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

Inclusion Criteria:

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

• A baseline fresh tumor sample (FFPE) from a metastatic or primary site (ifsafe/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 multiplegated acquisition scan (MUGA).

• Adequate organ function

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

SINGLE AGENT:

• SECOND-/THIRD-LINE HNSCC PATIENTS (cohort closed to enrolment): patients who haveprogressed on or after, or are intolerant to, anti-PD-(L)1 therapy and platinumtherapy as monotherapy or in combination with other agents and no previous exposureto EGFR inhibitors. Patients treated with platinum-containing therapy only in theadjuvant setting, or in the context of multimodal therapy for locally advanceddisease should have disease progression within 6 months of the last dose of platinumcontaining therapy. Patients with no more than 2 prior lines of treatment inrecurrent or metastatic disease.

• Human papilloma virus (HPV) status determined by p16 immunohistochemistry (IHC)or molecular HPV test for all oropharyngeal tumors should be reported whenavailable.

• 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 noHER2 (ERBB2) amplification, as detected in plasma by ctDNA NGS central testingperformed during screening.

• A microsatellite stable (MSS) tumor.

COMBINATION:

• FIRST-LINE HNSCC (cohort closed to enrolment): patients eligible to receivepembrolizumab as first-line monotherapy with tumors expressing programmed cell deathprotein ligand 1 (PD-L1), combined positive score (CPS) ≥1, as determined by a Foodand Drug Administration (FDA) approved test in the US, or by an approved equivalenttest in other countries; patients should not have previous systemic therapyadministered in the recurrent or metastatic setting, although previous systemictherapy as part of multimodal treatment for locally advanced disease is allowed ifended ≥6 months prior to signing the ICF. The eligible HNSCC primary tumor locationsare oropharynx, oral cavity, hypopharynx, and larynx. Previous treatments with antiPD-(L)1 or anti-EGFR therapies are not allowed.

• mCRC (cohorts open to enrolment): Patients should have been previously diagnosedwith histologically or cytologically confirmed unresectable or metastaticadenocarcinoma of the colon or rectum. Patients must be RAS/RAF WT as determinedusing tumor tissue (primary or metastatic) by an appropriate tumor tissue basedassay, to be confirmed by the sponsor, and must have an MSS tumor. Patients must benaive to prior anti-EGFR therapy.

• Cohort to be treated with petosemtamab and FOLFIRI: patients may have receivedup to 1 prior chemotherapy regimen for the metastatic setting, consisting of 1Lfluoropyrimidine-oxaliplatin-based chemotherapy ± bevacizumab.

• Cohort to be treated with petosemtamab and FOLFOX: patients may have receivedup to 1 prior chemotherapy regimen in the metastatic setting consisting of 1Lfluoropyrimidine-irinotecan-based chemotherapy ± bevacizumab.

Exclusion Criteria:

• Central nervous system metastases that are untreated or symptomatic, or requireradiation, surgery, or continued steroid therapy to control symptoms within 14 daysof study entry.

• Known leptomeningeal involvement.

• Participation in another clinical study or treatment with any investigational drugwithin 4 weeks prior to study entry.

• Any systemic anticancer therapy within 4 weeks or 5 half-lives whichever is shorterof the first dose of study treatment. For cytotoxic agents that have major delayedtoxicity ( e.g. mitomycin C,nitrosoureas), or anticancer immunotherapies, a washoutperiod 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 priorantineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2NCI-CTCAE v4.03 is allowed.

• History of hypersensitivity reaction to any of the excipients of petosemtamab, humanproteins or any non-IMP treatment required for this study.

• Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg and/or diastolicBP > 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 atrialfibrillation, paroxysmal supraventricular tachycardia).

• History of myocardial infarction within 6 months of study entry.

• History of prior malignancies with the exception of excised cervical intraepithelialneoplasia or nonmelanoma skin cancer, or curatively treated cancer deemed at lowrisk for recurrence with no evidence of disease for 3 years.

• Current dyspnea at rest of any origin, or other diseases requiring continuous oxygentherapy.

• Patients with a history of interstitial lung disease (e.g., pneumonitis or pulmonaryfibrosis) or evidence of ILD on baseline chest computerized tomography (CT) scan.

• Current serious illness or medical conditions including, but not limited touncontrolled active infection,clinically significant pulmonary, metabolic orpsychiatric 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 usehighly effective contraception methods prior to study entry, for the duration ofstudy participation, and for 6 months after the last dose of MCLA-158.