Introduction
Materials and methods
Study design
Patients
Study treatment
Safety assessments
Pharmacokinetic assessments
Results
Baseline patient characteristics
Cohort 1 25 mg/m2 normal hepatic function n = 6 | Cohort 2 mild hepatic impairment | Cohort 3 moderate hepatic impairment | Cohort 4 severe hepatic impairment | All patients N = 43 | ||||||
---|---|---|---|---|---|---|---|---|---|---|
20 mg/m2 (MTD) n = 12 | 25 mg/m2
n = 6 | 10 mg/m2
n = 3 | 15 mg/m2 (MTD) n = 7 | 20 mg/m2
n = 2 | 10 mg/m2
n = 3 | 15 mg/m2
n = 3 | 20 mg/m2
n = 1 | |||
Male/female, n (%) | 3 (50.0)/3 (50.0) | 5 (41.7)/7 (58.3) | 4 (66.7)/2 (33.3) | 3 (100)/0 | 4 (57.1)/3 (42.9) | 0/2 (100) | 2 (66.7)/1 (33.3) | 0/3 (100) | 1 (100)/0 | 22 (51.2)/21 (48.8) |
Age in years, median (range) | 68.0 (50–79) | 59.0 (18–75) | 54.0 (37–70) | 64.0 (50–74) | 56.0 (52–67) | 54.0 (48–60) | 64.0 (47–68) | 62.0 (38–62) | 60.0 (60–60) | 60.0 (18–79) |
ECOG performance status, n (%) | ||||||||||
0 | 1 (16.7) | 1 (8.3) | 2 (33.3) | 0 | 1 (14.3) | 0 | 0 | 0 | 0 | 5 (11.6) |
1 | 5 (83.3) | 11 (91.7) | 4 (66.7) | 3 (100) | 5 (71.4) | 1 (50.0) | 2 (66.7) | 3 (100) | 1 (100) | 35 (81.4) |
2 | 0 | 0 | 0 | 0 | 1 (14.3) | 1 (50.0) | 1 (33.3) | 0 | 0 | 3 (7.0) |
Months since diagnosis, median (range) | 2.91 (1.0–17.9) | 3.02 (0.5–17.2) | 3.61 (1.1–8.8) | 6.17 (1.5–8.7) | 2.38 (1.6–3.7) | 2.16 (0.7–3.6) | 1.38 (0.8–14.1) | 3.34 (1.8–4.9)a
| 2.99 (3.0–3.0) | 2.93 (0.5–17.9)b
|
Primary tumor site, n (%) | ||||||||||
Breast | 2 (33.3) | 1 (8.3) | 0 | 0 | 1 (14.3) | 0 | 0 | 1 (33.3) | 0 | 5 (11.6) |
Colon | 0 | 2 (16.7) | 0 | 1 (33.3) | 1 (14.3) | 1 (50.0) | 1 (33.3) | 1 (33.3) | 1 (100) | 8 (18.6) |
Head/neck | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 0 | 1 (2.3) |
Liver | 0 | 3 (25.0) | 1 (16.7) | 0 | 4 (57.1) | 0 | 0 | 0 | 0 | 8 (18.6) |
Lungs | 2 (33.3) | 0 | 1 (16.7) | 0 | 0 | 1 (50.0) | 0 | 0 | 0 | 4 (9.3) |
Pancreas | 1 (16.7) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (2.3) |
Prostate | 0 | 2 (16.7) | 0 | 1(33.3) | 0 | 0 | 0 | 0 | 0 | 3 (7.0) |
Otherc
| 1 (16.7) | 4 (33.3) | 4 (66.7) | 1 (33.3) | 1 (14.3) | 0 | 1 (33.3) | 1 (33.3) | 0 | 13 (30.2) |
Disease extent at study entry, n (%) | ||||||||||
Locally advanced | 0 | 0 | 0 | 0 | 3 (42.9) | 0 | 0 | 0 | 0 | 3 (7.0) |
Locoregional recurrence | 0 | 0 | 0 | 0 | 1 (14.3) | 0 | 0 | 0 | 0 | 1 (2.3) |
Metastatic | 6 (100) | 12 (100) | 6 (100) | 3 (100) | 3 (42.9) | 2 (100) | 3 (100) | 3 (100) | 1 (100) | 39 (90.7) |
Prior anticancer regimens, n (%) | ||||||||||
1 | 0 | 1 (8.3) | 2 (33.3) | 0 | 2 (28.6) | 1 (50.0) | 0 | 0 | 0 | 6 (14.0) |
2 | 2 (33.3) | 4 (33.3) | 0 | 0 | 1 (14.3) | 0 | 0 | 2 (66.7) | 0 | 9 (20.9) |
≥3 | 4 (66.7) | 7 (58.3) | 4 (66.7) | 3 (100) | 4 (57.1) | 1 (50.0) | 3 (100) | 1 (33.3) | 1 (100) | 28 (65.1) |
Treatment
Cohort 1 25 mg/m2 normal hepatic function n = 6 | Cohort 2 mild hepatic impairment | Cohort 3 moderate hepatic impairment | Cohort 4 severe hepatic impairment | All patients N = 43 | ||||||
---|---|---|---|---|---|---|---|---|---|---|
20 mg/m2 (MTD) n = 12 | 25 mg/m2
n = 6 | 10 mg/m2
n = 3 | 15 mg/m2 (MTD) n = 7 | 20 mg/m2
n = 2 | 10 mg/m2
n = 3 | 15 mg/m2
n = 3 | 20 mg/m2
n = 1 | |||
Total cabazitaxel cycles by patient, n
| 16 | 54 | 12 | 6 | 13 | 2 | 6 | 8 | 1 | 118 |
Median caba zitaxel cycles by patient, n (range) | 3 (1–4) | 2 (1–31) | 1 (1–6) | 1 (1–4) | 2 (1–3) | 1 (1–1) | 1 (1–4) | 3 (1–4) | 1 (1–1) | 2 (1–31) |
Relative dose intensity, mg/m2/week, median (range) | 0.99 (0.63–1.01) | 0.97 (0.84–1.02) | 1.01 (0.70–1.02) | 0.99 (0.81–1.01) | 0.90 (0.72–1.01) | 1.03 (1.00–1.05) | 1.00 (0.92–1.02) | 1.01 (0.88–1.05) | 0.99 (0.99–0.99) | 0.99 (0.63–1.05) |
Weeks of study treatment, median (range) | 9.07 (3.0–16.1) | 6.14 (3.0–107.0) | 3.00 (3.0–20.9) | 3.00 (3.0–12.1) | 6.00 (3.0–10.0) | 3.00 (3.0–3.0) | 3.00 (3.0–13.1) | 10.29 (3.0–12.0) | 3.00 (3.0–3.0) | 6.00 (3.0–107.0) |
Treatment discontinuation, n (%) | 6 (100) | 11 (91.7) | 6 (100) | 3 (100) | 7 (100) | 2 (100) | 3 (100) | 3 (100) | 1 (100) | 42 (97.7) |
Adverse event | 1 (16.7) | 2 (16.7) | 1 (16.7) | 1 (33.3) | 3 (42.9) | 0 | 0 | 0 | 1 (100) | 9 (20.9) |
Disease progression | 4 (66.7) | 8 (66.7) | 4 (66.7) | 2 (66.7) | 4 (57.1) | 2 (100) | 3 (100) | 1 (33.3) | 0 | 28 (65.1) |
Other reason | 1 (16.7) | 1 (8.3) | 1 (16.7) | 0 | 0 | 0 | 0 | 2 (66.7) | 0 | 5 (11.6) |
Safety data
Cohort 1 25 mg/m2 normal hepatic function n = 6 | Cohort 2 mild hepatic impairment | Cohort 3 moderate hepatic impairment | Cohort 4 severe hepatic impairment | All patients N = 43 | ||||||
---|---|---|---|---|---|---|---|---|---|---|
20 mg/m2 (MTD) n = 12 | 25 mg/m2
n = 6 | 10 mg/m2
n = 3 | 15 mg/m2 (MTD) n = 7 | 20 mg/m2
n = 2 | 10 mg/m2
n = 3 | 15 mg/m2
n = 3 | 20 mg/m2
n = 1 | |||
n = 4 |
n = 11 |
n = 5 |
n = 3 |
n = 6 |
n = 2 |
n = 3 |
n = 3 |
n = 1 |
N = 38a
| |
DLT during Cycle 1, n (%) | 3 (75.0) | 3 (27.3) | 3 (60.0) | 0 | 1 (16.7) | 2 (100) | 0 | 0 | 1 (100) | 13 (34.2) |
Hematologic | 2 (50.0) | 3 (27.3) | 2 (40.0) | 0 | 0 | 1 (50.0) | 0 | 0 | 0 | 8 (21.1) |
Non-hematologic | 1 (25.0) | 2 (18.2) | 1 (20.0) | 0 | 1 (16.7) | 2 (100) | 0 | 0 | 1 (100) | 8 (21.1) |
Liver | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Grade 3–4 TEAE, n (%) | 6 (100) | 11 (91.7) | 6 (100) | 3 (100) | 6 (85.7) | 2 (100) | 3 (100) | 2 (66.7) | 1 (100) | 40 (93.0) |
Grade 3–4 treatment-related TEAE, n (%) | 5 (83.3) | 9 (75.0) | 6 (100) | 1 (33.3) | 6 (85.7) | 2 (100) | 1 (33.3) | 1 (33.3) | 1 (100) | 32 (74.4) |
Grade 3–4 treatment-related TEAEs occurring in >1 patient, n (%) | ||||||||||
Neutropenia | 5 (83.3) | 3 (25.0) | 4 (66.7) | 1 (33.3) | 4 (57.1) | 0 | 0 | 1 (33.3) | 0 | 18 (41.9) |
Febrile neutropenia | 1 (16.7) | 3 (25.0) | 1 (16.7) | 0 | 1 (14.3) | 1 (50.0) | 0 | 0 | 0 | 7 (16.3) |
Anemia | 1 (16.7) | 2 (16.7) | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 1 (100) | 5 (11.6) |
Leukopenia | 0 | 2 (16.7) | 0 | 0 | 2 (28.6) | 0 | 0 | 0 | 0 | 4 (9.3) |
Fatigue | 2 (33.3) | 0 | 0 | 0 | 0 | 1 (50.0) | 0 | 0 | 0 | 3 (7.0) |
Lymphopenia | 1 (16.7) | 1 (8.3) | 1 (16.7) | 0 | 0 | 0 | 0 | 0 | 0 | 3 (7.0) |
Diarrhea | 0 | 1 (8.3) | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 2 (4.7) |
Dehydration | 0 | 1 (8.3) | 0 | 0 | 0 | 0 | 0 | 0 | 1 (100) | 2 (4.7) |
Urinary tract infection | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 1 (100) | 2 (4.7) |
Platelet count decreased | 0 | 2 (16.7) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 (4.7) |
White blood cell count decreased | 0 | 1 (8.3) | 0 | 0 | 0 | 1 (50.0) | 0 | 0 | 0 | 2 (4.7) |
Any grade, any causality TEAE leading to discontinuation, n (%) | 1 (16.7) | 2 (16.7) | 1 (16.7) | 1 (33.3) | 3 (42.9) | 0 | 0 | 0 | 1 (100) | 9 (20.9) |
Any grade, any causality hepatobil i aryTEAE, n (%) | 0 | 0 | 1 (16.7) | 1 (33.3) | 4 (57.1) | 0 | 0 | 0 | 0 | 6 (14.0) |
Hepatic failure | 0 | 0 | 1 (16.7) | 0 | 1 (14.3) | 0 | 0 | 0 | 0 | 2 (4.7) |
Jaundice | 0 | 0 | 0 | 1 (33.3) | 1 (14.3) | 0 | 0 | 0 | 0 | 2 (4.7) |
Cholangitis | 0 | 0 | 0 | 0 | 1 (14.3) | 0 | 0 | 0 | 0 | 1 (2.3) |
Hyperbilirubinemia | 0 | 0 | 0 | 0 | 1 (14.3) | 0 | 0 | 0 | 0 | 1 (2.3) |
Pharmacokinetics
Parameter: mean ± SD (geometric mean) [CV%] | Cohort 1 25 mg/m2 normal hepatic function n = 6 | Cohort 2 mild hepatic impairment | Cohort 3 moderate hepatic impairment | Cohort 4 severe hepatic impairment | |||||
---|---|---|---|---|---|---|---|---|---|
20 mg/m2 (MTD) n = 9 | 25 mg/m2
n = 6 | 10 mg/m2
n = 2a
| 15 mg/m2 (MTD) n = 7 | 20 mg/m2
n = 2 | 10 mg/m2
n = 2 | 15 mg/m2
n = 3 | 20 mg/m2
n = 1 | ||
Cmax, ng/mL | 691 ± 563 (545) [82] | 294 ± 253 (213) [86] | 328 ± 189 (287) [57] | 16.4 ± NC (15.4) [NC] | 212 ± 275 (131) [130] | 333 ± NC (294) [NC] | 378 ± NC (207) [NC] | 117 ± 93.9 (92.7) [81] | 77.4 ± NC (77.4) [NC] |
AUClast, ng*h/mL | 2010 ± 1420 (1610) [70] | 893 ± 1000 (612) [112] | 1040 ± 1050 (787) [100] | 184 ± NC (54.0) [NC] | 387 ± 154 (360) [40] | 684 ± NC (674) [NC] | 998 ± NC (542) [NC] | 585 ± 507 (454) [87] | 591 ± NC (591) [NC] |
t1/2z, h | 77.9 ± 36.9 (69.7) [47] | 90.4 ± 38.8 (81.0) [43] | 94.7 ± 12.0 (94.1) [13] | 3.47 ± NC (2.27) [NC] | 98.4 ± 62.3 (78.6) [63] | 111 ± NC (110) [NC] | 76.3 ± NC (76.2) [NC] | 111 ± 5.23 (111) [5] | 141 ± NC (141) [NC] |
AUCinf, ng*h/mL | 2220 ± 1410 (1860) [63] | 1110 ± 1090 (829) [98] | 1420 ± 1300 (1110) [92]b
| 206 ± NC (62.8) [NC] | 526 ± 243 (478) [46]c
| 931 ± NC (925) [NC] | NC ± NC (NC) [NC]d
| 974 ± NC (909) [NC]e
| 915 ± NC (915) [NC] |
CL, L/h | 27.6 ± 16.7 (23.1) [60] | 55.0 ± 38.5 (44.0) [70] | 46.9 ± 25.4 (40.0) [54]b
| 970 ± NC (314) [NC] | 62.5 ± 33.0 (56.1) [53]c
| 39.6 ± NC (39.4) [NC] | NC ± NC (NC) [NC]d
| 33.4 ± NC (31.7) [NC]e
| 36.7 ± NC (36.7) [NC] |
Vss, L | 2220 ± 2450 (1410) [110] | 4940 ± 2440 (3820) [49] | 4040 ± 1630 (3740) [40]b
| 2580 ± NC (2440) [NC] | 4800 ± 3160 (3950) [66]c
| 4660 ± NC (4410) [NC] | NC ± NC (NC) [NC]d
| 5330 ± NC (4170) [NC]e
| 7230 ± NC (7230) [NC] |
CL/BSA, L/h/m2
| 15.9 ± 9.70 (13.4) [61] | 30.2 ± 20.1 (24.0) [67] | 26.6 ± 13.8 (22.7) [52]b
| 517 ± NC (143) [NC] | 33.3 ± 16.1 (30.1) [48]c
| 22.1 ± NC (22.0) [NC] | NC ± NC (NC) [NC]d
| 17.7 ± NC (16.5) [NC]e
| 21.6 ± NC (21.6) [NC] |
Vss/BSA, L/m2
| 1250 ± 1300 (820) [104] | 2770 ± 1440 (2080) [52] | 2310 ± 924 (2120) [40]b
| 1130 ± NC (1110) [NC] | 2380 ± 1130 (2120) [47]c
| 2610 ± NC (2460) [NC] | NC ± NC (NC) [NC]d
| 2860 ± NC (2180) [NC]e
| 4250 ± NC (4250) [NC] |
Parameter | Cohort (hepatic function/impairment) |
n
| Geometric mean (90% CI) | Versus cohort 1 (normal hepatic function) Ratio (90% CI) | Versus cohort 2 (mild hepatic impairment) Ratio (90% CI) |
---|---|---|---|---|---|
CL, L/h | Cohort 1 (normal) | 6 | 23.00 (14.73, 35.92) | 1.00 | – |
Cohort 2 (mild)a
| 14 | 42.54 (31.92, 56.71) | 1.85 (1.09, 3.14) | – | |
Cohort 3 (moderate)b
| 8 | 51.50 (35.12, 75.53) | 2.24 (1.24, 4.05) | 1.21 (0.75, 1.95) | |
Cohort 4 (severe)c
| 3 | 33.32 (17.91, 62.01) | 1.45 (0.67, 3.12) | 0.78 (0.40, 1.55) | |
CL/BSA, L/h/m2
| Cohort 1 (normal) | 6 | 13.42 (8.64, 20.83) | 1.00 | – |
Cohort 2 (mild)a
| 14 | 23.51 (17.63, 31.35) | 1.75 (1.04, 2.96) | – | |
Cohort 3 (moderate)b
| 8 | 27.86 (19.03, 40.77) | 2.08 (1.16, 3.72) | 1.19 (0.74, 1.91) | |
Cohort 4 (severe)c
| 3 | 18.13 (9.73, 33.76) | 1.35 (0.63, 2.89) | 0.77 (0.39, 1.53) | |
AUCinf/dose, ng*h/mL/mg/m2
| Cohort 1 (normal) | 6 | 74.52 (48.01, 115.68) | 1.00 | – |
Cohort 2 (mild)a
| 14 | 42.53 (31.89, 56.72) | 0.57 (0.34, 0.97) | – | |
Cohort 3 (moderate)b
| 8 | 35.91 (24.53, 52.55) | 0.48 (0.27, 0.86) | 0.84 (0.52, 1.36) | |
Cohort 4 (severe)c
| 3 | 55.17 (29.62, 102.75) | 0.74 (0.35, 1.59) | 1.30 (0.65, 2.57) | |
AUClast/dose, ng*h/mL/mg/m2
| Cohort 1 (normal) | 6 | 64.21 (38.39, 107.40) | 1.00 | – |
Cohort 2 (mild) | 15 | 31.09 (22.46, 43.05) | 0.48 (0.26, 0.89) | – | |
Cohort 3 (moderate)d
| 9 | 26.6 (17.48, 40.48) | 0.41 (0.21, 0.80) | 0.86 (0.50, 1.46) | |
Cohort 4 (severe) | 6 | 36.24 (21.67, 60.62) | 0.56 (0.27, 1.17) | 1.17 (0.63, 2.14) | |
Cmax/dose, ng/mL/mg/m2
| Cohort 1 (normal) | 6 | 21.78 (12.11, 39.18) | 1.00 | – |
Cohort 2 (mild) | 15 | 11.01 (7.60, 15.97) | 0.51 (0.25, 1.01) | – | |
Cohort 3 (moderate)d
| 9 | 10.08 (6.24, 16.28) | 0.46 (0.22, 0.99) | 0.92 (0.50, 1.68) | |
Cohort 4 (severe) | 6 | 8.46 (4.71, 15.23) | 0.39 (0.17, 0.89) | 0.77 (0.38, 1.54) | |
t1/2z, h | Cohort 1 (normal) | 6 | 71.07 (49.36, 102.31) | 1.00 | – |
Cohort 2 (mild) | 15 | 85.92 (68.55, 107.69) | 1.21 (0.79, 1.86) | – | |
Cohort 3 (moderate)d
| 9 | 83.64 (62.30, 112.29) | 1.18 (0.73, 1.89) | 0.97 (0.67, 1.41) | |
Cohort 4 (severe) | 6 | 102.12 (71.46, 145.92) | 1.44 (0.86, 2.39) | 1.19 (0.78, 1.81) | |
Vss, L | Cohort 1 (normal) | 6 | 1442.95 (802.87, 2593.34) | 1.00 | – |
Cohort 2 (mild)a
| 14 | 3785.17 (2593.95, 5523.44) | 2.62 (1.31, 5.27) | – | |
Cohort 3 (moderate)b
| 8 | 4005.9 (2421.05, 6628.21) | 2.78 (1.27, 6.06) | 1.06 (0.56, 1.99) | |
Cohort 4 (severe)c
| 3 | 4981.61 (2201.05, 11,274.82) | 3.45 (1.26, 9.46) | 1.32 (0.54, 3.24) | |
Vss/BSA, L/m2
| Cohort 1 (normal) | 6 | 819.68 (464.42, 1446.71) | 1.00 | – |
Cohort 2 (mild)a
| 14 | 2093.46 (1443.24, 3036.63) | 2.55 (1.30, 5.04) | – | |
Cohort 3 (moderate)b
| 8 | 2201.19 (1345.79, 3600.29) | 2.69 (1.27, 5.69) | 1.05 (0.57, 1.95) | |
Cohort 4 (severe)c
| 3 | 2729.48 (1222.20, 6095.62) | 3.33 (1.24, 8.91) | 1.30 (0.54, 3.16) |