A Phase 1/2 Study Evaluating MCLA-129, a Human Anti-EGFR and Anti-c-MET Bispecific Antibody, in Patients With Advanced NSCLC and Other Solid Tumors

Inclusion Criteria:

1. Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced unresected disease that is incurable.
2. Patients with NSCLC, GC/GEJ, HNSCC, or ESCC who have failed prior standard first-line treatment. Patients must have progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens.
3. Part Two: Patients with NSCLC, HNSCC, other solid tumors and applicable mutations as determined by the investigator
4. Availability of archival or a fresh tumor tissue sample.
5. Measurable disease as defined by RECIST version 1.1 by radiologic methods.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Life expectancy ≥ 12 weeks, as per Investigator.

Adequate organ function:

1. Absolute neutrophil count (ANC) ≥1.5 X 10^9/L
2. Hemoglobin ≥9 g/dL
3. Platelets ≥100 x 10^9/L
4. Corrected total serum calcium within normal ranges
5. Serum magnesium within normal ranges (or corrected with supplements)
6. Serum potassium within normal ranges
7. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN (patients with Gilbert's syndrome are eligible if conjugated bilirubin value is within normal limits); in cases of liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed
8. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min calculated according to the Cockcroft and Gault formula or MDRD formula for patients aged >65 years
9. Serum albumin >3.3 g/dL

Exclusion Criteria:

1. Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or continued steroid therapy (> 10 mg prednisone or equivalent) to control symptoms within 14 days of study entry.
2. Known leptomeningeal involvement.
3. Participation in another clinical study or treatment with any investigational drug within 4 weeks prior to study entry.
4. Systemic anticancer therapy or immunotherapy within 4 weeks or 5 half-lives, whichever is shorter, of the first dose of study drug. For cytotoxic agents that have major delayed toxicity (e.g., mitomycin C, nitrosoureas), a washout period of 6 weeks is required.
5. Major surgery or radiotherapy within 3 weeks of the first dose of study drug. Patients who received prior radiotherapy to ≥25% of bone marrow at any time are not eligible.
6. Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 NCI-CTCAE v5.0 and hypothyroidism ≤ grade 2 which is stable on hormone replacement are allowed.
7. History of hypersensitivity reaction or any toxicity attributed to human proteins or any of the excipients that warranted permanent cessation of these agents.

History of clinically significant cardiovascular disease including, but not limited to:

1. Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to first dose of study drug, or any of the following within 6 months prior to the first dose of study drug: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome.
2. Prolonged QT interval > 480 msec or clinically significant cardiac arrythmia or electrophysiologic disease (i.e., placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate) or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities. Patients with cardiac pacemakers who are clinically stable are eligible.
3. Heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.
4. Uncontrolled (persistent) arterial hypertension: systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 100 mm Hg.
5. Congestive heart failure (CHF) defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF within 6 months of the first dose of study drug.
6. Clinically significant pericardial effusion.
7. Myocarditis.
8. History of interstitial lung disease including drug-induced interstitial lung disease, radiation pneumonitis that requires treatment with prolonged steroids or other immune suppressive agents within 1 year.
9. Previous or concurrent malignancy, excluding non-basal cell carcinomas of skin or carcinoma in situ of the uterine cervix, unless the tumor was treated with curative or palliative intent and in the opinion of the Investigator, with Sponsor agreement, the previous or concurrent malignancy condition does not affect the assessment of safety and efficacy of the study drug.
10. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders
11. Active Hepatitis B infection (HBsAg positive) without receiving antiviral treatment.
12. Positive test for Hepatitis C ribonucleic acid (HCV RNA);
13. Known history of HIV (HIV 1/2 antibodies).