E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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, 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 |
|
E.2.2 | Secondary objectives of the trial |
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 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 24 months before screening.. b. Documented disease progression (by investigator assessment) on up to a maximum of 5 lines of HER2-directed therapy administered in the metastatic setting, and have progressed on the most recent line. Trastuzumab, pertuzumab and an HER2 antibody drug conjugate (e.g. T-DM1) must have been previously administered in any sequence and in any setting.. 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 24 months before screening (preferably metastatic otherwise primary). c. No more than 3 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 two 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. In Cohort 1, patients must have at least one lesion with measurable disease as defined by RECIST version 1.1. In Cohort 2, patients must have at least one lesion with measurable disease as defined by RECIST version 1.1. Patients with bone-only disease are eligible, even in the absence of measurable disease. Patients with bone-only disease must have lytic or mixed lesions (lytic + sclerotic). For Cohort 2, imaging documenting progression on the last line of hormone therapy 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 |
|
E.4 | Principal 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 excipeint 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. 20. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites or other visceral locations). 21. Patients with bone-only disease with blastic-only metastasis. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cohorts 1 and 2: CBR per investigator radiologic review at 24 weeks |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor assessment 24 weeks after treatment start |
|
E.5.2 | 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 |
|
E.5.2.1 | 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 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Belgium |
France |
Netherlands |
Portugal |
Spain |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |