MCLA-128 With Trastuzumab/Chemotherapy in HER2+ and With Endocrine Therapy in ER+ and Low HER2 Breast Cancer.

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).

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer Metastatic
• Intervention / Treatment: Drug: Trastuzumab; Drug: Vinorelbine; Drug: Endocrine therapy; Drug: Zenocutuzumab

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 Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1000
    • Institut Jules Bordet
  • Charleroi, Belgium, 6000
    • Grand Hôpital de Charleroi (GHdC)
  • Leuven, Belgium, 3000
    • UZ Leuven
• France
  • Besançon, France, 25030
    • Hôpital Jean Minjoz
  • Clermont-Ferrand, France, 63011
    • Centre Jean Perrin
  • Dijon, France, 21000
    • Centre Georges-Francois Leclerc
  • Lyon, France, 69008
    • Centre Leon Bérard
  • Marseille, France, 13009
    • Institut Paoli Calmette
  • Saint-Cloud, France, 92210
    • Centre René Huguenin
  • Strasbourg, France, 67000
    • Centre Paul Strauss
  • Toulouse, France, 31100
    • Centre Claudius Régaud
  • Villejuif, France, 94800
    • Institute Gustave Roussy
• Netherlands
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1066 CX
      • Netherlands Cancer Institute NKI
• Portugal
  • Lisbon, Portugal, 1400-038
    • Champalimaud Clinical Centre
  • Porto, Portugal, 4099-001
    • Hopistal San Antonio
  • Porto, Portugal, 4200-072
    • Instituto Português Oncologia
• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron Institute of Oncology (VHIO)
  • Barcelona, Spain, 08036
    • Hospital Clinic. C/Villaroel
  • Madrid, Spain, 28034
    • Ramon Y Cajal Universitary Hospital
  • Madrid, Spain, 28041
    • Hospital Universitario 12de Octubre
  • Valencia, Spain, 46009
    • Instituto Valenciano de Oncología
• United Kingdom
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute UK
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 64131
      • HCA Midwest Health
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (zenocutuzumab + trastuzumab ± vinorelbine)

   1. 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.
   2. 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)

   1. 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.
   2. 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).
   3. 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.
   4. Progression on a cyclin-dependent kinase inhibitor.
   5. 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.
3. 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.
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:

   1. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L.
   2. Hemoglobin ≥ 9 g/dL.
   3. Platelets ≥ 100 x 109/L.
   4. Serum calcium within normal ranges (or corrected with supplements).
   5. 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).
   6. 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).
   7. Serum albumin >3.0 g/dL.

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, 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.
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 were 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 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 was 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:

    1. Doxorubicin or liposomal doxorubicin >360 mg/m².
    2. Epirubicin >720 mg/m².
    3. Mitoxantrone >120 mg/m² and idarubicin >90 mg/m².
    4. Other anthracycline at a dose equivalent to >360 mg/m² doxorubicin
    5. 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 > 00 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
19. 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.
20. Patients with only non-measurable lesions other than bone metastasis (eg, pleural effusion, ascites, or other visceral locations).
21. Patients with bone-only disease with blastic-only metastasis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 doublet; zenocutuzumab + trastuzumab	Drug: Trastuzumab; humanised IgG1 monoclonal antibody; Other Names: Herceptin; Drug: Zenocutuzumab; full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3; Other Names: MCLA-128
Experimental: Cohort 1 triplet; zenocutuzumab + trastuzumab + vinorelbine	Drug: Trastuzumab; humanised IgG1 monoclonal antibody; Other Names: Herceptin; Drug: Vinorelbine; antineoplastic drug of vinca alkaloid family; Other Names: Navelbine; vinorelbine tartrate; Drug: Zenocutuzumab; full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3; Other Names: MCLA-128
Experimental: Cohort 2; zenocutuzumab + endocrine therapy	Drug: Endocrine therapy; same endocrine therapy is administered as the last line of endocrine therapy; Other Names: exemestane; letrozole; fulvestrant; anastrazole; Drug: Zenocutuzumab; full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3; Other Names: MCLA-128

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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).	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).	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.	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.	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.	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	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)	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	Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit.

Collaborators and Investigators

• Sponsor: Merus N.V.
• Investigators: Study Director: Ernesto Wasserman, MD, Merus N.V.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2018
• Primary Completion (Actual): October 26, 2022
• Study Completion (Actual): July 26, 2023

Study Registration Dates

• First Submitted: October 11, 2017
• First Submitted That Met QC Criteria: October 23, 2017
• First Posted (Actual): October 26, 2017

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: February 11, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Cytokines; Immunologic Factors; MCLA-128; zenocutuzumab; Antibodies, bispecific; combination Trastuzumab with and without Vinorelbine; Bispecific Antibody immunoglobulin gamma-1(IgG1), Human Epidermal Growth Factor Receptor (HER)2, HER3
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Trastuzumab; Letrozole; Fulvestrant; Vinorelbine; Exemestane
• Other Study ID Numbers: MCLA-128-CL02; 2017-002821-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No