advanced NSCLC and other solid tumors MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: LLT Classification code 10049280 Term: Solid tumour System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Code: MCLA-129
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: MCLA-129
Current Sponsor code: MCLA-129
Other descriptive name: MCLA-129
Concentration unit: mg/ml milligram(s)/m
Sponsors
Merus N.V.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed informed consent before initiation of any study procedures. 2. Age = 18 years at signature of informed consent. 3. Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced unresected disease that is incurable: • Dose Escalation Part - Patients 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. Patients must have: - Non-small cell lung cancer (NSCLC) harboring activating EGFR mutations including tyrosine kinase inhibitor (TKI) sensitizing mutations (e.g., 19del and L858R), and/or approved TKI-resistance mutations (e.g., acquired TKI-resistance mutations, i.e., T790M, C797S, L792, L798I, exon 20 insertion), or any activating c-MET mutation/amplification (e.g., high-level c-MET amplification [MET/CEP7 > 5 or cfDNA = 2 copies], or c-MET exon 14 skipping mutation). - Gastric/gastroesophageal junction (GC/GEJ) adenocarcinoma harboring an EGFR amplification (EGFR/CEP7 =2 or cfDNA = 8 copies) or c-MET amplification (MET/CEP7 > 5 or cfDNA = 2 copies). - Head and neck squamous cell cancer (HNSCC) or esophageal squamous cell cancer (ESCC). *NOTE: Patient identification will be based on previous treatment history with EGFR tyrosine kinase inhibitors and on local tests performed in CLIA-certified laboratories. • Cohort Expansion Part - Patients 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. Patients must have: - Cohort A: NSCLC harboring EGFR exon 20 insertions. Patients who have received a prior EGFR TKI or who are TKI-naïve are eligible. - Cohort B: NSCLC harboring acquired EGFR C797S TKI resistance. - Cohort C: NSCLC harboring a c-MET amplification (c-MET/CEP7 > 5 copies or cfDNA = 2 copies). - Cohort D: GC/GEJ adenocarcinoma or other selected solid tumors harboring an EGFR amplification (EGFR/CEP7 = 2 or cfDNA = 8 copies) or c-MET amplification (MET/CEP7 > 5 copies or cfDNA = 2 copies). *NOTE: Patient identification will be based on local tests performed in CLIA-certified laboratories or on commercial diagnostics (e.g., FoundationOne). Genetic aberrations in EGFR or c-MET will be retrospectively confirmed by central testing using a validated assay. 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. 8. Adequate organ function: • Absolute neutrophil count (ANC) =1.5 X 109/L • Hemoglobin =9 g/dL • Platelets =100 x 109/L • Corrected total serum calcium within normal ranges • Serum magnesium within normal ranges (or corrected with supplements) • 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 Cockroft and Gault formula or MDRD formula for patients aged >65 years • Serum albumin >3.3 g
Exclusion criteria
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. Prior treatment with a bispecific EGFR-c-MET antibody. 5. 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. Note: For agents with long half-lives, enrollment before the fifth half-life requires Sponsor approval. 6. 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. 7. 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. 8. History of hypersensitivity reaction or any toxicity attributed to human proteins or any of the excipients that warranted permanent cessation of these agents. 9. 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). Patients with cardiac pacemakers who are clinically stable are eligible. • Uncontrolled (persistent) arterial hypertension: systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 100 mm Hg. • Congestive heart failure defined as New York Heart Association class III-IV or hospitalization for CHF within 6 months of the first dose of study drug. • Clinically significant pericardial effusion. • Myocarditis. 10. 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. 11. 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. 12. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. 13. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders. 14. Active Hepatitis B infection (HBsAg positive) without receiving antiviral treatment. Note: Patients with active hepatitis B must receive antiviral treatment with lamivudi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1 Primary Objective • 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. Phase 2 Primary Objective • To evaluate the ORR in molecularly defined populations of advanced/metastatic solid tumors including NSCLC, GC/GEJ adenocarcinoma, and other selected solid tumors selected according to their molecular profile.;Secondary Objective: Phase 1 Secondary Objectives • To evaluate preliminary antitumor activity in terms of best overall response (BOR), overall response rate (ORR), disease control rate (DCR), and duration of response (DoR). • To evaluate progression-free survival (PFS) and overall survival (OS). • To characterize the pharmacokinetics (PK) of MCLA-129 including development of a population PK model. • To assess changes in cytokines following administration of MCLA-129. • To assess the immunogenicity of MCLA-129. Phase 2 Secondary Objectives • To evaluate preliminary antitumor activity in terms of BOR, DCR, and DoR. • To evaluate PFS and OS. • To characterize the safety and tolerability of MCLA-129 at the RP2D. • To characterize the PK of MCLA-129 including development of a population PK model. • To assess the immunogenicity of MCLA-129.;Primary end point(s): Phase 1 Primary endpoint 1. Incidence and severity of DLTs during Cycle 1. Phase 2 Primary endpoint 2. ORR per RECIST v.1.1 based on Investigator assessment;Timepoint(s) of evaluation of this end point: 1. Cycle 1 2. Along the study phase 2 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1 Secondary endpoints 1. Safety: Incidence, severity and relationship of AEs and SAEs; incidence, severity and changes in laboratory values; measures and changes in ECG and vital signs. 2. Tolerability: Discontinuations due to AEs, dose modifications due to AEs. 3. Efficacy: BOR, ORR, DCR, DoR, PFS and OS, per RECIST v1.1 based on Investigator assessment. 4. Pharmacokinetics: MCLA-129 concentration CEOI, Cmax, C0h and PK parameters including AUC, CL, Vss, tmax and t1/2 and to develop a population PK model. 5. Immunogenicity: Incidence and serum titers of antidrug antibodies against MCLA-129. 6. Cytokines: Change from baseline in systemic cytokines. Exploratory endpoints 7. Biomarkers: Change from baseline in biomarkers, and correlative analyses of biomarkers with antitumor response. Phase 2 Secondary endpoints 8. Efficacy: BOR, DCR, DoR, PFS and OS, per RECIST v1.1 based on Investigator assessment. 9. Safety: Incidence, severity and relationship of AEs and SAEs; incidence, severity and changes in laboratory values; measures and changes in ECG and vital signs. 10. Tolerability: Discontinuations due to AEs, dose modifications due to AEs. 11. Pharmacokinetics: MCLA-129 concentration CEOI, Cmax, C0h, and PK parameters including AUC, CL, Vss, tmax and t1/2 and to develop a population PK model. 12. Immunogenicity: Incidence and serum titers of antidrug antibodies against MCLA-129. Exploratory: 13. Biomarkers: Change from baseline in biomarkers, and correlative analyses of biomarkers with antitumor response.;Timepoint(s) of evaluation of this end point: 1,2.Along phase1 3.Every 8 wks after start treatment until progression 4.Cycle 1:Day1,4,8,15,22. Cycle 2:Day1&15. Cycle 3:Day1, then every 4 cycles after Day1 5.Day1 Cycles1,2,3 then every 4 cycles & EoT visit 6.Cycle1 only, on Day1 pre-dose, 2,4&22 h post-end of infusion (EOI) and Day15, pre-dose, 2&4 h post-EOI 7.Cycle1:Pre-dose Day1,EOI,22 h post- EOI; Any time on Days4 or 5 & 8; pre-dose | — |
Countries
Belgium, France, Korea, Republic of, Netherlands, Singapore, Spain, United States
Contacts
Public ContactMCLA-129-CL01 Project Manager
Merus N.V
Outcome results
None listed