MCLA-128 With Trastuzumab/Chemotherapy in HER2+ and With Endocrine Therapy in ER+ and Low HER2 Breast Cancer.
- Conditions
- Breast Cancer Metastatic
- Interventions
- Registration Number
- NCT03321981
- Lead Sponsor
- Merus N.V.
- Brief 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.
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 105
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1 triplet Zenocutuzumab zenocutuzumab + trastuzumab + vinorelbine Cohort 1 triplet Vinorelbine zenocutuzumab + trastuzumab + vinorelbine Cohort 1 doublet Zenocutuzumab zenocutuzumab + trastuzumab Cohort 1 doublet Trastuzumab zenocutuzumab + trastuzumab Cohort 2 Zenocutuzumab zenocutuzumab + endocrine therapy Cohort 2 Endocrine therapy zenocutuzumab + endocrine therapy Cohort 1 triplet Trastuzumab zenocutuzumab + trastuzumab + vinorelbine
- Primary Outcome Measures
Name Time Method Clinical Benefit Rate at 24 Weeks 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.
- Secondary Outcome Measures
Name Time Method Progression Free Survival (PFS) Per Central Review 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) 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.
Overall Response Rate (ORR) Per Investigator Assessment 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) The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
Overall Response Rate (ORR) Per Central Review 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) The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
Duration of Response (DoR) Per Investigator Assessment 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) 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.
Duration of Response (DoR) Per Central Review 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) 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.
Overall Survival (OS) 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) The time from treatment start until death due to any cause.
Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug 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). Evaluation of number of participants with Adverse Events leading to leading to discontinuation of study drug
Number of Patients With AE's of Special Interest (AESI) 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). 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)Anti-drug Antibodies Serum Titers Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit. Number of patients with anti-drug antibodies at baseline and on treatment
Progression Free Survival (PFS) Per Investigator Assessment 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) 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.
Trial Locations
- Locations (25)
Champalimaud Clinical Centre
🇵🇹Lisbon, Portugal
Hopistal San Antonio
🇵🇹Porto, Portugal
Instituto Valenciano de Oncologia
🇪🇸Valencia, Spain
Instituto Português Oncologia
🇵🇹Porto, Portugal
Hospital Clinic. C/Villaroel
🇪🇸Barcelona, Spain
Institute Gustave Roussy
🇫🇷Villejuif, France
Centre Léon Bérard
🇫🇷Lyon, France
UZ Leuven
🇧🇪Leuven, Belgium
Centre Claudius Régaud
🇫🇷Toulouse, France
Ramon Y Cajal Universitary Hospital
🇪🇸Madrid, Spain
Hospital Universitario 12de Octubre
🇪🇸Madrid, Spain
Centre Jean Perrin
🇫🇷Clermont-Ferrand, France
Centre Georges-Francois Leclerc
🇫🇷Dijon, France
Centre René Huguenin
🇫🇷Saint-Cloud, France
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
HCA Midwest Health
🇺🇸Kansas City, Kansas, United States
Grand Hôpital de Charleroi (GHdC)
🇧🇪Charleroi, Belgium
Institut Jules Bordet
🇧🇪Brussel, Belgium
Hôpital Jean Minjoz
🇫🇷Besançon, France
Institut Paoli Calmette
🇫🇷Marseille, France
Netherlands Cancer Institute NKI
🇳🇱Amsterdam, Noord Holland, Netherlands
Centre Paul Strauss
🇫🇷Strasbourg, France
Vall D'Hebron Institute of Oncology (VHIO)
🇪🇸Barcelona, Spain
Sarah Cannon Research Institute UK
🇬🇧London, United Kingdom