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.

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.

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.