Introduction
Materials and methods
Clinical trials and analysis set
Study | Part | Design | Number of patients | Berzosertib dose levels |
---|---|---|---|---|
Study 001—dose escalation | Parts A and B | Berzosertib monotherapy lead-in only | 2 | 72, 140 mg/m2 (day -14 and -7) |
Part A1 | Berzosertib in combination with gemcitabine | 45 (30 also in lead-in) | 18, 36, 60, 72, 90, 140, 210 mg/m2 (day -14 or -7 for lead-in, then days 2 and 9 in a 21-day cycle) | |
Part A2 | Berzosertib in combination with gemcitabine and cisplatin | 8 | 90, 120 mg/m2 (days 2 and 9 in a 21-day cycle) | |
Part B | Berzosertib in combination with cisplatin | 28 (2 also in lead-in) | 90, 140, 210 mg/m2 (day -14 for lead-in, then days 2 and 9 in a 21-day cycle) | |
Study 001—expansion cohorts | Part C1 (NSCLC) | Berzosertib in combination with gemcitabine | 36 | 210 mg/m2 (days 2 and 9 in a 21-day cycle) |
Part C2 (TNBC) | Berzosertib in combination with cisplatin or carboplatin | 37 | 90, 140 mg/m2 (days 2 and 9 in a 21-day cycle) | |
Part C3 (SCLC) | Berzosertib in combination with cisplatin or carboplatin | 14 | 90, 140 mg/m2 (days 2 and 9 in a 21-day cycle) | |
Study 002—dose escalation | Part A1 | Berzosertib monotherapy once weekly | 11 | 60, 120, 240, 480 mg/m2 (on days 1, 8, and 15 in a 21-day cycle) |
Part A2 | Berzosertib monotherapy twice weekly | 6 | 240 mg/m2 (on days 1 and 4, 8 and 11, and 15 and 18 in a 21-day cycle) | |
Part B1-1 | Berzosertib in combination with carboplatin | 23 | 90, 120, 240 mg/m2 (days 2 and 9 in a 21-day cycle) | |
Part B1-2 | Berzosertib in combination with carboplatin and paclitaxel | 15 | 45, 90 mg/m2 (days 2 and 9 in a 21-day cycle) | |
Study 002—expansion cohort | Part C (DDR) | Berzosertib monotherapy followed by (upon progression) berzosertib in combination with carboplatin | 15 | 240 mg/m2 twice weekly (days 1, 4, 8, 11, 15, 18 in a 21-day cycle) followed by 90 mg/m2 (days 2 and 9 in a 21-day cycle) |
Bioanalytical methods
Population PK analysis
Structural and statistical model development
Covariate analysis model development
Model-based simulations
Modeling methodology and software
Results
Patient population
Variable | Value (N = 240) |
---|---|
Demographics | |
Age [years] | 60 {58.4} (26–79) [0] |
Body weight [kg] | 72.8 {75.4} (46–150) [0] |
BSA [kg/m2] | 1.82 {1.84} (1.4–2.59) [0] |
Lean body mass [kg] | 49.9 {52.3} (35.7–78.9) [1] |
Height [cm] | 168 {167} (99–191) [0] |
Sex [n (%)] | |
Male | 95 (39.6%) |
Female | 145 (60.4%) |
Race [n (%)] | |
White | 224 (93.3%) |
Black | 3 (1.25%) |
Asian | 5 (2.08%) |
Other | 6 (2.5%) |
Missing | 2 (0.833%) |
Ethnicity [n (%)] | |
Hispanic/latino | 7 (2.92%) |
Not hispanic/latino | 226 (94.2%) |
Missing | 7 (2.92%) |
Lab values | |
Creatinine [µmol/L] | 66.6 {69.8} (32.7–148) [0] |
Creatinine clearance [mL/min] | 95 {100} (50–150) [0] |
Platelet count [109/L] | 274 {289} (93–816) [0] |
White cell count [cells/µL] | 7.2 {7.65} (1.37–25.2) [0] |
Albumin [g/L] | 38 {37.6} (23–49) [0] |
Bilirubin [µmol/L] | 7 {8.16} (0.5–21) [0] |
ALT [U/L] | 20 {26.9} (4–178) [0] |
AST [U/L] | 24 {31.1} (9–159) [0] |
Renal impairment [n (%)] | |
None | 137 (57.1%) |
Mild | 88 (36.7%) |
Moderate | 15 (6.25%) |
Severe | 0 (0%) |
Hepatic impairment [n (%)] | |
None | 166 (69.2%) |
Mild | 43 (17.9%) |
Moderate | 0 (0%) |
Severe | 1 (0.417%) |
Missing | 30 (12.5%) |
Disease status | |
Tumor burden [mm] | 75 {84.1} (10–312) [0] |
Tumor type [n (%)] | |
NSCLC | 48 (20.0%) |
TNBC | 33 (13.8%) |
SCLC | 16 (6.67%) |
PrCa | 7 (2.92%) |
Breast | 11 (4.58%) |
H&N | 1 (0.417%) |
CRC | 44 (18.3%) |
Ovarian | 9 (3.75%) |
Mesothelioma | 12 (5.0%) |
Other | 59 (24.6%) |
ECOG PS [n (%)] | |
0 | 65 (27.1%) |
1 | 164 (68.3%) |
2 | 5 (2.08%) |
3 | 6 (2.5%) |
Base model
Full covariate model
Parameter | Estimate | RSE %a | Asymptotic 95% CI | Shrinkage (%)b |
---|---|---|---|---|
Clearance CL [L/h] | 65 | 5.2 | 58–71 | – |
Central volume V1 [L] | 118 | 12 | 91–150 | – |
Peripheral volume V2 [L] | 1030 | 3.9 | 950–1100 | – |
Intercompartmental clearance Q [L/h] | 295 | 3.5 | 270–320 | – |
IIV on CL [var] | 0.066 | 6.5 | 0.049–0.083 | 8.7 |
cov (CL, V1) | 0.060 | 12.0 | 0.031–0.089 | – |
cov (CL, Q) | 0.054 | 16.0 | 0.021–0.087 | – |
cov (CL, V2) | 0.041 | 7.3 | 0.029–0.052 | – |
IIV on V1 [var] | 0.32 | 7.1 | 0.24–0.42 | 8.1 |
cov (V1, Q) | 0.25 | 7.7 | 0.18–0.33 | – |
cov (V1, V2) | 0.081 | 9.0 | 0.052–0.11 | – |
IIV on Q [var] | 0.24 | 9.2 | 0.16–0.33 | 5.4 |
cov (Q, V2) | 0.090 | 16.0 | 0.021–0.087 | – |
IIV on V2 [var] | 0.047 | 7.9 | 0.033–0.062 | 6.8 |
Proportional residual error [sd] | 0.22 | 4.6 | 0.2–0.24 | – |
Additive residual error [ng/mL] | 1.73 | 19.0 | 1.1–2.4 | – |