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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03526835
• Other study ID #: MCLA-158-CL01
• Secondary ID: 2017-004745-24
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 2, 2018
• Est. completion date: June 2025

Study information

• Verified date: March 2024
• Source: Merus N.V.
• Contact: Eduardo Pennella, MD
• Phone: +1 617 401 4499
• Email: USenquiries[@]merus.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 360
• Est. completion date: June 2025
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• MCLA-158
full-length IgG1 bispecific antibody targeting EGFR and LGR5

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.

Locations

Country	Name	City	State
Belgium	Cliniques universitaires Saint-Luc	Brussels
Belgium	Institut Jules Bordet	Brussels
Belgium	UZ Gent	Gent
Belgium	Chu Ucl Namur Site De Sainte-Elisabeth	Namur
France	Hopital Saint Andre, CHU Bordeaux	Bordeaux
France	Centre Leon Berard	Lyon
France	Hopital La Timone	Marseille
France	Institut Régional du Cancer de Montpellier	Montpellier
France	Centre Antoine Lacassagne	Nice
France	Institut Curie	Paris
France	Institut Gustave Roussy	Paris
France	Centre Henri Becquerel	Rouen
Netherlands	NKI - Antoni van Leeuwenhoek	Amsterdam
Netherlands	UMC Radboud	Nijmegen
Netherlands	UMC Utrecht	Utrecht
Spain	Vall d'Hebron	Barcelona
Spain	Hospital 12 de Octubre	Madrid
Spain	Clinica Universidad de Navarra	Pamplona
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	Instituto Valenciano de Oncologia	Valencia
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Sarah Cannon Research Institute	London
United States	Cleveland Clinic	Cleveland	Ohio
United States	Texas Oncology	Dallas	Texas
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Oncology Consultants	Houston	Texas
United States	UCSD	La Jolla	California
United States	Rocky Mountain Cancer Centers	Lone Tree	Colorado
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	The University Of Tennessee Health Science Center	Memphis	Tennessee
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	SSM OKC Hightower Clinical	Oklahoma City	Oklahoma
United States	Sarah Cannon Research Institute (Lake Nona)	Orlando	Florida
United States	Oncology & Hematology Associates of Southwest Virginia	Roanoke	Virginia
United States	SSM Health Saint Louis University Hospital	Saint Louis	Missouri
United States	University of Utah Health Huntsman Cancer Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Cancer Care Northwest	Spokane	Washington
United States	Texas Oncology	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Merus N.V.

Countries where clinical trial is conducted

United States,  Belgium,  France,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Escalation & Expansion: Biomarkers for Wnt signaling proteins	Evaluation of biomarker results for Wnt signaling proteins	36 months
Other	Escalation & Expansion: Biomarkers for genetic aberrations in ctDNA	Evaluation of biomarker results in genetic aberrations in ctDNA	36 months
Other	Escalation & Expansion: Biomarkers for differential expression of miRNA	Evaluation of biomarker results for differential expression of miRNA	36 months
Other	Escalation & Expansion: Biomarkers for differential expression of mRNA	Evaluation of biomarker results for differential expression of mRNA	36 months
Primary	Escalation: Number of patients with Dose Limiting Toxicities (DLTs)	Evaluation of number of participants with treatment related toxicities observed during the dose escalation.	6-12 months
Primary	Escalation: Severity of Dose Limiting Toxicities (DLT)	Evaluation of the severity of treatment related toxicities observed during the dose escalation.	6-12 months
Primary	Escalation and Expansion: Safety and tolerability: laboratory values	Number of participants with abnormal laboratory tests results	6-12 months
Primary	Dose Expansion (Combination): Safety and tolerability: AEs and SAEs	Incidence, severity, and relationship of AEs and SAEs, in combination with pembrolizumab in HNSCC	6-12 months
Primary	Escalation and Expansion: Safety and tolerability: (ECG)	Number of participants with abnormal ECG readings	6-12 months
Primary	Escalation and Expansion: Safety and tolerability: vital signs	Number of participants with abnormal vital signs	6-12 months
Primary	Escalation and Expansion: Safety and tolerability	Treatment discontinuations due to AEs and dose modifications due to AEs	6-12 months
Primary	Expansion (single agent - non-randomized): Objective overall response rate (ORR)	Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)	36 months
Primary	Escalation: RP2D	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)	36 months
Primary	Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Incidence and severity and relationship of AEs and SAEs	To descriptively characterize all relevant clinical safety and efficacy data within the study	12 months
Primary	Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Treatment discontinuations due to AEs and dose modifications due to AEs	To descriptively characterize all relevant clinical safety and efficacy data within the study	12 months
Primary	Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Best overall response	To descriptively characterize all relevant clinical safety and efficacy data within the study	12 months
Primary	Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Incidence of AEs and SAEs	To characterize the exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg Q2W in terms of TEAEs	12 months
Primary	Expansion (single agent, randomized expansion in 2/3L Head and Neck cancer- Incidence of TEAEs	To characterize the incidence of TEAEs at Week 8	8 weeks
Secondary	Escalation & Expansion: Incidence of anti-drug antibodies against MCLA-158	Number of participants with anti-drug antibodies against MCLA-158	36 months
Secondary	Escalation & Expansion: Serum titers of anti-drug antibodies	Serum titers of anti-drug antibodies against MCLA-158	36 months
Secondary	Escalation & Expansion (non-randomized cohort): Cytokine Panel Expression Profile	Evaluation of the cytokine expression profile	36 months
Secondary	Escalation & Expansion: Biomarkers for EGFR activation and signaling	Evaluation of biomarker results for EGFR activation and signaling	36 months
Secondary	Escalation & Expansion: EGFR expression	Biomarkers in tumor samples relevant to EGFR expression in relation to early tumor response profile of MCLA-158	36 months
Secondary	Escalation & Expansion: LGR5 expression	Biomarkers in tumor samples relevant to LGR5 expression in relation to early tumor response profile of MCLA-158	36 months
Secondary	Escalation & Expansion: Duration of response (DOR)	Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)	36 months
Secondary	Escalation & Expansion: Progression Free Survival (PFS) and survival	Evaluation of clinical benefit assessed by RECIST v1.1 determining objective progression free survival (PFS) and/or survival	36 months
Secondary	Escalation & Expansion: End of infusion (EOI) plasma concentration [Ceoi]	End of infusion (EOI) plasma concentration [Ceoi] as measured from all individual plasma concentrations	36 months
Secondary	Escalation & Expansion: Maximum plasma concentration [Cmax]	Maximum plasma concentration as measured from all individual plasma concentrations	36 months
Secondary	Escalation & Expansion: Plasma concentration at 0 hours [C0h]	Plasma concentration at 0 hours [C0h] as measured from all individual plasma concentrations	36 months
Secondary	Escalation & Expansion: Area under the concentration versus time curve from time zero to time t [AUC0-t]	Area under the concentration versus time curve from time zero to time t [AUC0-t]	36 months
Secondary	Escalation & Expansion: Area under the concentration versus time curve [AUC0-8]	Area under the concentration versus time curve [AUC0-8]	36 months
Secondary	Escalation & Expansion: Clearance of plasma [CL]	Clearance of plasma [CL]	36 months
Secondary	Escalation & Expansion: Volume of distribution at steady state [Vss]	Volume of distribution at steady state [Vss]	36 months
Secondary	Escalation & Expansion: Time to reach maximum concentration [tmax]	Time to reach maximum concentration [tmax]	36 months
Secondary	Escalation & Expansion: Half-life [t1/2]	Half-life [t1/2]	36 months
Secondary	Expansion: Frequency of Treatment-Related Adverse Events (AE)	Evaluation of the number of participants with AEs or SAEs that are related to treatment as assessed by CTCAE version 4.03	up to 30 days post-last dose
Secondary	Expansion: Severity of Treatment-Related Adverse Events (AE)	Evaluation of the severity of AEs that are related to treatment as assessed by CTCAE version 4.03	up to 30 days post-last dose
Secondary	Expansion: Frequency of dose interruptions and reductions	Evaluation of the number of dose interruptions and reductions	up to 30 days post-last dose
Secondary	Escalation & Expansion: Overall survival (OS)	Evaluation of clinical benefit assessed by RECIST v1.1 determining overall survival (OS)	36 months
Secondary	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	Percentage change from baseline in sum of the diameters of target lesions at Week 8	8 weeks
Secondary	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	Incidence of Grade 3-4 TEAEs at Week 8	8 weeks
Secondary	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	Incidence of IRR TEAEs at Week 8	8 weeks
Secondary	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	Incidence of non-IRR TEAEs at Week 8	8 weeks