Efficacy Study of MCS110 Given With Carboplatin and Gemcitabine in Advanced Triple Negative Breast Cancer (TNBC)

Study Overview
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Brief Summary
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To determine whether MCS110 antibody therapy improves the efficacy of carboplatin and gemcitabine (carbo/gem) in advanced TNBC patients

Official Title
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A Randomized Phase II Study of MCS110 Combined With Carboplatin and Gemcitabine in Advanced Triple Negative Breast Cancer (TNBC)

Conditions
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Advanced Triple Negative Breast Cancer (TNBC) With High TAMs

Intervention / Treatment
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* Drug: MCS110
* Drug: carboplatin
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult women (≥ 18 years of age) with advanced TNBC. Histological or cytological evidence of estrogen-receptor negative (ER-), progesterone receptor negative (PgR-) and human epidermal growth factor-2 receptor negative (HER2-) Breast Cancer by local laboratory testing, based on last available tumor tissue. ER/PgR negativity to follow local guidelines If IHC HER2 2+, a negative FISH test is required A pre-treatment tumor biopsy demonstrating high TAM content as assessed per the central laboratory Patients must have: At least one measurable lesion per RECIST 1.1. (Note: Measurable lesions include lytic or mixed (lytic + blastic) bone lesions, with an identifiable soft tissue component that meets the measurability criteria) Exclusion Criteria: Prior chemotherapy for advanced BC. Previous adjuvant/neoadjuvant chemotherapy is allowed (carboplatin, cisplatin or gemcitabine only if > 12 months has passed since last administration). Therapy for underlying malignancy within 2 weeks prior to start of study treatment: Chemotherapy, biologic therapy (antibodies and biologically targeted small molecules) Radiotherapy Major surgery Patients receiving concomitant immunosuppressive agents or chronic corticosteroids (≥10 mg of prednisone or equivalent) at the time of first study dose. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening. Known history of human immunodeficiency virus or active infection with hepatitis virus or any uncontrolled active systemic infection. Patients with the following laboratory values during screening and on Day 1 predose: Absolute Neutrophil Count (ANC) < 1.5x109/L Hemoglobin < 9 g/dL Platelets < 100x109/L Serum creatinine > 1.5 x ULN Serum total bilirubin > 1.5 x ULN AST/SGOT and ALT/SGPT > 3.0 x ULN

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: MCS110+carboplatin+gemcitabine<br>MCS110+carboplatin+gemcitabine | Drug: MCS110<br>* taken by I.V<br>Drug: carboplatin<br>* taken by I.V<br>Drug: gemcitabine<br>* taken by I.V<br>|
| Active Comparator: Arm 2: carboplatin+gemcitabine<br>carboplatin+gemcitabine | Drug: carboplatin<br>* taken by I.V<br>Drug: gemcitabine<br>* taken by I.V<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Per RECIST v1.1 (by Local Investigator Assessment) | PFS Results presented for all MCS110 treated patients (with and without day 8 dose), in line with phase 2 study design. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free MCS110 : Derived Pharmacokinetics (PK) Parameters: AUCtau | AUC tau derived from day 0 to 21 (cycle 1) from day 0 to 21 (cycle 4) Cycle duration is 21 days | day 21 (end cycle 1); day 84 (end cycle 4) | 
| Free MCS110 : Derived Pharmacokinetics (PK) Parameters: Cmax |  | day 21 (end cycle 1); day 84 (end cycle 4) | 
| Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | day 21 (end cycle 1); day 84 (end cycle 4) | day 21, day 84 | 
| AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | day 21 (end cycle 1); day 84 (end cycle 4) | day 21, day 84 | 
| Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | results expressed as a the ratio change from baseline expressed in percentage. Cycle duration is 21 days. These Biomarker Analyses were performed for MCS110 treated patients only. | baseline, day 1, 4, 15, 22, 43, 64, 85, 106, 127, 148 | 
| Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | results expressed as a the ratio change from baseline expressed in percentage. Cycle duration is 21 days. Biomarker Analyses performed for MCS110 treated patients only. | baseline, day 2, 4, 15, 22, 43, 64, 85, 106, 127, 148 | 
| Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | CR: complete response. PR: partial response. SD: stable disease: CBR: clinical benefit rate =CR + PR + SD lasting at least for 6 months. ORR = CR + PR. Efficacy Results presented for all MCS110 treated patients (with and without day 8 dose), in line with phase 2 study design. | 4 years | 
| Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) Duration of Response | CR: complete response. PR: partial response. SD: stable disease: CBR: clinical benefit rate =CR + PR + SD lasting at least for 6 months. ORR = CR + PR. Efficacy Results presented for all MCS110 treated patients (with and without day 8 dose), in line with phase 2 study design. | 4 years | 
| Number of Patients With at Least One MCS110 Dose Reduction, and Number of Patients With at Least One MCS110 Dose Interruption | patients treated with MCS110 only | 4 years | 
| MCS110 Dose Intensity | Relative dose intensity by categories. Patients treated with MCS110 only. The dose intensity measures the dose actually taken versus the planned dose, and is expressed in percentage: <50%: less than 50 % of the planned dose received; 50-<75 %: dose received is 50% or more, but less than 75 %; 75-<90 %: dose received is 75% or more, but less than 90%; 90-<110 %: dose received is 90% or more, but less than 110% | 4 years | 
| Tumor Associated Macrophage (TAM) and Tumor Infiltrating Lymphocyte (TIL) Content in Pre- and Post-dose Tumor Biopsies. | results expressed as a the ratio change from baseline expressed in percentage: Biopsies were taken at baseline and between Day 29 and Day 43. Patients treated with MCS110 only | Baseline, Day 29-43 | 
| Circulating Monocytes Cells in Blood | Cycle duration is 21 days results expressed in percentage of cells. Only 1 arm reported as results were available for 1 patient only. | day 15, 29, 43, 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MCS110; carboplatin; gemcitabine; TNBC; TAMs