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

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ClinicalTrials.gov Identifier: NCT03321981
Recruitment Status : Recruiting
First Posted : October 26, 2017
Last Update Posted : August 13, 2018
Sponsor:
Collaborators:
Oncology Therapeutic Development
Chiltern International Inc.
4Clinics
Q2 Solutions
Information provided by (Responsible Party):
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 is given in combinations in two metastatic breast cancer (MBC) populations, HER2-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 MCLA-128 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 MCLA-128 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.


Condition or disease Intervention/treatment Phase
Breast Cancer Metastatic Drug: MCLA-128 Drug: Trastuzumab Drug: Vinorelbine Drug: Endocrine therapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 15, 2018
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : March 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Trastuzumab

Arm Intervention/treatment
Experimental: Cohort 1 doublet
two step evaluation with safety review after 4-6 patients receiving combination of MCLA-128, 750mg 2hour intravenous infusion in combination with trastuzumab, 8mg/kg first cycle, 6mg/kg other cycles, 90minute intravenous infusion; once per cycle of 21 days.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Drug: Trastuzumab
humanised IgG1 monoclonal antibody
Other Name: Herceptin

Experimental: Cohort 1 triplet
two step evaluation with safety review after 4-6 patients receiving combination of MCLA-128, 750mg 2hour intravenous infusion once per cycle of 21 days in combination with trastuzumab, 8mg/kg 90minute first cycle, 6mg/kg other cycles, intravenous infusion once per cycle of 21 days and vinorelbine, 25 mg/M2 10minute intravenous infusion twice per cycle of 21 days;
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Drug: Trastuzumab
humanised IgG1 monoclonal antibody
Other Name: Herceptin

Drug: Vinorelbine
antineoplastic drug of vinca alkaloid family
Other Names:
  • Navelbine
  • vinorelbine tartrate

Experimental: Cohort 2
MCLA-128, 750mg 2hour intravenous infusion once per cycle of 21 days in combination with same dose and regimen of endocrine therapy prior to study entry and on which the patient progressed.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Drug: Endocrine therapy
same endocrine therapy is administered as the last line of endocrine therapy
Other Names:
  • fulvestrant
  • exemestane
  • letrozole
  • anastrazole




Primary Outcome Measures :
  1. Clinical Benefit Rate at 24 weeks [ Time Frame: 24 weeks ]
    The proportion of patients with a best overall response of Complete Response, Partial Response or Stable Disease at 24 weeks based upon RECIST 1.1


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Baseline, every 6 weeks until progression up to one year after last patient first treatment ]
    the time from treatment start until radiologic progression or death due to any cause

  2. Overall Response Rate (ORR) [ Time Frame: Baseline, every 6 weeks until progression up to one year after last patient first treatment ]
    the proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1

  3. Duration of Response (DoR) [ Time Frame: Baseline, every 6 weeks until progression up to one year after last patient first treatment ]
    the time from response (Complete Response or Partial Response) until progression or death due to underlying cancer based upon RECIST 1.1

  4. Overall Survival (OS) [ Time Frame: Every 3 months after last visit up to 1 year after last patient first treatment ]
    the time from treatment start until death due to any cause

  5. number of participants with treatment emergent Adverse Events (AE) [ Time Frame: continuous until 1 year after last patient last treatment ]
    Evaluation of number of participants with Adverse Events

  6. number of patients that discontinue due to intolerability of study drug [ Time Frame: continuous through study completion, an average of 6 months ]
    discontinuations due to AEs, dose modifications due to AEs and immunogenicity assessments

  7. maximum plasma concentration [Cmax] [ Time Frame: baseline and 3-12 weeks until last patient last treatment ]
    maximum plasma concentration [Cmax] for MCLA-128 as measured from all individual plasma concentration

  8. trough plasma concentration [C0h] [ Time Frame: baseline and 3-12 weeks until last patient last treatment ]
    plasma concentration of MCLA-128 as measured at trough level t=0h

  9. area under curve [AUC] [ Time Frame: baseline and 3-12 weeks until last patient last treatment ]
    area under the concentration curve [AUC] for MCLA-128

  10. clearance [CL] [ Time Frame: 6 weeks ]
    clearance [CL] of MCLA-128

  11. volume of distribution at steady state [Vss] [ Time Frame: 6 weeks ]
    volume of distribution at steady state [Vss] of MCLA-128

  12. time to reach maximum concentration [tmax] [ Time Frame: 6 weeks ]
    time to reach maximum concentration [tmax] for MCLA-128

  13. half life [t1/2] [ Time Frame: 6 weeks ]
    half life [t1/2] of MCLA-128

  14. concentration of trastuzumab at end of infusion [C EOI] [ Time Frame: 6 weeks ]
    concentration of trastuzumab at end of infusion [C EOI]

  15. trough plasma concentration [C0h] trastuzumab [ Time Frame: 6 weeks ]
    plasma concentration of trastuzumab as measured at trough level t=0h

  16. anti-drug antibodies serum titers [ Time Frame: baseline and 6-12 weeks until last patient last treatment ]
    serum titers of anti-drug antibodies against MCLA-128



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  3. Measurable disease as defined by RECIST version 1.1 by radiologic methods on or after the most recent line of therapy. For Cohort 2, imaging must be available for central review.
  4. Eastern Cooperative Oncology Group performance status of 0 or 1.
  5. Life expectancy of ≥ 12 weeks, as per investigator.
  6. Left ventricular ejection fraction ≥ 50% by echocardiogram or multiple gated acquisition scan.
  7. Patients must have adequate organ function

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.
  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. 4.0 is allowed.
  8. History of prior ≥ grade 3 hypersensitivity reaction or any toxicity attributed to trastuzumab or murine proteins 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. Chronic use of high-dose oral corticosteroid therapy .
  11. Uncontrolled hypertension or unstable angina.
  12. 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).
  13. History of myocardial infarction within 6 months of study entry.
  14. 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.
  15. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy.
  16. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders.
  17. Known HIV, HBV, or HCV infection.
  18. Pregnant or lactating women; women of childbearing potential must use effective contraception methods prior to study entry, for the duration of study participation, and for 6 months after the last dose of MCLA-128.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03321981


Contacts
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Contact: Ernesto Wasserman, MD +31302538800 enquiries@merus.nl
Contact: Andres L Sirulnik, MD PhD +31 30 2538800 enquiries@merus.nl

Locations
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United States, California
Cedars-Sinai Medical Center Not yet recruiting
Los Angeles, California, United States, 90048
Contact: Monica Mita, MD         
Principal Investigator: Monica Mita, MD         
United States, Illinois
Feinberg School of Medicine Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Bill Gradishar, MD         
Principal Investigator: Bill Gradishar, MD         
United States, Kansas
HCA Midwest Health Recruiting
Kansas City, Kansas, United States, 64131
Contact: Stephany Graff, MD         
Principal Investigator: Stephany Graff, MD         
United States, Tennessee
Tennessee Oncology Chattanooga Recruiting
Chattanooga, Tennessee, United States, 37404
Contact: Brooke Daniel, MD         
Principal Investigator: Brooke Daniel, MD         
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Erika Hamilton, MD         
Principal Investigator: Erika Hamilton, MD         
Belgium
Institut Jules Bordet Recruiting
Brussel, Belgium, 1000
Contact: Philippe AFTIMOS, MD         
Principal Investigator: Philippe AFTIMOS, MD         
Grand Hôpital de Charleroi (GHdC) Recruiting
Charleroi, Belgium, 6000
Contact: Jean Luc CANON, MD         
Principal Investigator: Jean Luc CANON, MD         
UZ Leuven Not yet recruiting
Leuven, Belgium, 3000
Contact: Hans WILDIERS, MD         
Principal Investigator: Hans WILDIERS, MD         
Hôpital Ambroise Paré Recruiting
Mons, Belgium, 7000
Contact: Nathalie CORNEZ, MD         
Principal Investigator: Nathalie CORNEZ, MD         
France
Hôpital Jean Minjoz Recruiting
Besançon, France, 25030
Contact: Fernando BAZAN, MD         
Principal Investigator: Fernando BAZAN, MD         
Centre Léon Bérard Not yet recruiting
Lyon, France, 69008
Contact: Thomas BACHELOT, MD         
Principal Investigator: Thomas BACHELOT, MD         
Centre René Huguenin Recruiting
Saint-Cloud, France, 92210
Contact: Francois-Clement BIDARD, MD         
Principal Investigator: Francois-Clement BIDARD, MD         
Centre Paul Strauss Recruiting
Strasbourg, France, 67000
Contact: Thierry PETIT, MD         
Principal Investigator: Thierry PETIT, MD         
Centre Claudius Régaud Recruiting
Toulouse, France, 31100
Contact: Florence DALENC, MD         
Principal Investigator: Florence DALENC, MD         
Institute Gustave Roussy Recruiting
Villejuif, France, 94800
Contact: Barbara PISTILLI, MD         
Principal Investigator: Barbara PISTILLI, MD         
Portugal
Champalimaud Clinical Centre Not yet recruiting
Lisbon, Portugal, 1400-038
Contact: Fatima Cardoso, MD         
Principal Investigator: Fatima Cardoso, MD         
Hopistal San Antonio Recruiting
Porto, Portugal, 4099-001
Contact: Noemia Afonso, MD         
Principal Investigator: Noemia Afonso, MD         
Instituto Português Oncologia Recruiting
Porto, Portugal, 4200-072
Contact: Ana Ferreira, MD         
Principal Investigator: Ana Ferreira, MD         
Spain
Vall D'Hebron Institute of Oncology (VHIO) Recruiting
Barcelona, Spain, 08035
Contact: Cristina SAURA, MD         
Principal Investigator: Cristina SAURA, MD         
Hospital Clinic. C/Villaroel Recruiting
Barcelona, Spain, 08036
Contact: Maria Jesus VIDAL, MD         
Principal Investigator: Maria Jesus VIDAL, MD         
Hospital Universitario 12de Octubre Recruiting
Madrid, Spain, 28041
Contact: Luis MANSO, MD         
Principal Investigator: Luis MANSO, MD         
Instituto Valenciano de Oncologia Recruiting
Valencia, Spain, 46009
Contact: Joaquin GAVILA, MD         
Principal Investigator: Joaquin GAVILA, MD         
Sponsors and Collaborators
Merus N.V.
Oncology Therapeutic Development
Chiltern International Inc.
4Clinics
Q2 Solutions
Investigators
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Study Director: Medical Director: Ernesto Wasserman, MD Merus N.V.

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Responsible Party: Merus N.V.
ClinicalTrials.gov Identifier: NCT03321981     History of Changes
Other Study ID Numbers: MCLA-128-CL02
2017-002821-39 ( EudraCT Number )
First Posted: October 26, 2017    Key Record Dates
Last Update Posted: August 13, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: individual participant data are made available only to the individual patient upon specific request of that individual patient or its treating physician

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merus N.V.:
Bispecific Antibody IgG1, HER2 HER3
MCLA-128
Antibodies, bispecific
Immunologic Factors
Cytokines
combination Trastuzumab with and without Vinorelbine
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Vinorelbine
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators