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

• ClinicalTrials.gov Identifier: NCT03321981
• Recruitment Status: Recruiting
• First Posted: October 26, 2017
• Last Update Posted: August 13, 2018
• Sponsor: Merus N.V.
• Collaborators: Oncology Therapeutic Development; Chiltern International Inc.; 4Clinics; Q2 Solutions
• Information provided by (Responsible Party): Merus N.V.

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Ernesto Wasserman, MD; +31302538800; enquiries@merus.nl

Contact: Andres L Sirulnik, MD PhD; +31 30 2538800; enquiries@merus.nl

Locations

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

• Study Director: Medical Director: Ernesto Wasserman, MD; Merus N.V.

More Information

• 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
• 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

• 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:

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