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

Sponsor
Merus N.V. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03321981
Collaborator
(none)
101
Enrollment
25
Locations
3
Arms
73
Anticipated Duration (Months)
4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

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
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
101 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 2three 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 :
Jan 15, 2018
Anticipated Primary Completion Date :
Dec 31, 2023
Anticipated Study Completion Date :
Feb 15, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1 doublet

Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Names:
  • bispecific

    • Drug: Trastuzumab
    humanised IgG1 monoclonal antibody
    Other Names:
  • Herceptin

    		•
    Experimental: Cohort 1 triplet

    Drug: MCLA-128
    full length IgG1 bispecific antibody targeting HER2 and HER3
    Other Names:
  • bispecific

    • Drug: Trastuzumab
    humanised IgG1 monoclonal antibody
    Other Names:
  • Herceptin

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

    		•
    Experimental: Cohort 2

    Drug: MCLA-128
    full length IgG1 bispecific antibody targeting HER2 and HER3
    Other Names:
  • 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 [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) [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) [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) [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) [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) [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 [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] [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] [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] [baseline and 3-12 weeks until last patient last treatment]

      area under the concentration curve [AUC] for MCLA-128

    10. clearance [CL] [6 weeks]

      clearance [CL] of MCLA-128

    11. volume of distribution at steady state [Vss] [6 weeks]

      volume of distribution at steady state [Vss] of MCLA-128

    12. time to reach maximum concentration [tmax] [6 weeks]

      time to reach maximum concentration [tmax] for MCLA-128

    13. half life [t1/2] [6 weeks]

      half life [t1/2] of MCLA-128

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

      concentration of trastuzumab at end of infusion [C EOI]

    15. trough plasma concentration [C0h] trastuzumab [6 weeks]

      plasma concentration of trastuzumab as measured at trough level t=0h

    16. anti-drug antibodies serum titers [baseline and 6-12 weeks until last patient last treatment]

      serum titers of anti-drug antibodies against MCLA-128

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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 patients with bone-only disease are eligible even in absence of measurable disease and must have lytic or mixed lesions. 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. 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 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. 4.03 is allowed.

    8. History of 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. Exposure to specific cumulative anthracycline doses

    11. Chronic use of high-dose oral corticosteroid therapy .

    12. Uncontrolled hypertension 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 HIV, HBV, or HCV infection.

    19. 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

    Locations

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

    Sponsors and Collaborators

    • Merus N.V.

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Merus N.V.
    ClinicalTrials.gov Identifier:
    NCT03321981
    Other Study ID Numbers:
    • MCLA-128-CL02
    • 2017-002821-39
    First Posted:
    Oct 26, 2017
    Last Update Posted:
    Aug 11, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Trastuzumab
    Letrozole
    Vinorelbine
    Fulvestrant
    Exemestane

    Study Results

    No Results Posted as of Aug 11, 2022