Metastatic Breast Cancer MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Code: MCLA-128
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Not assigned
CAS Number: Not assigned
Current Sponsor code: MCLA-128
Other descriptive name: MCLA-128
Concentrati
Sponsors
Merus N.V.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed informed consent before initiation of any study procedures. 2. Women with histologically or cytologically confirmed breast cancer with evidence of metastatic or locally advanced disease not amenable to any local therapy with curative intent: 2.1 Cohort 1 (MCLA-128 + trastuzumab ± vinorelbine) a. Documented HER2 overexpression/amplification, defined as immunohistochemistry (IHC) 3+ positive, or IHC 2+ combined with positive fluorescence in situ hybridization (FISH), based on local analysis on the most recent tumor biopsy (preferably metastatic, otherwise primary), either fresh or archival collected within 12 months before screening.. b. Documented disease progression (by investigator assessment) on 2 to 4 lines of HER2-directed therapy administered in the adjuvant/neoadjuvant, unresectable locally advanced/metastatic setting; trastuzumab plus pertuzumab and an HER2 antibody drug conjugate (e.g. T-DM1) must all have been previously administered (in any sequence). 2.2 Cohort 2 (MCLA-128 + endocrine therapy) a. Documented hormone receptor positive status (estrogen receptor positive [ER+] and/or progesterone receptor positive [PR+]), defined as = 1% positive stained cells by local standards, based on local analysis on the most recent tumor biopsy b. Documented low-level HER2 expression, defined as IHC HER2 1+, or IHC HER2 2+ combined with negative FISH, based on local testing on a fresh tumor biopsy or an archival biopsy collected within 12 months before screening (preferably metastatic otherwise primary). c. One or two lines of prior endocrine therapy (aromatase inhibitor or fulvestrant) for metastatic disease, with radiologically documented disease progression on the last line, after at least 12 weeks of therapy. d. Progression on a cyclin-dependent kinase inhibitor. e. No more than one previous chemotherapy regimen for advanced/metastatic disease. Note: Pre/peri-menopausal women can be enrolled if amenable to be treated with the LHRH agonist goserelin. Such patients must have commenced treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to study entry, and patients who received an alternative LHRH agonist prior to study entry must switch to goserelin for the duration of the trial. 3. Measurable disease as defined by RECIST version 1.1 on or after the most recent line of therapy. For Cohort 2, imaging must be available for central review. 4. Age = 18 years at signature of informed consent. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Life expectancy of = 12 weeks, as per investigator. 7. Left ventricular ejection fraction (LVEF) = 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA). 8. Adequate organ function: a. Absolute neutrophil count (ANC) = 1.5 X 109/L b. Hemoglobin = 9 g/dL c. Platelets = 100 x 109/L d. Serum calcium within normal ranges (or corrected with supplements) e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) = 2.5 x upper limit of normal (ULN) and total bilirubin = 1.5 x ULN (in cases of liver involvement, ALT/AST = 5 x ULN and total bilirubin within normal ranges will be allowed) f. Serum creatinine = 1.5 x ULN or creatinine clearance = 60 mL/min calculated according to the Cockroft and Gault formula or MDRD formula for patients aged > 65 years (Appendix 19.2) g. Serum albumin > 3.0 g/dL Are the trial subjects under 18? no Number of subjects for this age range:
Exclusion criteria
Exclusion criteria: 1. 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. 2. Known leptomeningeal involvement. 3. Advanced/metastatic, symptomatic, visceral spread, with a risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement). 4. Participation in another interventional clinical trial or treatment with any investigational drug within 4 weeks prior to study entry. 5. Any systemic anticancer therapy within 3 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, or anticancer immunotherapies, a washout period of 6 weeks is required. For patients in Cohort 2, this does not apply to the most recently received hormone therapy. 6. 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. 7. Persistent grade > 1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy = grade 1 NCI-CTCAE v. 4.0 is allowed. 8. History of hypersensitivity reaction or any toxicity attributed to trastuzumab, murine proteins or any of the excipients that warranted permanent cessation of these agents (applicable for Cohort 1 only). 9. Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only) 10. Exposure to the following cumulative anthracycline doses: a. Doxorubicin or liposomal doxorubicin > 360 mg/m² b. Epirubicin > 720 mg/m² c. Mitoxantrone > 120 mg/m² and idarubicin > 90 mg/m² d. Other anthracycline at a dose equivalent to > 360 mg/m² doxorubicin e. For patients having received > 1 anthracycline, the cumulative dose must not exceed the equivalent of 360 mg/m² doxorubicin 11. Chronic use of high-dose oral corticosteroid therapy (>10 mg of prednisone equivalent a day). 12. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina. 13. 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). 14. History of myocardial infarction within 6 months of study entry. 15. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of study entry. 16. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. 17. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders. 18. Known HIV, HBV, or HCV infection. 19. Pregnant or lactating women; women of childbearing potential must use effective contraception methods (patient and/or partner, e.g., surgical sterilization, a reliable barrier method) prior to study entry, for the duration of study participation, and for 7 months after the last dose of MCLA-128/trastuzumab. See Section 8.10.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Cohort 1 (HER2-positive/amplified MBC): MCLA-128 + trastuzumab ± vinorelbine: Evaluate efficacy of MCLA-128 combined with trastuzumab ± vinorelbine in terms of clinical benefit rate (CBR) at 24 weeks based on RECIST 1.1 (per investigator review) in HER2-positive/amplified MBC patients who have progressed on prior HER2-directed therapy that included trastuzumab with pertuzumab, and an HER2 antibody drug conjugate (ADC) Cohort 2 (estrogen receptor [ER]-positive/low HER2 expression MBC): MCLA-128 + endocrine therapy: Evaluate efficacy of MCLA-128 combined with endocrine therapy in terms of CBR at 24 weeks based on RECIST 1.1 (per investigator review) in ER-positive and low HER2 expression MBC patients who have previously progressed on the same endocrine therapy;Secondary Objective: Cohort 1, evaluate: - CBR at 24 weeks (RECIST 1.1 per central review) - progression-free survival (PFS; per investigator/central review) - overall response rate (ORR) based on RECIST 1.1 (per investigator/central review). - duration of response (DoR) based on RECIST v1.1 (per investigator/central review) - overall survival (OS) - safety and tolerability of MCLA-128 in combination with trastuzumab ± vinorelbine - pharmacokinetics (PK) of MCLA-128 in combination with trastuzumab ± vinorelbine - immunogenicity of MCLA-128 in combination with trastuzumab Cohort 2, evaluate: - CBR at 24 weeks based on RECIST 1.1 per central review - PFS (per investigator/central review) - ORR based on RECIST 1.1 (per investigator/central review) - DoR based on RECIST 1.1 (per investigator/central review) - OS - safety and tolerability of MCLA-128 combined with endocrine therapy - PK of MCLA-128 combined with endocrine therapy - immunogenicity of MCLA-128 combined with endocrine therapy;Primary end point(s): Cohorts 1 and 2: CBR per investigator radiologic review at 24 weeks;Timepoint(s) of evaluation of this end point: Tumor assessment 24 weeks after treatment start | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Cohort 1: CBR at 24 weeks per central review, and ORR, PFS, and DoR per investigator and central review Cohort 2: CBR at 24 weeks per central review, and PFS per investigator and central review;Timepoint(s) of evaluation of this end point: CBR and ORR per central review: tumor assessment at 24 weeks PFS and DoR: at patient's disease progression | — |
Countries
Belgium, France, Netherlands, Portugal, Spain, United Kingdom, United States
Contacts
Public ContactMCLA-128-CL02 project manager
Oncology Therapeutic Development
Outcome results
None listed