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

NCT03321981 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: MCLA-128-CL022017-002821-39
• Study Type: interventional
• Target: 105
• Locations: 7 countries
• Sites: 25

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (3)

Cohort 1 doublet

EXPERIMENTAL

zenocutuzumab + trastuzumab

Drug: Zenocutuzumab; Drug: Trastuzumab

Cohort 1 triplet

EXPERIMENTAL

zenocutuzumab + trastuzumab + vinorelbine

Drug: Zenocutuzumab; Drug: Trastuzumab; Drug: Vinorelbine

Cohort 2

EXPERIMENTAL

zenocutuzumab + endocrine therapy

Drug: Zenocutuzumab; Drug: Endocrine therapy

Interventions

Zenocutuzumab DRUG

full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3

Also known as: MCLA-128

Cohort 1 doublet; Cohort 1 triplet; Cohort 2

Trastuzumab DRUG

humanised IgG1 monoclonal antibody

Also known as: Herceptin

Cohort 1 doublet; Cohort 1 triplet

Vinorelbine DRUG

antineoplastic drug of vinca alkaloid family

Also known as: Navelbine, vinorelbine tartrate

Cohort 1 triplet

Endocrine therapy DRUG

same endocrine therapy is administered as the last line of endocrine therapy

Also known as: fulvestrant, exemestane, letrozole, anastrazole

Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.
• Cohort 2 (zenocutuzumab + endocrine therapy)
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Merus B.V.: lead

Study Sites (25)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

HCA Midwest Health

Kansas City, Kansas, 64131, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Institut Jules Bordet

Brussels, 1000, Belgium

Location

Grand Hôpital de Charleroi (GHdC)

Charleroi, 6000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Hôpital Jean Minjoz

Besançon, 25030, France

Location

Centre Jean Perrin

Clermont-Ferrand, 63011, France

Location

Centre Georges-Francois Leclerc

Dijon, 21000, France

Location

Centre Léon Bérard

Lyon, 69008, France

Location

Institut Paoli Calmette

Marseille, 13009, France

Location

Centre René Huguenin

Saint-Cloud, 92210, France

Location

Centre Paul Strauss

Strasbourg, 67000, France

Location

Centre Claudius Régaud

Toulouse, 31100, France

Location

Institute Gustave Roussy

Villejuif, 94800, France

Location

Netherlands Cancer Institute NKI

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Champalimaud Clinical Centre

Lisbon, 1400-038, Portugal

Location

Hopistal San Antonio

Porto, 4099-001, Portugal

Location

Instituto Português Oncologia

Porto, 4200-072, Portugal

Location

Vall D'Hebron Institute of Oncology (VHIO)

Barcelona, 08035, Spain

Location

Hospital Clinic. C/Villaroel

Barcelona, 08036, Spain

Location

Ramon Y Cajal Universitary Hospital

Madrid, 28034, Spain

Location

Hospital Universitario 12de Octubre

Madrid, 28041, Spain

Location

Instituto Valenciano de Oncologia

Valencia, 46009, Spain

Location

Sarah Cannon Research Institute UK

London, W1G 6AD, United Kingdom

Location

MeSH Terms

Conditions

Lethal Congenital Contracture Syndrome 2

Interventions

zenocutuzumab; Trastuzumab; Vinorelbine; Fulvestrant; exemestane; Letrozole; Anastrozole

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Executive Director Clinical Trials
• Organization: Merus N.V.

USenquiries@merus.nl

+16174014499

Study Officials

• Ernesto Wasserman, MD

  Merus B.V.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2

Study Record Dates

• First Submitted: October 11, 2017
• First Posted: October 26, 2017
• Study Start: January 15, 2018
• Primary Completion: October 26, 2022
• Study Completion: July 26, 2023
• Last Updated: March 7, 2024
• Results First Posted: March 7, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (9); NL (1); BE (3); ES (5); GB (1); US (3); PT (3)