-tumor activity of MCLA-158.

Detailed Description

Study Design:

This open label, multicenter, first-in-human study consists of 2 parts. Part 1 is a dose escalation to find the recommended Phase II dose (RP2D) of MCLA-158 studying patients with metastatic colorectal cancer. Enrollment in the dose escalation part has been completed.

Dose expansion (single-agent cohorts) In an expansion part of the study, the activity, safety, and tolerability of MCLA-158 at 1500 mg every 2 weeks (Q2W) (preliminary RP2D) as a single agent will be evaluated in cohorts of selected solid tumor indications with dependency on EGFR signaling. Eligible solid tumor indications may include locally advanced unresectable or metastatic HNSCC, gastric/gastroesophageal junction adenocarcinoma (GEA) with EGFR amplification and/or high EGFR expression, esophageal carcinoma and pancreatic adenocarcinoma. Additionally, safety will be characterized at two dose levels in this setting.

Dose expansion (in combination with pembrolizumab cohort)

MCLA-158 in combination with pembrolizumab will be explored first in HNSCC patients eligible to receive pembrolizumab as first-line monotherapy. Other expansion cohorts may be considered for combination treatment in the future.

• 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

• Advanced/Metastatic Solid Tumors
• Colorectal Cancer
• Gastric Cancer
• Gastroesophageal-junction Cancer
• NSCLC
• HNSCC
• Head and Neck Squamous Cell Carcinoma

Intervention

• Drug: MCLA-158
  full-length IgG1 bispecific antibody targeting EGFR and LGR5
  Other Name: petosemtamab
• Combination Product: MCLA-158 +Pembrolizumab
  MCLA-158 in combination with pembrolizumab (non-IMP) will be explored first in HNSCC patients eligible to receive pembrolizumab as first-line monotherapy.
  Other Name: petosemtamab

Study Arms

• Experimental: MCLA-158

  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 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 the expansion phase, 2 doses (1100 mg and 1500 mg) of MCLA-158 will be evaluated in a cohort of head and neck squamous cell carcinoma patients

  Intervention: Drug: MCLA-158
• 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.
  Intervention: Combination Product: MCLA-158 +Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 15, 2023): 360
• Original Estimated Enrollment (submitted: May 15, 2018): 120
• Estimated Study Completion Date: June 2025
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent.

• Expansion cohorts: patients with locally advanced unresectable or metastatic disease for the following indications:

  • COMBINATION FIRST-LINE HNSCC: 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.

  • SINGLE AGENT SECOND-/THIRD-LINE HNSCC PATIENTS: patients who have progressed on or after, or are intolerant to, anti-PD-(L)1 therapy as monotherapy or in combination with other agents, and have progressed to a platinum-based chemotherapy less than 6 months from the last platinum dose, with no previous exposure to EGFR inhibitors. Patients with no more than 2 prior lines of treatment in recurrent or metastatic disease not amenable to standard therapy with curative intent.

    • 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.
  • GEA with histologically confirmed EGFR amplification (fluorescence in situ hybridization [FISH] score EGFR/CEP7 ratio ≥2.0, or next generation sequencing [NGS] EGFR copy ≥8, or cfDNA ≥2.5, or EGFR IHC H-score ≥200)
  • Esophageal carcinoma
  • Pancreatic adenocarcinoma
  • Patients with other indications must have been previously treated with at least 2 lines of the standard approved therapy (when applicable) in the locally advanced/unresectable or metastatic setting. Patients with malignant salivary gland tumors and squamous esophageal cancer may be enrolled after progression on 1 line of systemic standard treatment.
• A baseline fresh tumor sample (FFPE) from a metastatic or primary site.
• Amenable for biopsy.
• 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

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 trial 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 longer 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 or any toxicity attributed to human proteins or any of the excipients that warranted permanent cessation of these agents.
• Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 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 at least 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 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 the following infectious diseases:

  • Active hepatitis B infection (HBsAg positive) without receiving antiviral treatment. Note: Patients with active hepatitis B (HBsAg positive) must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least ≥7 days before the initiation of the study treatment. Patients with antecedents of hepatitis B (anti-HBc positive, HBsAg and HBV-DNA negative) are eligible.
  • Positive test for hepatitis C ribonucleic acid (HCV RNA). Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or who achieved a sustained response after antiviral treatment and show absence of detectable HCV RNA ≥6 months (with the use of IFN-free regimens) or ≥ 12 months (with t the use of IFN-based regimens) after cessation of antiviral treatment are eligible.
• Patients with current cirrhotic status of Child-Pugh class B or C; known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Pregnant or lactating women; 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.

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: Eduardo Pennella, MD; +1 617 401 4499; USenquiries@merus.nl

Contact: Ernesto Wasserman, MD; +1 617 401 4499; USenquiries@merus.nl

• Listed Location Countries: Belgium, France, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03526835
• Other Study ID Numbers: MCLA-158-CL01; 2017-004745-24 ( 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

• Current Responsible Party: Merus N.V.
• Original Responsible Party: Same as current
• Current Study Sponsor: Merus N.V.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Eduardo Pennella, MD; Merus N.V.

• PRS Account: Merus N.V.
• Verification Date: March 2024