Breast Cancer MetastaticPhase 2NCT03321981
MCLA-128 With Trastuzumab/Chemotherapy in HER2+ and With Endocrine Therapy in ER+ and Low HER2 Breast Cancer.
A Phase 2 study testing Zenocutuzumab, Trastuzumab and Vinorelbine in people with Breast Cancer Metastatic, run by Merus B.V. at 25 sites in 7 countries.
Trial summary
A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer Metastatic
- What is being tested?
- Zenocutuzumab, Trastuzumab and Vinorelbine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 105 participants
- Where
- 25 sitesin 7 countries
- Study dates
- 15 Jan 2018to 26 Jul 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed informed consent before initiation of any study procedures.
- 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 (zenocutuzumab + trastuzumab ± vinorelbine)
- Documented Human Epidermal Growth Factor Receptor (HER)2 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.
- Documented disease progression (by investigator assessment) on up to a maximum of 5 lines of HER2- directed therapy administered in the metastatic setting and progression on the most recent line. Trastuzumab, pertuzumab and an HER2 Antibody drug conjugates (ADC) (eg. Trastuzumab emtansine (T-DM1)) must have been previously administered in any sequence and in any setting.
- 2.2 Cohort 2 (zenocutuzumab + endocrine therapy)
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- Documented hormone receptor positive status (estrogen receptor positive and/or progesterone receptor positive), defined as ≥ 1% positive stained cells by local standards, based on local analysis on the most recent tumor biopsy.
- 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 tumor biopsy or an archival biopsy collected within 24 months before screening (preferably metastatic, otherwise primary).
- No more than 3 lines of prior endocrine therapy (aromatase inhibitor or fulvestrant) for metastatic disease, with radiologic or photographic evidence of disease progression on the last line, after at least 12 weeks of therapy.
- Progression on a cyclin-dependent kinase inhibitor.
- No more than 2 previous chemotherapy regimens for advanced/metastatic disease. Note: Pre/peri-menopausal women could be enrolled if amenable to be treated with the Luteinizing Hormone-Releasing Hormone (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.
- At least one lesion with measurable disease as defined by Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1. For Cohort 2, patients with bone-only disease were eligible, even in the absence of measurable disease. Patients with bone-only disease must have lytic or mixed lesions (lytic + sclerotic), and imaging documenting progression on the last line of hormone therapy must be available for central review.
- Age ≥ 18 years at signature of informed consent.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Life expectancy of ≥ 12 weeks, as per investigator.
- Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA).
- Adequate organ function:
- Absolute neutrophil count (ANC) ≥ 1.5 X 109/L.
- Hemoglobin ≥ 9 g/dL.
- Platelets ≥ 100 x 109/L.
- Serum calcium within normal ranges (or corrected with supplements).
- 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 was allowed).
- Serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 60 mL/min calculated according to the Cockcroft and Gault formula or Modification of Diet in Renal Disease (MDRD) formula for patients aged >65 years (Protocol Appendix 19.2).
- Serum albumin >3.0 g/dL.
Who cannot join
- 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.
- Known leptomeningeal involvement.
- 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).
- Participation in another interventional clinical trial or treatment with any investigational drug within 4 weeks prior to study entry.
- Any systemic anticancer therapy within 3 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, eg, mitomycin C and nitrosoureas, or anticancer immunotherapies, a washout period of 6 weeks was required. For patients in Cohort 2, this did not apply to the most recently received hormone therapy.
- Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who received prior radiotherapy to ≥25% of bone marrow were not eligible, irrespective of when it was received.
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- Persistent grade >1 clinically-significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ Grade 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 was allowed.
- 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).
- Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only).
- Exposure to the following cumulative anthracycline doses:
- Doxorubicin or liposomal doxorubicin >360 mg/m².
- Epirubicin >720 mg/m².
- Mitoxantrone >120 mg/m² and idarubicin >90 mg/m².
- Other anthracycline at a dose equivalent to >360 mg/m² doxorubicin
- For patients having received > 1 anthracycline, the cumulative dose must not exceed the equivalent of 360 mg/m² doxorubicin.
- Chronic use of high-dose oral corticosteroid therapy (>10 mg of prednisone equivalent per day).
- Uncontrolled hypertension (systolic >150 mmHg and/or diastolic > 00 mmHg) or unstable angina.
- 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).
- History of myocardial infarction within 6 months of study entry.
- 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.
- Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy.
- Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic, or psychiatric disorders.
- Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
- Pregnant or lactating women; women of childbearing potential must use effective contraception methods (patient and/or partner, eg, 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 zenocutuzumab/trastuzumab. See Protocol Section 8.10.
- Patients with only non-measurable lesions other than bone metastasis (eg, pleural effusion, ascites, or other visceral locations).
- Patients with bone-only disease with blastic-only metastasis.
Trial locations and contacts
25 sites in 7 countries.
25 sites in 7 countries
France9 sites
Hôpital Jean Minjoz
Besançon, 25030
Centre Jean Perrin
Clermont-Ferrand, 63011
Centre Georges-Francois Leclerc
Dijon, 21000
Centre Léon Bérard
Lyon, 69008
Institut Paoli Calmette
Marseille, 13009
Centre René Huguenin
Saint-Cloud, 92210
Centre Paul Strauss
Strasbourg, 67000
Centre Claudius Régaud
Toulouse, 31100
Institute Gustave Roussy
Villejuif, 94800
Spain5 sites
Vall D'Hebron Institute of Oncology (VHIO)
Barcelona, 08035
Hospital Clinic. C/Villaroel
Barcelona, 08036
Ramon Y Cajal Universitary Hospital
Madrid, 28034
Hospital Universitario 12de Octubre
Madrid, 28041
Instituto Valenciano de Oncologia
Valencia, 46009
United States3 sites
HCA Midwest Health
Kansas City, Kansas, 64131
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Sarah Cannon Research Institute
Nashville, Tennessee, 37203
Belgium3 sites
Institut Jules Bordet
Brussels, 1000
Grand Hôpital de Charleroi (GHdC)
Charleroi, 6000
UZ Leuven
Leuven, 3000
Portugal3 sites
Champalimaud Clinical Centre
Lisbon, 1400-038
Hopistal San Antonio
Porto, 4099-001
Instituto Português Oncologia
Porto, 4200-072
Netherlands1 site
Netherlands Cancer Institute NKI
Amsterdam, North Holland, 1066 CX
United Kingdom1 site
Sarah Cannon Research Institute UK
London, W1G 6AD
About this study
Official title: Phase 2 Study of MCLA-128-based Combinations in Metastatic Breast Cancer (MBC): MCLA-128/Trastuzumab/Chemotherapy in HER2-positive MBC and MCLA-128/Endocrine Therapy in Estrogen Receptor Positive and Low HER2 Expression MBC
A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2.
MCLA-128 (zenocutuzumab) is given in combinations in two metastatic breast cancer (MBC) populations, Human Epidermal Growth Factor Receptor (HER) 2-positive/amplified (Cohort 1) and Estrogen Receptor-positive/low HER2 expression (Cohort2).
Read more
Two combinations treatments will be evaluated in Cohort 1, the doublet and triplet. Initially zenocutuzumab is given in combination with trastuzumab in the doublet. After the safety of the doublet has been assessed in 4-6 patients, MCLA-128 is given in combination with trastuzumab and vinorelbine in the triplet, in parallel to the efficacy expansion of the doublet.
The doublet and triplet combinations are both evaluated in two steps with an initial safety run-in followed by a cohort efficacy expansion. In total up to 40 patients evaluable for efficacy are included in both the doublet and triplet.
In Cohort 2 zenocutuzumab is administered in combination with the same previous endocrine therapy on which progressive disease is radiologically documented. A total of up to 40 patients evaluable for efficacy are included in the Cohort 2.
Read the detailed description
Study Design Phase 2, open-label, multicenter international study to evaluate the efficacy of MCLA-128 (zenocutuzumab)-based combinations in 2 metastatic breast cancer populations, Human Epidermal Growth Factor Receptor (HER)2-positive/amplified (Cohort 1) and estrogen receptor-positive/low-HER2 expression (Cohort 2). Three combination treatments were evaluated, 2 in Cohort 1 and 1 in Cohort 2.
Cohort 1: To be eligible, patients had to have HER2-positive/amplified metastatic breast cancer, with confirmed HER2 overexpression by Immunohistochemistry (IHC) with a score of 3+ or of 2+ combined with positive Fluorescence in Situ Hybridization (FISH), have received up to 5 lines of HER2-directed therapy in the metastatic setting, and have progressed on the most recent line per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, and have been previously treated with trastuzumab, pertuzumab and an HER2 Antibody-Drug Conjugates (ADC) in any sequence and any setting.
Initially zenocutuzumab was administered with trastuzumab (doublet combination). Safety was reviewed by an Independent Data Monitoring Committee (IDMC). If the safety of the doublet was approved, the triplet combination of zenocutuzumab plus trastuzumab and vinorelbine was to be evaluated in parallel with the doublet combination.
The doublet and triplet Cohort 1 combinations were each evaluated in 2 steps with an initial safety run-in period in 4 to 6 patients who were reviewed by the IDMC before deciding to expand the cohort. The triplet combination go/no-go decision was made by the IDMC after evaluation of the doublet safety run-in patients (based on Adverse Avents [AEs], Serious Adverse Events [SAEs], relationship to study drug, and other clinically relevant parameters [eg, laboratory parameters], available pharmacokinetics, immunogenicity, and cytokine data). If the triplet combination was considered safe, the expansion of the doublet and triplet combinations was performed in parallel. Patients were included in the triplet or doublet in a 3:1 ratio, taking into account previous exposure to vinorelbine.
After the safety run-in, if Cohort 1 doublet and Cohort 1 triplet combination therapies were considered tolerable by the IDMC, they were each to be expanded to a total of up to 40 patients evaluable for efficacy. If the doublet combination regimen was not well tolerated, Cohort 1 was to be closed. If the triplet combination was not well tolerated but the doublet was acceptable, the doublet expansion was to be continued.
Cohort 2: To be eligible, patients had to have estrogen receptor-positive and low-HER2 expression metastatic breast cancer (IHC 1+, or IHC 2+ combined with negative FISH), and radiologic or photographic evidence of disease progression on the last line of prior endocrine therapy (administered for ≥12 weeks) that included an aromatase inhibitor (AI) or fulvestrant. Patients who had received up to 3 prior endocrine therapies in the metastatic setting and had progressed on a Cyclin-Dependent Kinase (CDK) inhibitor (in any line) were eligible.
Zenocutuzumab was administered in combination with the same previous endocrine therapy on which progressive disease was radiologically/photographically documented. Up to 40 patients evaluable for efficacy were included.
- Conditions
- Breast Cancer Metastatic
- Being tested
- Zenocutuzumab, Trastuzumab, Vinorelbine, Endocrine therapy
- Keywords
- Bispecific Antibody immunoglobulin gamma-1(IgG1), Human Epidermal Growth Factor Receptor (HER)2, HER3, MCLA-128, Antibodies, bispecific, Immunologic Factors, Cytokines, combination Trastuzumab with and without Vinorelbine, zenocutuzumab
- Medical subject headings
- Lethal Congenital Contracture Syndrome 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZenocutuzumabDrug
Also called MCLA-128
full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3
TrastuzumabDrug
Also called Herceptin
humanised IgG1 monoclonal antibody
VinorelbineDrug
Also called Navelbine, vinorelbine tartrate
antineoplastic drug of vinca alkaloid family
Endocrine therapyDrug
Also called fulvestrant, exemestane, letrozole, anastrazole
same endocrine therapy is administered as the last line of endocrine therapy
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 doublet | Experimental | zenocutuzumab + trastuzumab Receives: Drug: Zenocutuzumab; Drug: Trastuzumab |
| Cohort 1 triplet | Experimental | zenocutuzumab + trastuzumab + vinorelbine Receives: Drug: Zenocutuzumab; Drug: Trastuzumab; Drug: Vinorelbine |
| Cohort 2 | Experimental | zenocutuzumab + endocrine therapy Receives: Drug: Zenocutuzumab; Drug: Endocrine therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Benefit Rate at 24 Weeks
Clinical benefit rate (CBR) at 24 weeks per investigator assessment. CBR is the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) lasting 24 weeks.
Measured: 24 weeks
Secondary outcomes (10)
Progression Free Survival (PFS) Per Investigator Assessment
For assessment per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause.
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Progression Free Survival (PFS) Per Central Review
For assessment per RECIST v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause.
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Overall Response Rate (ORR) Per Investigator Assessment
The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Overall Response Rate (ORR) Per Central Review
The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Duration of Response (DoR) Per Investigator Assessment
DoR applies only to patients with a Best Overall Response (BOR) of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DoR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause.
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Duration of Response (DoR) Per Central Review
DoR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DOR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause.
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Overall Survival (OS)
The time from treatment start until death due to any cause.
Measured: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug
Evaluation of number of participants with Adverse Events leading to leading to discontinuation of study drug
Measured: During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
Number of Patients With AE's of Special Interest (AESI)
AESIs for MCLA-128 combinations include:
Infusion-related reactions (for any antibodies, known AESI for MCLA-128) Cardiotoxicity (anti-Human Epidermal Growth Factor Receptor (HER)2 therapy) Diarrhea (anti-HER2 therapy) Myelosuppression (vinorelbine)
Measured: During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
Anti-drug Antibodies Serum Titers
Number of patients with anti-drug antibodies at baseline and on treatment
Measured: Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Oct 2017
- Study start15 Jan 2018
- Primary completion26 Oct 2022
- Study completion26 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Breast Cancer MetastaticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2
- Masking
- None (open label)
- Enrolment
- 105 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merus B.V.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Ernesto Wasserman, MD, Study director, Merus B.V.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03321981
- Sponsor's protocol ID
- MCLA-128-CL02
- Other IDs
- 2017-002821-39, 2017
- Status last verified
- Feb 2024
- First submitted
- 11 Oct 2017
- Last updated
- 7 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2 Study of MCLA-128-based Combinations in Metastatic Breast Cancer (MBC): MCLA-128/Trastuzumab/Chemotherapy in HER2-positive MBC and MCLA-128/Endocrine Therapy in Estrogen Receptor Positive and Low HER2 Expression MBC
- ClinicalTrials.gov ID
- NCT03321981
- Acronym / sponsor ID
- MCLA-128-CL02
- Conditions
- Breast Cancer Metastatic
- Keywords
- Bispecific Antibody immunoglobulin gamma-1(IgG1), Human Epidermal Growth Factor Receptor (HER)2, HER3, MCLA-128, Antibodies, bispecific, Immunologic Factors, Cytokines, combination Trastuzumab with and without Vinorelbine, zenocutuzumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 105 participants (actual)
- Lead sponsor
- Merus B.V.Industry (pharma, biotech, devices)
- Study start
- 15 Jan 2018 (actual)
- Primary completion
- 26 Oct 2022 (actual)
- Study completion
- 26 Jul 2023 (actual)
- First posted
- 26 Oct 2017 (actual)
- Results
- Posted 7 Mar 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2.
MCLA-128 (zenocutuzumab) is given in combinations in two metastatic breast cancer (MBC) populations, Human Epidermal Growth Factor Receptor (HER) 2-positive/amplified (Cohort 1) and Estrogen Receptor-positive/low HER2 expression (Cohort2).
Two combinations treatments will be evaluated in Cohort 1, the doublet and triplet. Initially zenocutuzumab is given in combination with trastuzumab in the doublet. After the safety of the doublet has been assessed in 4-6 patients, MCLA-128 is given in combination with trastuzumab and vinorelbine in the triplet, in parallel to the efficacy expansion of the doublet.
The doublet and triplet combinations are both evaluated in two steps with an initial safety run-in followed by a cohort efficacy expansion. In total up to 40 patients evaluable for efficacy are included in both the doublet and triplet.
In Cohort 2 zenocutuzumab is administered in combination with the same previous endocrine therapy on which progressive disease is radiologically documented. A total of up to 40 patients evaluable for efficacy are included in the Cohort 2.
Detailed description
Study Design Phase 2, open-label, multicenter international study to evaluate the efficacy of MCLA-128 (zenocutuzumab)-based combinations in 2 metastatic breast cancer populations, Human Epidermal Growth Factor Receptor (HER)2-positive/amplified (Cohort 1) and estrogen receptor-positive/low-HER2 expression (Cohort 2). Three combination treatments were evaluated, 2 in Cohort 1 and 1 in Cohort 2.
Cohort 1: To be eligible, patients had to have HER2-positive/amplified metastatic breast cancer, with confirmed HER2 overexpression by Immunohistochemistry (IHC) with a score of 3+ or of 2+ combined with positive Fluorescence in Situ Hybridization (FISH), have received up to 5 lines of HER2-directed therapy in the metastatic setting, and have progressed on the most recent line per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, and have been previously treated with trastuzumab, pertuzumab and an HER2 Antibody-Drug Conjugates (ADC) in any sequence and any setting.
Initially zenocutuzumab was administered with trastuzumab (doublet combination). Safety was reviewed by an Independent Data Monitoring Committee (IDMC). If the safety of the doublet was approved, the triplet combination of zenocutuzumab plus trastuzumab and vinorelbine was to be evaluated in parallel with the doublet combination.
The doublet and triplet Cohort 1 combinations were each evaluated in 2 steps with an initial safety run-in period in 4 to 6 patients who were reviewed by the IDMC before deciding to expand the cohort. The triplet combination go/no-go decision was made by the IDMC after evaluation of the doublet safety run-in patients (based on Adverse Avents [AEs], Serious Adverse Events [SAEs], relationship to study drug, and other clinically relevant parameters [eg, laboratory parameters], available pharmacokinetics, immunogenicity, and cytokine data). If the triplet combination was considered safe, the expansion of the doublet and triplet combinations was performed in parallel. Patients were included in the triplet or doublet in a 3:1 ratio, taking into account previous exposure to vinorelbine.
After the safety run-in, if Cohort 1 doublet and Cohort 1 triplet combination therapies were considered tolerable by the IDMC, they were each to be expanded to a total of up to 40 patients evaluable for efficacy. If the doublet combination regimen was not well tolerated, Cohort 1 was to be closed. If the triplet combination was not well tolerated but the doublet was acceptable, the doublet expansion was to be continued.
Cohort 2: To be eligible, patients had to have estrogen receptor-positive and low-HER2 expression metastatic breast cancer (IHC 1+, or IHC 2+ combined with negative FISH), and radiologic or photographic evidence of disease progression on the last line of prior endocrine therapy (administered for ≥12 weeks) that included an aromatase inhibitor (AI) or fulvestrant. Patients who had received up to 3 prior endocrine therapies in the metastatic setting and had progressed on a Cyclin-Dependent Kinase (CDK) inhibitor (in any line) were eligible.
Zenocutuzumab was administered in combination with the same previous endocrine therapy on which progressive disease was radiologically/photographically documented. Up to 40 patients evaluable for efficacy were included.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 doublet | Experimental | Drug: Zenocutuzumab, Drug: Trastuzumabzenocutuzumab + trastuzumab |
| Cohort 1 triplet | Experimental | Drug: Zenocutuzumab, Drug: Trastuzumab, Drug: Vinorelbinezenocutuzumab + trastuzumab + vinorelbine |
| Cohort 2 | Experimental | Drug: Zenocutuzumab, Drug: Endocrine therapyzenocutuzumab + endocrine therapy |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- Signed informed consent before initiation of any study procedures.
- 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 (zenocutuzumab + trastuzumab ± vinorelbine)
- 2.2 Cohort 2 (zenocutuzumab + endocrine therapy)
- At least one lesion with measurable disease as defined by Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1. For Cohort 2, patients with bone-only disease were eligible, even in the absence of measurable disease. Patients with bone-only disease must have lytic or mixed lesions (lytic + sclerotic), and imaging documenting progression on the last line of hormone therapy must be available for central review.
Key exclusion criteria (26 listed)
- 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.
- Known leptomeningeal involvement.
- 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).
- Participation in another interventional clinical trial or treatment with any investigational drug within 4 weeks prior to study entry.
- Any systemic anticancer therapy within 3 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, eg, mitomycin C and nitrosoureas, or anticancer immunotherapies, a washout period of 6 weeks was required. For patients in Cohort 2, this did not apply to the most recently received hormone therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZenocutuzumabAlso: MCLA-128full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3 | Drug | Cohort 1 doublet, Cohort 1 triplet, Cohort 2 |
| TrastuzumabAlso: Herceptinhumanised IgG1 monoclonal antibody | Drug | Cohort 1 doublet, Cohort 1 triplet |
| VinorelbineAlso: Navelbine, vinorelbine tartrateantineoplastic drug of vinca alkaloid family | Drug | Cohort 1 triplet |
| Endocrine therapyAlso: fulvestrant, exemestane, letrozole, anastrazolesame endocrine therapy is administered as the last line of endocrine therapy | Drug | Cohort 2 |
Primary outcome
Clinical Benefit Rate at 24 Weeks
Time frame: 24 weeks
Clinical benefit rate (CBR) at 24 weeks per investigator assessment. CBR is the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) lasting 24 weeks.
10 secondary outcomes
Progression Free Survival (PFS) Per Investigator Assessment
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Progression Free Survival (PFS) Per Central Review
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Overall Response Rate (ORR) Per Investigator Assessment
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Overall Response Rate (ORR) Per Central Review
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Duration of Response (DoR) Per Investigator Assessment
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Duration of Response (DoR) Per Central Review
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Overall Survival (OS)
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug
Time frame: During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
Number of Patients With AE's of Special Interest (AESI)
Time frame: During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
Anti-drug Antibodies Serum Titers
Time frame: Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ernesto Wasserman, MD study director
Merus B.V.
25 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Zenocutuzumab, Trastuzumab and Vinorelbine in people with Breast Cancer Metastatic, run by Merus B.V. at 25 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 25 sites in France, Spain, United States, Belgium, Portugal and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical Benefit Rate at 24 Weeks (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Mar 2024.