| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Breast Cancer (MBC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer that has spread beyond the brest to other organs |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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: The primary objective of the study is to evaluate the 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) in any sequence and in any setting.
Cohort 2: Evaluate the 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:
1. Evaluate CBR at 24 weeks based on RECIST 1.1 per central review.
2. Evaluate progression-free survival (PFS; per investigator and central review.
3. Evaluate overall response rate (ORR) based on RECIST 1.1 (per investigator and central review).
4. Evaluate duration of response (DoR) based on RECIST v1.1 (per investigator and central review).
5. Evaluate overall survival (OS)
6. Evaluate safety and tolerability of MCLA-128 in combination with trastuzumab ± vinorelbine.
7. Characterize pharmacokinetics (PK) of MCLA-128 in combination with trastuzumab ± vinorelbine.
8. Characterize immunogenicity of MCLA-128 in combination with trastuzumab.
Cohort 2:
1. Evaluate CBR at 24 weeks based on RECIST 1.1 per central review.
2. Evaluate PFS (per investigator and central review).
3. Evaluate ORR based on RECIST 1.1 (per investigator and central review).
4. Evaluate DoR based on RECIST 1.1 (per investigator and central review).
5. Evaluate OS.
6. Evaluate safety and tolerability of MC |
|
| 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 12 months before screening.
b) Documented disease progression (by investigator assessment) on up to a maximum of five 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 analysis on a fresh tumour biopsy or an archival biopsy collected within 12 months before screening (preferably metastatic otherwise primary).
c) No more than three lines of prior endocrine therapy (aromatase inhibitor or fulvestrant) for metastatic disease, with radiologic or photographic evidence of 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 regimens for advanced/metastatic disease.
Note: Pre/peri-menopausal women can be enrolled if amendable to be treated with the LHRH agent 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 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 or multiple gated acquisition scan.
8. Adequate organ function
a) Absolute neutrophil count ≥1.5 x 10(exp)9/L
b) Hemoglobin ≥ 9 g/dL
c) Platelets ≥ 100 x 10(exp)9/L
d) Serum calcium within normal range (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.
g) Serum albumin > 3.0 g/dL.
Note: For both cohorts, patients will be enrolled based on their HER2 status, HR status (Cohort 2 only), and disease progression on the prior line of therapy, as reported in their medical records. Evaluability for the primary endpoint will be confirmed by central review after enrolment. Any patient found to be ineligible retrospectively will not be evaluable for the primary endpoint and may be replaced. |
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| 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. 4.03 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 of 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 per 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) |
Cohort 1: 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: Clinical benefit rate (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.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Cohort 1
1. CBR at 24 weeks based on RECIST v1.1 per central review.
2. Progression-Free Survival (PFS)
3. Overall Response Rate (ORR)
4. Duration of Response (DoR)
5. Overall Survival (OS)
6. Safety and tolerability by evaluating adverse events and serious adverse events; laboratory parameters (including hematology, biochemistry, coagulation, urinalysis, cytokines); electrocardiograms and echocardiograms; changes in vital signs, performance status, and physical examinations.
7. Plasma concentration of MNLA-128 when given in combination with trastuzumab and vinorelbine (pharmacokinetic parameters will be derived).
8. Characterize immunogenicity of MCLA-128
Cohort 2
1. CBR at 24 weeks based on RECIST v1.1 per central review.
2. Progression-Free Survival (PFS)
3. Overall Response Rate (ORR)
4. Duration of Response (DoR)
5. Overall Survival (OS)
6. Safety and tolerability by evaluating adverse events and serious adverse events; laboratory parameters (including hematology, biochemistry, coagulation, urinalysis, cytokines); electrocardiograms and echocardiograms; changes in vital signs, performance status, and physical examinations.
7. Plasma concentration of MNLA-128 when given in combination with trastuzumab and vinorelbine (pharmacokinetic parameters will be derived).
8. Characterize immunogenicity of MCLA-128
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients will be evaluated every 3 months for up to 1 year for disease status or until initiation of alternative treatment. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Belgium |
| France |
| Netherlands |
| Portugal |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Planned end date for clinical interventions is LVLS, planned end date for all trial procedures is database lock (DBL) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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