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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer Metastatic

Intervention / Treatment
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* Drug: MCLA-128
* Drug: Trastuzumab
* Drug: Vinorelbine
* Drug: Endocrine therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Eastern Cooperative Oncology Group performance status of 0 or 1. Life expectancy of ≥ 12 weeks, as per investigator. Left ventricular ejection fraction ≥ 50% by echocardiogram or multiple gated acquisition scan. Adequate organ function Exclusion Criteria: 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. 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 a washout period of 6 weeks is required. For patients in Cohort 2, this does 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 are 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 NCI-CTCAE v. 4.03 is allowed. 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). Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only) Exposure to specific cumulative anthracycline doses Chronic use of high-dose oral corticosteroid therapy . Uncontrolled hypertension or unstable angina. 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). History of myocardial infarction within 6 months of study entry. 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. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic or psychiatric disorders. Known HIV, HBV, or HCV infection. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 doublet<br> | Drug: MCLA-128<br>* full length IgG1 bispecific antibody targeting HER2 and HER3<br>* Other names: bispecific;Drug: Trastuzumab<br>* humanised IgG1 monoclonal antibody<br>* Other names: Herceptin;|
| Experimental: Cohort 1 triplet<br> | Drug: MCLA-128<br>* full length IgG1 bispecific antibody targeting HER2 and HER3<br>* Other names: bispecific;Drug: Trastuzumab<br>* humanised IgG1 monoclonal antibody<br>* Other names: Herceptin;Drug: Vinorelbine<br>* antineoplastic drug of vinca alkaloid family<br>* Other names: vinorelbine tartrate;|
| Experimental: Cohort 2<br> | Drug: MCLA-128<br>* full length IgG1 bispecific antibody targeting HER2 and HER3<br>* Other names: bispecific;Drug: Endocrine therapy<br>* same endocrine therapy is administered as the last line of endocrine therapy<br>* Other names: anastrazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate at 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 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | the time from treatment start until radiologic progression or death due to any cause | Baseline, every 6 weeks until progression up to one year after last patient first treatment | 
| Overall Response Rate (ORR) | the proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 | Baseline, every 6 weeks until progression up to one year after last patient first treatment | 
| Duration of Response (DoR) | the time from response (Complete Response or Partial Response) until progression or death due to underlying cancer based upon RECIST 1.1 | Baseline, every 6 weeks until progression up to one year after last patient first treatment | 
| Overall Survival (OS) | the time from treatment start until death due to any cause | Every 3 months after last visit up to 1 year after last patient first treatment | 
| number of participants with treatment emergent Adverse Events (AE) | Evaluation of number of participants with Adverse Events | continuous until 1 year after last patient last treatment | 
| number of patients that discontinue due to intolerability of study drug | discontinuations due to AEs, dose modifications due to AEs and immunogenicity assessments | continuous through study completion, an average of 6 months | 
| maximum plasma concentration [Cmax] | maximum plasma concentration [Cmax] for MCLA-128 as measured from all individual plasma concentration | baseline and 3-12 weeks until last patient last treatment | 
| trough plasma concentration [C0h] | plasma concentration of MCLA-128 as measured at trough level t=0h | baseline and 3-12 weeks until last patient last treatment | 
| area under curve [AUC] | area under the concentration curve [AUC] for MCLA-128 | baseline and 3-12 weeks until last patient last treatment | 
| clearance [CL] | clearance [CL] of MCLA-128 | 6 weeks | 
| volume of distribution at steady state [Vss] | volume of distribution at steady state [Vss] of MCLA-128 | 6 weeks | 
| time to reach maximum concentration [tmax] | time to reach maximum concentration [tmax] for MCLA-128 | 6 weeks | 
| half life [t1/2] | half life [t1/2] of MCLA-128 | 6 weeks | 
| concentration of trastuzumab at end of infusion [C EOI] | concentration of trastuzumab at end of infusion [C EOI] | 6 weeks | 
| trough plasma concentration [C0h] trastuzumab | plasma concentration of trastuzumab as measured at trough level t=0h | 6 weeks | 
| anti-drug antibodies serum titers | serum titers of anti-drug antibodies against MCLA-128 | baseline and 6-12 weeks until last patient last treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bispecific Antibody IgG1, HER2 HER3, MCLA-128, Antibodies, bispecific, Immunologic Factors, Cytokines, combination Trastuzumab with and without Vinorelbine