1 Introduction
2 Methods
2.1 Eligibility Criteria
2.2 Study Design and Dose Escalation Scheme
Demographic or patient characteristic | BEZ235 200 mg/d + 2.5 mg/d Everolimus (N = 4) | BEZ235 400 mg/d + 2.5 mg/d Everolimus (N = 7) | BEZ235 800 mg/d + 2.5 mg/d Everolimus (N = 8) | Total (N = 19) |
---|---|---|---|---|
Age (median, years) | 59 (range 36–64) | 57 (range 54–73) | 52 (range 38–62) | 56 |
Male | 3 | 3 | 6 | 12 |
Female | 1 | 4 | 2 | 7 |
ECOG PS = 0 | 0 | 2 | 1 | 3 |
ECOG PS = 1 | 4 | 5 | 6 | 15 |
ECOG PS = 2 | 0 | 0 | 1 | 1 |
White | 3 | 6 | 6 | 15 |
Black | 1 | 1 | 1 | 3 |
Hispanic | 0 | 0 | 1 | 1 |
# Prior treatments | 3.5 (range 2–5) | 3 (range 2–9) | 3.5 (range 1–5) | 3 (range 1–9) |
Days of treatment received | 56 (range 18–56) | 19 (range 6–56) | 15 (range 5–46) | 24 (range 5–56) |
Tumor types | ||||
NSCLC | 1 | 1 | 0 | 2 |
Brain tumor | 1 | 1 | 1 | 3 |
Colon carcinoma | 1 | 1 | 1 | 3 |
HCC | 1 | 0 | 0 | 1 |
Pancreatic Ca | 0 | 1 | 0 | 1 |
Esophageal Ca | 0 | 1 | 1 | 2 |
Laryngeal ca (adenoid cystic) | 0 | 1 | 0 | 1 |
Appendix ca | 0 | 1 | 0 | 1 |
HNSCC | 0 | 0 | 1 | 1 |
Prostate ca | 0 | 0 | 1 | 1 |
Ovarian ca | 0 | 0 | 1 | 1 |
Rectal NET | 0 | 0 | 1 | 1 |
Endometrial Ca | 0 | 0 | 1 | 1 |
2.3 Patient Evaluation
2.4 Pharmacokinetic Assessment and Determination of Everolimus and BEZ235 Concentrations
2.5 Pharmacokinetic and Statistical Analysis
3 Results
3.1 Patient Characteristics
3.2 Dose Escalation, Safety and Maximum Tolerated Dose
Toxicity category | Toxicity | Cohort 1 | Cohort 2 | Cohort 3 |
---|---|---|---|---|
General symptoms | Fatigue | 1 (14) | 1 (13) | |
Angioedema | 1 (14) | |||
Dehydration | 2 (28) | |||
Lab abnormalities | ALT Elevation | 1 (13) | ||
AST Elevation | 1 (25) | 1+ (14) | 2 (25) | |
Alkaline phosphatase elevation | 2+ (28) | 1 (13) | ||
Elevated bilirubin | 1+ (14) | |||
Tumor lysis syndrome | 1* (13) | |||
Hypophosphatemia | 1 (13) | |||
Anemia | 2 (28) | 1 (13) | ||
Neutropenia | 1* (14) | |||
Thrombocytopenia | 1 (13) | |||
Gastrointestinal symptoms | Mucositis | 1 (14) | 1 (13) | |
Diarrhea | 1 (14) | 1 (13) | ||
Nausea/vomiting | 1 (13) | |||
Hepatorenal syndrome | 1* (13) | |||
Infectious complications | Gram positive bacteremia | 2+** (25) | ||
Pneumonia+
| 1 (25) | |||
Perforated diverticulitis+
| 1* (13) | |||
Neurologic symptoms | Gait imbalance+
| 1 (14) | ||
Hydrocephalus+
| 1* (25) | |||
Peripheral neuropathy | 1 (13) |
3.3 Tumor Response
3.4 Pharmacokinetics of BEZ235
Pharmacokinetic parameter (Mean ± SE) | BEZ235 Dose | Everolimus Dose | ||||||
---|---|---|---|---|---|---|---|---|
200 mg | 400 mg | 800 mg | 2.5 mg | |||||
Day 1 | Day 28 | Day 1 | Day 28 | Day 1 | Day 28 | Day 1 | Day 28 | |
AUC 0-24(ng*hr/mL) | 433.4 ± 96 | 1474 ± 515.2 | 741.3 ± 171.2 | 1458.1 ± 1253.6 | 2081.5 ± 666.2 | 7795.1 ± 5608.7 | 124.32 ± 12.72 | 218.8 ± 33.26*
|
AUC 0-∞(ng*hr/mL) | 468.5 ± 118.2 | 1487.9 ± 690.9 | 830.8 ± 163.1 | 2707.6 ± 2343.3 | 2167.3 ± 674.9 | 8877 ± 6589.9 | 191.15 ± 33.72 | 693.76 ± 148.08 |
Cmax (ng/mL) | 45.2 ± 11.4 | 214.4 ± 114.4 | 101.8 ± 22.4 | 227.3 ± 197.6 | 243 ± 52.7 | 880.3 ± 570.5 | 14.08 ± 1.5 | 31.68 ± 7.4 |
Cmax / Dose (ng/mL/mg) | 0.2 ± 0.1 | 1.1 ± 0.6 | 0.3 ± 0.1 | 0.6 ± 0.5 | 0.3 ± 0.1 | 1.1 ± 0.7 | 5.63 ± 0.6 | 12.67 ± 2.96 |
Tmax (hr) | 3.8 ± 1.6 | 2.7 ± 0.7 | 2.5 ± 0.9 | 1.5 ± 0.5 | 2.6 ± 0.8 | 2 ± 0 | 4.3 ± 1.2 | 1.3 ± 0.2*
|
Terminal half-life (hr) | 3.2 ± 1 | 19.2 ± 2.5 | 8.6 ± 1.5 | 43.4 ± 10.8 | 5.9 ± 0.7 | 15 ± 6.4 | 15.69 ± 2.33 | 47.64 ± 9.1*
|
Apparent clearance, CL/F (L/hr) | 629.6 ± 278.1 | 116.3 ± 24.4 | 644.3 ± 192.9 | 309.3 ± 241.3 | 773.9 ± 262.1 | 355.9 ± 246.6 | 24.76 ± 2.91 | 13.41 ± 2.31*
|
*
P < 0.05 |