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

Open to people ages 18 years and up

• 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

• 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.