Introduction
Materials and methods
Study oversight
Patient selection
Study objectives
Study design and treatment plan
Safety assessments
Response assessments
Pharmacokinetics
Biomarkers
Results
Patient characteristics
Characteristics | BEZ235 qd (N = 27) | BEZ235 bid | |||||
---|---|---|---|---|---|---|---|
400 mg (n = 3) | 800 mg (n = 3) | 1000 mg (n = 8) | 1200 mg (n = 6) | 1400 mg (n = 7) | All patients (N = 27) | 400 mg (N = 8) | |
Age, years, median (range) | 65 (52–69) | 62 (61–74) | 59 (31–70) | 65 (37–67) | 55 (38–74) | 62 (31–74) | 50 (36–74) |
Sex, N (%) | |||||||
Male | 0 | 2 (66.7) | 8 (100) | 4 (66.7) | 2 (28.6) | 16 (59.3) | 4 (50.0) |
Female | 3 (100) | 1 (33.3) | 0 | 2 (33.3) | 5 (71.4) | 11 (40.7) | 4 (50.0) |
ECOG PS, N (%) | |||||||
0 | 2 (66.7) | 0 | 4 (50.0) | 3 (50.0) | 2 (28.6) | 11 (40.7) | 3 (37.5) |
1 | 1 (33.3) | 3 (100) | 4 (50.0) | 3 (50.0) | 5 (71.4) | 16 (59.3) | 5 (62.5) |
Primary site of cancer, N (%) | |||||||
Rectum | 0 | 0 | 2 (25.0) | 1 (16.7) | 2 (28.6) | 5 (18.5) | 1 (12.5) |
Lung | 0 | 0 | 1 (12.5) | 0 | 2 (28.6) | 3 (11.1) | 0 |
Pancreas | 0 | 1 (33.3) | 0 | 0 | 1 (14.3) | 2 (7.4) | 2 (25.0) |
Colon | 0 | 0 | 0 | 2 (33.3) | 0 | 2 (7.4) | 1 (12.5) |
Bone | 1 (33.3) | 0 | 0 | 0 | 1 (14.3) | 2 (7.4) | 1 (12.5) |
Soft tissue | 0 | 0 | 2 (25.0) | 0 | 0 | 2 (7.4) | 0 |
Stomach | 0 | 0 | 1 (12.5) | 0 | 0 | 1 (3.7) | 2 (25.0) |
Other | 1 (33.3) | 2 (66.7) | 1 (12.5) | 1 (16.7) | 1 (14.3) | 6 (22.2) | 1 (12.5) |
Unknown | 1 (33.3) | 0 | 1 (12.5) | 2 (33.3) | 0 | 4 (14.8) | 0 |
Number of prior regimens, N (%) | |||||||
0 | 0 | 0 | 0 | 0 | 1 (14.3) | 1 (3.7) | 0 |
1–2 | 3 (100) | 2 (66.7) | 2 (25.0) | 4 (66.7) | 3 (42.9) | 14 (51.9) | 3 (37.5) |
3–4 | 0 | 0 | 6 (75.0) | 1 (16.7) | 1 (14.3) | 8 (29.6) | 3 (37.5) |
≥ 5 | 0 | 1 (33.3) | 0 | 1 (16.7) | 2 (28.6) | 4 (14.8) | 2 (25.0) |
Safety
Regimen | Dose (mg) | Full analysis set | Dose-determining analysis set | Number of patients who experienced a DLT | DLT |
---|---|---|---|---|---|
BEZ235 qd (N = 27) | 400 | 3 | 3 | 0 | – |
800 | 3 | 3 | 0 | – | |
1000 | 8 | 6 | 0 | – | |
1200 | 6 | 6 | 1 | Grade 2 allergic reaction | |
1400 | 7 | 6 | 1 | Grade 4 thrombocytopenia | |
BEZ235 bid (N = 8) | 400 | 8 | 6 | 1 | Grade 2 liver dysfunction |
Overall exposure | BEZ235 qd | BEZ235 bid | |||||
---|---|---|---|---|---|---|---|
400 mg (n = 3) | 800 mg (n = 3) | 1000 mg (n = 8) | 1200 mg (n = 6) | 1400 mg (n = 7) | All patients (N = 27) | 400 mg (N = 8) | |
Exposure (weeks) | |||||||
≤ 4 | 0 | 0 | 3 (37.5%) | 2 (33.3%) | 1 (14.3%) | 6 (22.2%) | 3 (37.5%) |
> 4 to ≤ 8 | 2 (66.7%) | 0 | 2 (25.0%) | 2 (33.3%) | 2 (28.6%) | 8 (29.6%) | 2 (25.0%) |
> 8 to ≤ 12 | 0 | 0 | 2 (25.0%) | 0 | 1 (14.3%) | 3 (11.1%) | 1 (12.5%) |
> 12 | 1 (33.3%) | 3 (100.0%) | 1 (12.5%) | 2 (33.3%) | 3 (42.9%) | 10 (37.0%) | 2 (25.0%) |
Duration of study treatment exposure (days) | |||||||
n | 3 | 3 | 8 | 6 | 7 | 27 | 8 |
Mean | 52.7 | 149.7 | 48.8 | 82.3 | 77.4 | 75.3 | 55.9 |
SD | 28.99 | 31.77 | 30.78 | 100.31 | 52.23 | 62.36 | 37.72 |
Median | 44.0 | 167.0 | 37.0 | 39.5 | 68.0 | 56.0 | 43.5 |
Minimum | 29.0 | 113.0 | 19.0 | 16.0 | 2.0 | 2.0 | 21.0 |
Maximum | 85.0 | 169.0 | 112.0 | 280.0 | 169.0 | 280.0 | 115.0 |
BEZ235 qd | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
400 mg (n = 3) | 800 mg (n = 3) | 1000 mg (n = 8) | 1200 mg (n = 6) | 1400 mg (n = 7) | All patients (N = 27) | |||||||
PT | All grades n (%) | Grade ¾ n (%) | All grades n (%) | Grade ¾ n (%) | All grades n (%) | Grade ¾ n (%) | All grades n (%) | Grade ¾ n (%) | All grades n (%) | Grade ¾ n (%) | All grades n (%) | Grade ¾ n (%) |
Total | 3 (100.0) | 2 (66.7) | 3 (100.0) | 1 (33.3) | 8 (100.0) | 4 (50.0) | 6 (100.0) | 6 (100.0) | 7 (100.0) | 5 (71.4) | 27 (100.0) | 18 (66.7) |
Diarrhea | 2 (66.7) | 0 | 3 (100.0) | 0 | 7 (87.5) | 0 | 6 (100.0) | 0 | 7 (100.0) | 1 (14.3) | 25 (92.6) | 1 (3.7) |
Decreased appetite | 2 (66.7) | 0 | 3 (100.0) | 0 | 7 (87.5) | 0 | 6 (100.0) | 1 (16.7) | 6 (85.7) | 0 | 24 (88.9) | 1 (3.7) |
Nausea | 3 (100.0) | 0 | 1 (33.3) | 0 | 7 (87.5) | 0 | 5 (83.3) | 0 | 6 (85.7) | 0 | 22 (81.5) | 0 |
Stomatitis | 2 (66.7) | 0 | 2 (66.7) | 0 | 3 (37.5) | 0 | 6 (100.0) | 1 (16.7) | 5 (71.4) | 0 | 18 (66.7) | 1 (3.7) |
Vomiting | 2 (66.7) | 0 | 1 (33.3) | 0 | 4 (50.0) | 0 | 5 (83.3) | 0 | 5 (71.4) | 0 | 17 (63.0) | 0 |
Fatigue | 1 (33.3) | 0 | 2 (66.7) | 0 | 6 (75.0) | 1 (12.5) | 4 (66.7) | 2 (33.3) | 4 (57.1) | 0 | 17 (63.0) | 3 (11.1) |
Rash | 1 (33.3) | 0 | 0 | 0 | 5 (62.5) | 1 (12.5) | 1 (16.7) | 1 (16.7) | 4 (57.1) | 0 | 11 (40.7) | 2 (7.4) |
Lymphopenia | 2 (66.7) | 2 (66.7) | 1 (33.3) | 1 (33.3) | 2 (25.0) | 2 (25.0) | 1 (16.7) | 1 (16.7) | 4 (57.1) | 1 (14.3) | 10 (37.0) | 7 (25.9) |
Neutropenia | 0 | 0 | 1 (33.3) | 0 | 1 (12.5) | 1 (12.5) | 2 (33.3) | 0 | 4 (57.1) | 3 (42.9) | 8 (29.6) | 4 (14.8) |
Thrombocytopenia | 0 | 0 | 1 (33.3) | 1 (33.3) | 4 (50.0) | 0 | 0 | 0 | 3 (42.9) | 2 (28.6) | 8 (29.6) | 3 (11.1) |
Dysgeusia | 0 | 0 | 1 (33.3) | 0 | 2 (25.0) | 0 | 3 (50.0) | 0 | 2 (28.6) | 0 | 8 (29.6) | 0 |
Cancer pain | 2 (66.7) | 1 (33.3) | 2 (66.7) | 0 | 2 (25.0) | 0 | 1 (16.7) | 0 | 0 | 0 | 7 (25.9) | 1 (3.7) |
Leukopenia | 0 | 0 | 1 (33.3) | 0 | 2 (25.0) | 1 (12.5) | 1 (16.7) | 0 | 2 (28.6) | 1 (14.3) | 6 (22.2) | 2 (7.4) |
Pyrexia | 1 (33.3) | 0 | 1 (33.3) | 0 | 2 (25.0) | 0 | 2 (33.3) | 0 | 0 | 0 | 6 (22.2) | 0 |
Alanine aminotransferase increased | 2 (66.7) | 0 | 0 | 0 | 0 | 0 | 1 (16.7) | 0 | 3 (42.9) | 1 (14.3) | 6 (22.2) | 1 (3.7) |
Blood alkaline phosphatase increased | 1 (33.3) | 0 | 0 | 0 | 2 (25.0) | 0 | 1 (16.7) | 1 (16.7) | 2 (28.6) | 1 (14.3) | 6 (22.2) | 2 (7.4) |
BEZ235 bid | ||
---|---|---|
400 mg N = 8 | ||
PT | All grades n (%) | Grade ¾ n (%) |
Total | 8 (100.0) | 7 (87.5) |
Diarrhea | 7 (87.5) | 1 (12.5) |
Nausea | 7 (87.5) | 0 |
Decreased appetite | 7 (87.5) | 1 (12.5) |
Thrombocytopenia | 5 (62.5) | 2 (25.0) |
Stomatitis | 5 (62.5) | 0 |
Fatigue | 5 (62.5) | 1 (12.5) |
Lymphopenia | 4 (50.0) | 2 (25.0) |
Vomiting | 4 (50.0) | 0 |
Alanine aminotransferase increased | 4 (50.0) | 0 |
Aspartate aminotransferase increased | 4 (50.0) | 1 (12.5) |
Haemoglobin decreased | 4 (50.0) | 1 (12.5) |
Insomnia | 4 (50.0) | 0 |
Dry skin | 4 (50.0) | 0 |
Rash | 4 (50.0) | 0 |
Hypoalbuminaemia | 4 (50.0) | 1 (12.5) |
Cheilitis | 3 (37.5) | 0 |
Dysphagia | 3 (37.5) | 0 |
Cancer pain | 3 (37.5) | 2 (25.0) |
Blood creatinine increased | 3 (37.5) | 0 |
Malaise | 2 (25.0) | 1 (12.5) |
Pyrexia | 2 (25.0) | 0 |
Urinary tract infection | 2 (25.0) | 0 |
Blood alkaline phosphatase increased | 2 (25.0) | 0 |
Gamma-glutamyltransferase increased | 2 (25.0) | 0 |
Hyperkalaemia | 2 (25.0) | 0 |
Hyponatraemia | 2 (25.0) | 1 (12.5) |
Anxiety | 2 (25.0) | 0 |
Efficacy
Pharmacokinetics
Timepoint/dose level/statistics | AUClast (ng h/mL) | AUCinf (ng h/mL) | AUC0 − 24 (ng h/mL) | Cmax (ng/mL) | Tmax (h) |
---|---|---|---|---|---|
Cycle 1 Day 1
| |||||
400 mg qd | |||||
n | 3 | 2 | 3 | 3 | 3 |
Median | 1036 | 978 | 1038 | 135 | 4.0 |
Min/Max | 821/13,782 | 895/1061 | 821/13,869 | 69.9/1000 | 4.0/4.0 |
800 mg qd | |||||
n | 3 | 1 | 3 | 3 | 3 |
Median | 2558 | 1488 | 2558 | 154 | 8.0 |
Min/Max | 1433/6096 | 1488/1488 | 1438/6096 | 150/466 | 4.0/8.0 |
1000 mg qd | |||||
n | 6 | 3 | 4 | 6 | 6 |
Median | 4492 | 1407 | 4334 | 472 | 5.0 |
Min/Max | 869/19,292 | 890/7301 | 869/19,265 | 106/970 | 1.0/8.0 |
1200 mg qd | |||||
n | 5 | 1 | 3 | 5 | 5 |
Median | 6420 | 2292 | 6417 | 403 | 6.0 |
Min/Max | 2261/25,472 | 2292/2292 | 2264/15,775 | 203/1500 | 4.0/23.4 |
1400 mg qd | |||||
n | 5 | 1 | 2 | 5 | 5 |
Median | 10,224 | 1286 | 13,736 | 733 | 8.0 |
Min/Max | 1208/37,073 | 1286/1286 | 1215/26,258 | 87.7/1940 | 4.0/24.0 |
400 mg bid | |||||
n | 7 | 2 | 4 | 7 | 7 |
Median | 2283 | 1995 | 1755 | 301 | 6.0 |
Min/Max | 606/7719 | 1402/2587 | 606/5450 | 84.6/1150 | 1.0/8.0 |
Cycle 1 Day 8
| |||||
400 mg qd | |||||
n | 3 | 2 | 3 | 3 | 3 |
Median | 7349 | 14,315 | 7351 | 754 | 4.0 |
Min/Max | 4311/17,295 | 7657/20,974 | 4310/17,465 | 314/1470 | 4.0/8.0 |
800 mg qd | |||||
n | 3 | 1 | 3 | 3 | 3 |
Median | 17,327 | 19,866 | 17,327 | 1170 | 6.0 |
Min/Max | 8497/19,617 | 19,866/19,866 | 8497/19,626 | 609/1700 | 4.0/8.0 |
1000 mg qd | |||||
n | 7 | 3 | 3 | 7 | 7 |
Median | 9347 | 8301 | 8261 | 912 | 6.0 |
Min/Max | 482/46,393 | 496/9469 | 482/9347 | 76.1/2850 | 1.0/8.0 |
1200 mg qd | |||||
n | 4 | 1 | 4 | 4 | 4 |
Median | 33,484 | 14,438 | 34,179 | 1810 | 4.0 |
Min/Max | 12,760/46,522 | 14,438/14,438 | 12,840/46,522 | 1130/2410 | 2.0/4.0 |
1400 mg qd | |||||
n | 5 | 0 | 3 | 5 | 5 |
Median | 35,882 | – | 36,375 | 2480 | 4.0 |
Min/Max | 13,688/74,490 | – | 26,544/40,807 | 720/3910 | 3.9/7.9 |
400 mg bid | |||||
n | 6 | 1 | 5 | 6 | 6 |
Median | 9702 | 2786 | 10,677 | 1046 | 4.0 |
Min/Max | 2616/52,196 | 2786/2786 | 2616/53,881 | 455/6070 | 2.0/12.0 |
Cycle 1 Day 28
| |||||
400 mg qd | |||||
n | 3 | 3 | 3 | 3 | 3 |
Median | 8916 | 10,192 | 8916 | 795 | 4.0 |
Min/Max | 7756/25,942 | 7947/29,223 | 7769/26,182 | 600/1860 | 4.0/4.0 |
800 mg qd | |||||
n | 3 | 2 | 3 | 3 | 3 |
Median | 24,870 | 13,540 | 24,955 | 1980 | 2.0 |
Min/Max | 417/26,167 | 428/26,651 | 417/26,167 | 41.2/2190 | 1.0/4.0 |
1000 mg qd | |||||
n | 4 | 2 | 2 | 4 | 4 |
Median | 4804 | 3769 | 3736 | 548 | 4.0 |
Min/Max | 641/11,714 | 649/6889 | 641/6831 | 153/935 | 1.0/6.0 |
1200 mg qd | |||||
n | 2 | 0 | 1 | 2 | 2 |
Median | 37,128 | – | 43,429 | 2170 | 5.9 |
Min/Max | 31,005/43,252 | – | 43,429/43,429 | 1720/2620 | 3.9/8.0 |
1400 mg qd | |||||
n | 4 | 3 | 4 | 4 | 4 |
Median | 18,270 | 30,688 | 18,343 | 1506 | 4.0 |
Min/Max | 4394/36,862 | 7815/45,815 | 4394/36,862 | 317/2510 | 4.0/6.0 |
400 mg bid | |||||
n | 4 | 1 | 3 | 4 | 4 |
Median | 34,083 | 2663 | 29,372 | 3650 | 4.0 |
Min/Max | 2493/80,497 | 2663/2663 | 2493/40,839 | 518/8290 | 1.0/6.0 |