Advanced Triple Negative Breast Cancer (TNBC) With High TAMs
Conditions
Keywords
MCS110; carboplatin; gemcitabine; TNBC; TAMs
Brief summary
To determine whether MCS110 antibody therapy improves the efficacy of carboplatin and gemcitabine (carbo/gem) in advanced TNBC patients
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Per RECIST v1.1 (by Local Investigator Assessment) | 4 years | PFS Results presented for all MCS110 treated patients (with and without day 8 dose), in line with phase 2 study design. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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, day 84 | day 21 (end cycle 1); day 84 (end cycle 4) |
| AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | day 21, day 84 | day 21 (end cycle 1); day 84 (end cycle 4) |
| Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | baseline, day 1, 4, 15, 22, 43, 64, 85, 106, 127, 148 | 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. |
| Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | baseline, day 2, 4, 15, 22, 43, 64, 85, 106, 127, 148 | 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. |
| Free MCS110 : Derived Pharmacokinetics (PK) Parameters: AUCtau | day 21 (end cycle 1); day 84 (end cycle 4) | AUC tau derived from day 0 to 21 (cycle 1) from day 0 to 21 (cycle 4) Cycle duration is 21 days |
| Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) Duration of Response | 4 years | 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. |
| Number of Patients With at Least One MCS110 Dose Reduction, and Number of Patients With at Least One MCS110 Dose Interruption | 4 years | patients treated with MCS110 only |
| MCS110 Dose Intensity | 4 years | 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% |
| Tumor Associated Macrophage (TAM) and Tumor Infiltrating Lymphocyte (TIL) Content in Pre- and Post-dose Tumor Biopsies. | Baseline, Day 29-43 | 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 |
| Circulating Monocytes Cells in Blood | day 15, 29, 43, 50 | Cycle duration is 21 days results expressed in percentage of cells. Only 1 arm reported as results were available for 1 patient only. |
| Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | 4 years | 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. |
Countries
Australia, Austria, Belgium, France, Germany, Hong Kong, Italy, South Korea, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
In total, 50 subjects were enrolled into the study and 49 subjects received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| MCS110+Carboplatin+Gemcitabine experimental. MCS110 10mg/kg intravenous infusion on day 1. | 21 |
| MCS110 With C1D8 Dose + Carboplatin +Gemcitabine experimental.MCS110 10mg/kg intravenous infusion on days 1 & 8 | 13 |
| Carboplatin+Gemcitabine comparator. Gemcitabine: Intravenous infusion 1000 mg/m2 Days 1 & 8 Carboplatin: Intravenous infusion AUC 2 Days 1 & 8 | 16 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 3 | 2 |
| Overall Study | not treated | 0 | 0 | 1 |
| Overall Study | Physician Decision | 3 | 0 | 0 |
| Overall Study | progressive disease | 10 | 7 | 11 |
| Overall Study | subject / guardian decision | 0 | 3 | 2 |
Baseline characteristics
| Characteristic | MCS110+Carboplatin+Gemcitabine | MCS110 With C1D8 Dose + Carboplatin +Gemcitabine | Carboplatin+Gemcitabine | Total |
|---|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 13.2 | 56.2 years STANDARD_DEVIATION 12.97 | 55.1 years STANDARD_DEVIATION 13.2 | 55.5 years STANDARD_DEVIATION 12.88 |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Caucasian | 15 Participants | 10 Participants | 11 Participants | 36 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 21 Participants | 13 Participants | 16 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 19 | 1 / 15 | 2 / 34 | 1 / 15 | 3 / 49 |
| other Total, other adverse events | 19 / 19 | 15 / 15 | 34 / 34 | 15 / 15 | 49 / 49 |
| serious Total, serious adverse events | 10 / 19 | 7 / 15 | 17 / 34 | 1 / 15 | 18 / 49 |
Outcome results
Primary
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.
Time frame: 4 years
Population: full analysis set: all MCS110 treated patients versus comparator
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Progression Free Survival (PFS) as Per RECIST v1.1 (by Local Investigator Assessment) | 5.6 months |
| Carboplatin+Gemcitabine | Progression Free Survival (PFS) as Per RECIST v1.1 (by Local Investigator Assessment) | 5.5 months |
Secondary
AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU)
day 21 (end cycle 1); day 84 (end cycle 4)
Time frame: day 21, day 84
Population: pharmacokinetic analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Carboplatin Day 21 | 24500 hours * nanogram /mL | Geometric Coefficient of Variation 31.1 |
| All MCS110+Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Carboplatin Day 84 | 18300 hours * nanogram /mL | Geometric Coefficient of Variation 21.8 |
| All MCS110+Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Gemcitabine Day 21 | 2390 hours * nanogram /mL | Geometric Coefficient of Variation 157.3 |
| All MCS110+Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Gemcitabine Day 84 | 2410 hours * nanogram /mL | Geometric Coefficient of Variation 115.2 |
| All MCS110+Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC dFdU Day 21 | 230000 hours * nanogram /mL | Geometric Coefficient of Variation 34.7 |
| All MCS110+Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC dFdU Day 84 | 229000 hours * nanogram /mL | Geometric Coefficient of Variation 31.9 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC dFdU Day 84 | 147000 hours * nanogram /mL | Geometric Coefficient of Variation 28.7 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Carboplatin Day 21 | 21400 hours * nanogram /mL | Geometric Coefficient of Variation 27.3 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Gemcitabine Day 84 | 2770 hours * nanogram /mL | Geometric Coefficient of Variation 118.8 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC dFdU Day 21 | 181000 hours * nanogram /mL | Geometric Coefficient of Variation 37.7 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Carboplatin Day 84 | 17500 hours * nanogram /mL | Geometric Coefficient of Variation 25 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Gemcitabine Day 21 | 4270 hours * nanogram /mL | Geometric Coefficient of Variation 79.3 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Carboplatin Day 84 | 20500 hours * nanogram /mL | Geometric Coefficient of Variation 34.6 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Gemcitabine Day 21 | 2620 hours * nanogram /mL | Geometric Coefficient of Variation 225.5 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC dFdU Day 84 | 211000 hours * nanogram /mL | Geometric Coefficient of Variation 24.7 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Gemcitabine Day 84 | 6320 hours * nanogram /mL | Geometric Coefficient of Variation 76.2 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC Carboplatin Day 21 | 21800 hours * nanogram /mL | Geometric Coefficient of Variation 56 |
| Carboplatin+Gemcitabine | AUClast Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | AUC dFdU Day 21 | 231000 hours * nanogram /mL | Geometric Coefficient of Variation 25.2 |
Secondary
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.
Time frame: day 15, 29, 43, 50
Population: safety set: only 1 patient with data collected
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 15 CD14+CD16- | 43.5 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 15 CD14+CD16+ | 54.8 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 29 (cycle 2 day 8) CD14+CD16- | 86.6 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 29 (cycle 2 day 8) CD14+CD16+ | 12.2 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 43 (cycle 3 day 1) CD14+CD16- | 9.1 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 43 (cycle 3 day 1) CD14+CD16+ | 89.7 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 50 (cycle 3 day 8) CD14+CD16- | 86 percentage |
| All MCS110+Carboplatin+Gemcitabine | Circulating Monocytes Cells in Blood | day 50 (cycle 3 day 8) CD14+CD16+ | 10 percentage |
Secondary
Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU)
day 21 (end cycle 1); day 84 (end cycle 4)
Time frame: day 21, day 84
Population: pharmacokinetic analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Carboplatin Day 21 | 12400 nanogram /mL | Geometric Coefficient of Variation 37.3 |
| All MCS110+Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Carboplatin Day 84 | 9550 nanogram /mL | Geometric Coefficient of Variation 33 |
| All MCS110+Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Gemcitabine Day 21 | 2750 nanogram /mL | Geometric Coefficient of Variation 194.5 |
| All MCS110+Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Gemcitabine Day 84 | 2470 nanogram /mL | Geometric Coefficient of Variation 227.3 |
| All MCS110+Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax dFdU Day 21 | 39100 nanogram /mL | Geometric Coefficient of Variation 21.6 |
| All MCS110+Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax dFdU Day 84 | 36600 nanogram /mL | Geometric Coefficient of Variation 88.6 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax dFdU Day 84 | 30300 nanogram /mL | Geometric Coefficient of Variation 11.8 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Carboplatin Day 21 | 12500 nanogram /mL | Geometric Coefficient of Variation 33.2 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Gemcitabine Day 84 | 3400 nanogram /mL | Geometric Coefficient of Variation 173.9 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax dFdU Day 21 | 33900 nanogram /mL | Geometric Coefficient of Variation 19.5 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Carboplatin Day 84 | 10000 nanogram /mL | Geometric Coefficient of Variation 28.9 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Gemcitabine Day 21 | 5480 nanogram /mL | Geometric Coefficient of Variation 95.1 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Carboplatin Day 84 | 11600 nanogram /mL | Geometric Coefficient of Variation 55 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Gemcitabine Day 21 | 2370 nanogram /mL | Geometric Coefficient of Variation 484.9 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax dFdU Day 84 | 32300 nanogram /mL | Geometric Coefficient of Variation 12.4 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Gemcitabine Day 84 | 8630 nanogram /mL | Geometric Coefficient of Variation 101.2 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax Carboplatin Day 21 | 11200 nanogram /mL | Geometric Coefficient of Variation 70.9 |
| Carboplatin+Gemcitabine | Cmax Derived From Plasma Concentration of Carboplatin, Gemcitabine and 2',2'-Difluoro-deoxyuridine (dFdU) | Cmax dFdU Day 21 | 37700 nanogram /mL | Geometric Coefficient of Variation 28.2 |
Secondary
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
Time frame: day 21 (end cycle 1); day 84 (end cycle 4)
Population: pharmacokinetic analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: AUCtau | day 21 | 1430 day * microgram / mL | Geometric Coefficient of Variation 23.5 |
| All MCS110+Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: AUCtau | day 84 | 1840 day * microgram / mL | Geometric Coefficient of Variation 34.9 |
| Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: AUCtau | day 21 | 2960 day * microgram / mL | Geometric Coefficient of Variation 22.7 |
| Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: AUCtau | day 84 | 3240 day * microgram / mL | Geometric Coefficient of Variation 30 |
Secondary
Free MCS110 : Derived Pharmacokinetics (PK) Parameters: Cmax
Time frame: day 21 (end cycle 1); day 84 (end cycle 4)
Population: pharmacokinetic analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: Cmax | day 21 | 186 microgram / mL | Geometric Coefficient of Variation 28.5 |
| All MCS110+Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: Cmax | day 84 | 240 microgram / mL | Geometric Coefficient of Variation 14.8 |
| Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: Cmax | day 21 | 281 microgram / mL | Geometric Coefficient of Variation 21.2 |
| Carboplatin+Gemcitabine | Free MCS110 : Derived Pharmacokinetics (PK) Parameters: Cmax | day 84 | 319 microgram / mL | Geometric Coefficient of Variation 27.8 |
Secondary
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%
Time frame: 4 years
Population: Safety set - MCS110 treated patients only
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | MCS110 Dose Intensity | <50% | 1 Participants |
| All MCS110+Carboplatin+Gemcitabine | MCS110 Dose Intensity | 50-<75% | 8 Participants |
| All MCS110+Carboplatin+Gemcitabine | MCS110 Dose Intensity | 75-<90% | 7 Participants |
| All MCS110+Carboplatin+Gemcitabine | MCS110 Dose Intensity | 90-<110% | 3 Participants |
| Carboplatin+Gemcitabine | MCS110 Dose Intensity | 90-<110% | 3 Participants |
| Carboplatin+Gemcitabine | MCS110 Dose Intensity | <50% | 4 Participants |
| Carboplatin+Gemcitabine | MCS110 Dose Intensity | 75-<90% | 5 Participants |
| Carboplatin+Gemcitabine | MCS110 Dose Intensity | 50-<75% | 3 Participants |
Secondary
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
Time frame: 4 years
Population: Safety set - MCS110 treated patients only
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Number of Patients With at Least One MCS110 Dose Reduction, and Number of Patients With at Least One MCS110 Dose Interruption | MCS110 dose reduction | 3 Participants |
| All MCS110+Carboplatin+Gemcitabine | Number of Patients With at Least One MCS110 Dose Reduction, and Number of Patients With at Least One MCS110 Dose Interruption | MCS110 dose interruption | 6 Participants |
| Carboplatin+Gemcitabine | Number of Patients With at Least One MCS110 Dose Reduction, and Number of Patients With at Least One MCS110 Dose Interruption | MCS110 dose reduction | 5 Participants |
| Carboplatin+Gemcitabine | Number of Patients With at Least One MCS110 Dose Reduction, and Number of Patients With at Least One MCS110 Dose Interruption | MCS110 dose interruption | 9 Participants |
Secondary
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.
Time frame: baseline, day 2, 4, 15, 22, 43, 64, 85, 106, 127, 148
Population: Safety set - MCS110 treated patients only
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 2 | 79.4 % change from baseline | Standard Deviation 22.8 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 4 | 72.5 % change from baseline | Standard Deviation 25.4 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 15 | 65.6 % change from baseline | Standard Deviation 44.3 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 22 (cycle 2 day 1) | 67.9 % change from baseline | Standard Deviation 43.6 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 43 (cycle 3 day 1) | 64.3 % change from baseline | Standard Deviation 58.7 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 64 (cycle 4 day 1) | 69.7 % change from baseline | Standard Deviation 62.2 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 85 (cycle 5 day 1) | 102 % change from baseline | Standard Deviation 124 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 106 (cycle 6 day 1) | 41.2 % change from baseline | Standard Deviation 13.2 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 127 (cycle 7 day 1) | 38.7 % change from baseline | Standard Deviation 14.9 |
| All MCS110+Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 148 (cycle 8 day 1) | 40.5 % change from baseline | Standard Deviation 13.7 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 106 (cycle 6 day 1) | 50.2 % change from baseline | Standard Deviation 45.3 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 2 | 85.0 % change from baseline | Standard Deviation 44 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 64 (cycle 4 day 1) | 29.5 % change from baseline | Standard Deviation 23.7 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 4 | 80.2 % change from baseline | Standard Deviation 39.6 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 148 (cycle 8 day 1) | 75.3 % change from baseline | Standard Deviation 103 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 15 | 69.4 % change from baseline | Standard Deviation 27.4 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 85 (cycle 5 day 1) | 40.6 % change from baseline | Standard Deviation 34.8 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 22 (cycle 2 day 1) | 52.9 % change from baseline | Standard Deviation 26.5 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 127 (cycle 7 day 1) | 68.7 % change from baseline | Standard Deviation 66.5 |
| Carboplatin+Gemcitabine | Serum C-terminal Telopeptide of Type I Collagen (CTX-I) | Day 43 (cycle 3 day 1) | 39.3 % change from baseline | Standard Deviation 23.8 |
Secondary
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.
Time frame: baseline, day 1, 4, 15, 22, 43, 64, 85, 106, 127, 148
Population: Safety set - MCS110 treated patients only
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 15 | 21600 % change from baseline | Standard Deviation 8290 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 64 (cycle 4 day 1) | 73600 % change from baseline | Standard Deviation 16200 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 4 | 4930 % change from baseline | Standard Deviation 2280 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 85 (cycle 5 day 1) | 79300 % change from baseline | Standard Deviation 27000 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 22 (cycle 2 day 1) | 32000 % change from baseline | Standard Deviation 9190 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 106 (cycle 6 day 1) | 97500 % change from baseline | Standard Deviation 15600 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 1 | 110 % change from baseline | Standard Deviation 19.8 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 43 (cycle 3 day 1) | 57900 % change from baseline | Standard Deviation 14100 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 148 (cycle 8 day 1) | 108000 % change from baseline | Standard Deviation 30300 |
| All MCS110+Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 127 (cycle 7 day 1) | 110000 % change from baseline | Standard Deviation 33800 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 148 (cycle 8 day 1) | 111000 % change from baseline | Standard Deviation 58800 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 1 | 115 % change from baseline | Standard Deviation 34.8 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 4 | 4350 % change from baseline | Standard Deviation 1620 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 15 | 19500 % change from baseline | Standard Deviation 6130 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 22 (cycle 2 day 1) | 34400 % change from baseline | Standard Deviation 14900 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 43 (cycle 3 day 1) | 70000 % change from baseline | Standard Deviation 27400 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 64 (cycle 4 day 1) | 78000 % change from baseline | Standard Deviation 41200 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 85 (cycle 5 day 1) | 107000 % change from baseline | Standard Deviation 51400 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 106 (cycle 6 day 1) | 103000 % change from baseline | Standard Deviation 50700 |
| Carboplatin+Gemcitabine | Total Colony Stimulation Factor -1 (CSF-I) Circulating Levels | Day 127 (cycle 7 day 1) | 109000 % change from baseline | Standard Deviation 40100 |
Secondary
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
Time frame: Baseline, Day 29-43
Population: Safety set - MCS110 treated patients only
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Tumor Associated Macrophage (TAM) and Tumor Infiltrating Lymphocyte (TIL) Content in Pre- and Post-dose Tumor Biopsies. | CD163 | 42.1 % change from baseline | Geometric Coefficient of Variation 62.1 |
| All MCS110+Carboplatin+Gemcitabine | Tumor Associated Macrophage (TAM) and Tumor Infiltrating Lymphocyte (TIL) Content in Pre- and Post-dose Tumor Biopsies. | CD8 | 102 % change from baseline | Geometric Coefficient of Variation 747.3 |
| Carboplatin+Gemcitabine | Tumor Associated Macrophage (TAM) and Tumor Infiltrating Lymphocyte (TIL) Content in Pre- and Post-dose Tumor Biopsies. | CD163 | 43.5 % change from baseline | Geometric Coefficient of Variation 239.5 |
| Carboplatin+Gemcitabine | Tumor Associated Macrophage (TAM) and Tumor Infiltrating Lymphocyte (TIL) Content in Pre- and Post-dose Tumor Biopsies. | CD8 | 99.0 % change from baseline | Geometric Coefficient of Variation 92.2 |
Secondary
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.
Time frame: 4 years
Population: full analysis set: all MCS110 treated patients versus comparator
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | SD | 19 Participants |
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | unknown | 2 Participants |
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | Non-CR/ Non-progressive disease | 1 Participants |
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | clinical benefit rate | 10 Participants |
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | progressive disease | 4 Participants |
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | ORR | 8 Participants |
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | PR | 8 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | ORR | 6 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | PR | 6 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | Non-CR/ Non-progressive disease | 0 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | SD | 7 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | progressive disease | 1 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | unknown | 2 Participants |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) | clinical benefit rate | 7 Participants |
Secondary
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.
Time frame: 4 years
Population: full analysis set: all MCS110 treated patients versus comparator
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All MCS110+Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) Duration of Response | 9.6 months |
| Carboplatin+Gemcitabine | Tumor Response Per RECIST v1.1 (by Local Investigator Assessment) Duration of Response | 5 months |