Clinical trial NCT03526835: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced/Metastatic Solid Tumors
Colorectal Cancer
Gastric Cancer
Gastroesophageal-junction Cancer
NSCLC
HNSCC
Head and Neck Squamous Cell Carcinoma
Esophageal Cancer
Keywords: Bispecific antibody
First-in-human
MCLA-158
Antibodies
Bispecific
immunologic factors
Cytokines
EGFR
LGR5
Lead sponsor: Merus N.V.
Sponsor class: INDUSTRY
First posted: 2018-05-16
Enrollment: 523
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 (mCRC). Enrollment in the dose escalation part has been completed.

In the dose expansion (single-agent cohorts) 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. The most recently enrolled cohorts were in patients with head and neck squamous cell carcinoma (HNSCC). Enrollment into the HNSCC cohort of single-agent MCLA-158 for the treatment of patients with second/third line (2L/3L) HNSCC is closed. In the dose expansion part of the study, safety was also characterized at two dose levels in this setting. Other closed cohort indications included gastric/gastroesophageal junction adenocarcinoma (GEA) with EGFR amplification and/or high EGFR expression, esophageal carcinoma, and pancreatic adenocarcinoma. Enrollment is currently being explored in mCRC (RAS/RAF wild type) patients in the 3L/4L/5L setting.

Additionally, in the dose expansion (combination cohorts) part of the study, the activity, safety, and tolerability of MCLA-158 at 1500 mg Q2W will be evaluated in combination with other therapies. Enrollment in the combination cohort of treatment of MCLA-158 with pembrolizumab for the treatment of patients with first line (1L) HNSCC is closed. Additionally, two combination cohorts of MCLA-158 with FOLFIRI or with FOLFOX chemotherapy (i.e., 5-fluorouracil \[5-FU\], leucovorin, and irinotecan (FOLFIRI) or oxaliplatin (FOLFOX)) will be explored in mCRC (RAS/RAF wild type) patients in the 1L/2L setting. Other expansion cohorts may be considered for monotherapy or combination treatment in the future.

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.
* 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) amplification, as detected in plasma by ctDNA NGS central testing performed during screening.
  * A microsatellite stable (MSS) tumor.

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.

  * 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.
  * 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:

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

Primary outcomes:
measure: Escalation: Number of patients with Dose Limiting Toxicities (DLTs) during Cycle 1
timeFrame: 4 weeks
measure: Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer, and combination cohorts): Safety and tolerability: AEs and SAEs
timeFrame: 6-12 months
measure: Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer): Treatment discontinuations and dose modifications due to AEs
timeFrame: 6-12 months
measure: Expansion (single agent - randomized expansion in 2/3L Head and Neck cancer): Best overall response (BOR)
timeFrame: 36 months
measure: Expansion (Single agent - non-randomized, and combination cohorts): Objective response rate (ORR)
timeFrame: 36 months
measure: 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
timeFrame: 8 weeks
Secondary outcomes:
measure: Escalation & Expansion: Duration of response (DOR)
timeFrame: 36 months
measure: Expansion: Progression Free Survival (PFS)
timeFrame: 36 months
measure: Expansion (mCRC combination cohorts): Progression Free Survival (PFS) rate at 4 months
timeFrame: 4 months
measure: Expansion (Single agent - non-randomized cohorts): Overall survival (OS)
timeFrame: 36 months
measure: Escalation & Expansion (single agent - non-randomized cohorts): Safety and tolerability: AEs and SAEs
timeFrame: up to 30 days post-last dose
measure: Escalation & Expansion (Single agent - non-randomized and Combination cohorts): Treatment discontinuations and dose modifications due to AEs
timeFrame: up to 30 days post-last dose
measure: 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
timeFrame: 8 weeks
measure: Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer): exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg: Grade 3-4 TEAEs
timeFrame: 8 weeks
measure: Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer): exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg: IRR TEAEs
timeFrame: 8 weeks
measure: Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer): exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg : non-IRR TEAEs
timeFrame: 8 weeks
measure: Escalation and Expansion: Safety and tolerability: laboratory values
timeFrame: 6-12 months
measure: Escalation and Expansion: Safety and tolerability: (ECG)
timeFrame: 6-12 months
measure: Escalation and Expansion: Safety and tolerability: vital signs
timeFrame: 6-12 months
measure: Expansion (Single agent - randomized expansion in 2/3L Head and Neck cancer): Objective response rate (ORR)
timeFrame: 36 months
measure: Escalation & Expansion: Incidence of anti-drug antibodies against MCLA-158
timeFrame: 36 months
measure: Escalation: Cytokine Panel Expression Profile
timeFrame: 36 months
measure: Escalation & Expansion: End of infusion (EOI) plasma concentration [Ceoi]
timeFrame: 36 months
measure: Escalation & Expansion: Maximum plasma concentration [Cmax]
timeFrame: 36 months
measure: Escalation & Expansion: Plasma concentration at 0 hours [C0h]
timeFrame: 36 months
measure: Escalation & Expansion: Area under the concentration versus time curve from time zero to time t [AUC0-t]
timeFrame: 36 months
measure: Escalation & Expansion: Area under the concentration versus time curve [AUC0-∞]
timeFrame: 36 months
measure: Escalation & Expansion: Clearance of plasma [CL]
timeFrame: 36 months
measure: Escalation & Expansion: Volume of distribution at steady state [Vss]
timeFrame: 36 months
measure: Escalation & Expansion: Half-life [t1/2]
timeFrame: 36 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: Sharp Healthcare
state: California
city: Lone Tree
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Orlando
country: United States
facility: Sarah Cannon Research Institute (Lake Nona)
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital - Dana Farber
state: Massachusetts
city: Saint Louis
country: United States
facility: SSM Health Saint Louis University Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine at St Louis
state: Missouri
city: Ithaca
country: United States
facility: Cayuga Medical Center
state: New York
city: Syracuse
country: United States
facility: Hematology-Oncology Associates of Central New York
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Maumee
country: United States
facility: Taylor Cancer Research Center
state: Ohio
city: Oklahoma City
country: United States
facility: SSM OKC Hightower Clinical
state: Oklahoma
city: Memphis
country: United States
facility: The University Of Tennessee Health Science Center
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Health Huntsman Cancer Hospital
state: Utah
city: Roanoke
country: United States
facility: Oncology & Hematology Associates of Southwest Virginia
state: Virginia
city: Spokane
country: United States
facility: Cancer Care Northwest
state: Washington
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Gent
country: Belgium
facility: UZ Gent
city: Namur
country: Belgium
facility: Chu Ucl Namur Site De Sainte-Elisabeth
city: Bordeaux
country: France
facility: Hopital Saint Andre, CHU Bordeaux
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hopital La Timone
city: Montpellier
country: France
facility: Institut Régional du Cancer de Montpellier
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Institut Gustave Roussy
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Amsterdam
country: Netherlands
facility: NKI - Antoni van Leeuwenhoek
city: Nijmegen
country: Netherlands
facility: UMC Radboud
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Barcelona
country: Spain
facility: Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Pamplona
country: Spain
facility: Hospital Universitario de Navarra
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncologia
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
Study officials:
affiliation: Merus N.V.
name: Gianluca Laus, MD
role: STUDY_DIRECTOR
References: