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

Study Overview
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Brief Summary
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A phase 1/2 open-label multicenter study will be performed with an initial dose escalation part to determine the MTD and/or the RP2D of MCLA-129 as monotherapy in patients with NSCLC, HNSCC, GC/GEJ, ESCC, or other solid tumors and who have progressed after receiving prior therapy for advanced/metastatic disease.

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

Conditions
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Non-Small Cell Lung Cancer Metastatic, Gastric Cancer, Esophageal Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: MCLA-129
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced unresected disease that is incurable. 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. Part Two: Patients with NSCLC, HNSCC, other solid tumors and applicable mutations as determined by the investigator Availability of archival or a fresh tumor tissue sample. 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. Adequate organ function: Absolute neutrophil count (ANC) ≥1.5 X 10^9/L Hemoglobin ≥9 g/dL Platelets ≥100 x 10^9/L Corrected total serum calcium within normal ranges Serum magnesium within normal ranges (or corrected with supplements) Serum potassium within normal ranges 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 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 Serum albumin >3.3 g/dL Exclusion Criteria: 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. Known leptomeningeal involvement. Participation in another clinical study or treatment with any investigational drug within 4 weeks prior to study entry. 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. 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. 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. 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: 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. 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. 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. Uncontrolled (persistent) arterial hypertension: systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 100 mm Hg. 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. Clinically significant pericardial effusion. Myocarditis. 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. 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. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders Active Hepatitis B infection (HBsAg positive) without receiving antiviral treatment. Positive test for Hepatitis C ribonucleic acid (HCV RNA); Known history of HIV (HIV 1/2 antibodies).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 2 NSCLC harboring EGFR exon 20 Insertion<br>Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D). | Drug: MCLA-129<br>* full length IgG1 bispecific antibody that specifically targets the receptor tyrosine kinases EGFR and c-MET<br>* Other names: bispecific;|
| Experimental: Part 2 NSCLC harboring cMet exon 14 skipping mutation<br>Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D). | Drug: MCLA-129<br>* full length IgG1 bispecific antibody that specifically targets the receptor tyrosine kinases EGFR and c-MET<br>* Other names: bispecific;|
| Experimental: Part 2 Select solid tumors harboring an EGFR or cMet driving mutation<br>Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D). | Drug: MCLA-129<br>* full length IgG1 bispecific antibody that specifically targets the receptor tyrosine kinases EGFR and c-MET<br>* Other names: bispecific;|
| Experimental: Part 2 NSCLC First-line<br>Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D) and Osimertinib orally once daily starting at a dose of 80mg. | Drug: MCLA-129<br>* full length IgG1 bispecific antibody that specifically targets the receptor tyrosine kinases EGFR and c-MET<br>* Other names: bispecific;Drug: Osimertinib<br>* Approved, 3rd-generation EGFR-TKI<br>* Other names: Tagrisso;|
| Experimental: Part 2 NSCLC Second-line or more<br>Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D) and Osimertinib orally once daily starting at a dose of 80mg. | Drug: MCLA-129<br>* full length IgG1 bispecific antibody that specifically targets the receptor tyrosine kinases EGFR and c-MET<br>* Other names: bispecific;Drug: Osimertinib<br>* Approved, 3rd-generation EGFR-TKI<br>* Other names: Tagrisso;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of single agent MCLA-129 in patients with NSCLC, GC/GEJ adenocarcinoma, HNSCC or ESCC, with disease progression after prior therapy for advanced/metastatic disease. |  | First 28 days of treatment | 
| To evaluate the ORR of MCLA-129 alone or in combination with Osimertinib in molecularly defined populations of advanced/metastatic solid tumors. |  | From first dose until 1 year after end of treatment or initiation of an alternative treatment, whichever occurs first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate preliminary antitumor activity in terms of best overall response (BOR) |  | Every 8 weeks until study ends, approximately 2 years | 
| To evaluate preliminary antitumor activity in terms of overall response rate (ORR) |  | Every 8 weeks until study ends, approximately 2 years | 
| To evaluate preliminary antitumor activity in terms of disease control rate (DCR) |  | Every 8 weeks until study ends, approximately 2 years | 
| To evaluate preliminary antitumor activity in terms of duration of response (DoR). |  | Every 8 weeks until study ends, approximately 2 years | 
| To evaluate progression-free survival (PFS) |  | Every 8 weeks until study ends, approximately 2 years | 
| To evaluate overall survival (OS). |  | Every 8 weeks until study ends, approximately 2 years | 
| Maximum plasma concentration [Cmax] |  | 12 months | 
| Plasma concentration at 0 hours [C0h] |  | 12 months | 
| Area under the concentration versus time curve from time zero to time t [AUC0-t] |  | 12 months | 
| Area under the concentration versus time curve [AUC0-∞] |  | 12 months | 
| Time to reach maximum concentration [tmax] |  | 12 months | 
| Half-life [t1/2] |  | 12 months | 
| To assess changes in cytokines (TNFα) in serum blood following administration of MCLA-129 |  | 12 months | 
| To assess changes in cytokines (IFNγ) in serum blood following administration of MCLA-129 |  | 12 months | 
| To assess changes in cytokines (IL-1β) in serum blood following administration of MCLA-129 |  | 12 months | 
| To assess changes in cytokines (IL-2) in serum blood following administration of MCLA-129 |  | 12 months | 
| To assess changes in cytokines (IL-6) in serum blood following administration of MCLA-129 |  | 12 months | 
| Incidence of anti-drug antibodies in serum blood against MCLA-129 |  | 12 months | 
| Serum titers of anti-drug (MCLA-129) antibodies in serum blood |  | 12 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 |  | 12 months | 
| Proportion of patient with treatment discontinuations |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MCLA-129, EGFR inhibitor, NSCLC, C-MET, GC/GEJ, Head and Neck Cancer