Background
Methods
Patient eligibility
Study design
Drug administration and dose escalation scheme
Definition of DLT and MTD
Patient evaluation and follow-up
18F-MISO PET Imaging
Pharmacokinetic analyses
Statistics
Results
Patient characteristics
Characteristic | Number of Patients (%) (n=42) | |
---|---|---|
Gender | ||
Female | 23 (55%) | |
Male | 19 (45%) | |
Age (Years) | ||
Median (range) | 60 (27–85) | |
Ethnicity | ||
Caucasian | 34 (81%) | |
Other | 8 (19%) | |
ECOG performance status | ||
Median (range) | 1 (0–1) | |
Tumour type | ||
NSCLC | 10 (24%) | |
Gastrointestinal | 7 (17%) | |
Genitourinary | 4 (10%) | |
Prostate | 4 (10%) | |
Head and neck | 3 (7%) | |
Melanoma | 3 (7%) | |
Sarcoma | 3 (7%) | |
Other | 8 (19%) | |
Number of prior chemotherapy regimens | ||
Median (range) | 1 (0–3) |
Study treatment assignment
Group | PR104 dose (mg/m2) | Combination Agents | Schedule | ||
---|---|---|---|---|---|
Starting | Maximum tolerated | Agent | Dose (mg/m2) | ||
A | 275 | 140 | Gemcitabine | 800 | iv days 1 and 8 q 3 weekly |
B | 400 | <200 | Docetaxel | 60 | iv day 1 q 3 weekly |
C | 200 | 770 | Docetaxel + G-CSF | 60 | iv day 1 q 3 weekly |
D | 770 | ≥770 | Docetaxel + G-CSF | 75 | iv day 1 q 3 weekly |
MTDs, DLTs and recommended phase II dose
PR104 Dose | Patients | Dose-limiting toxicities | ||
---|---|---|---|---|
Level | mg/m2
| (n) | ||
Group A PR104 + gemcitabine | 1 | 275 | 3 | Grade 4 thrombocytopenia (n=2) |
2 | 140 | 6 | - | |
Group B PR104 + docetaxel 60 | 1 | 400 | 3 | Grade 3 neutropenic fever (n=1) |
2 | 200 | 3 | Grade 3 neutropenic fever (n=2) | |
Group C PR104 + docetaxel 60 + GCSF | 1 | 200 | 3 | - |
2 | 400 | 3 | - | |
3 | 550 | 3 | - | |
4 | 770 | 6 | - | |
5 | 1100 | 6 | Grade 4 thrombocytopenia (=1) Grade 3 Fatigue (n=1) | |
Group D PR104 + docetaxel 75 + GCSF | 1 | 770 | 6 | - |
Other toxicities
Adverse event | Group A2(n=9) | Group B3(n=6) | Group C4(n=21) | Group D5(n=6) | ||||
---|---|---|---|---|---|---|---|---|
Gd 3 | Gd 4 | Gd 3 | Gd 4 | Gd 3 | Gd 4 | Gd 3 | Gd 4 | |
Fatigue | 2 | - | - | - | 6 | - | 2 | 2 |
Febrile neutropenia | - | 3 | 2 | - | 1 | - | - | - |
Alopecia | - | - | - | - | 3 | - | - | - |
Nausea | 1 | - | - | - | 1 | - | - | - |
Respiratory infection | - | - | 1 | - | - | - | 1 | - |
Vomiting | - | - | - | - | 2 | - | - | - |
Anaemia | - | - | - | - | 1 | - | - | - |
Anorexia | - | - | - | - | 1 | - | - | - |
Dehydration | - | - | - | - | 1 | - | - | - |
Diarrhoea | - | - | - | - | 1 | - | - | - |
Leukopenia | 1 | - | - | - | - | - | - | - |
QT/QTc prolongation | - | - | - | - | - | - | 1 | - |
Weight loss | - | - | - | - | 1 | - | - | - |
Adverse event | Group A2(n=9) | Group B3(n=6) | Group C4(n=21) | Group D5(n=6) | ||||
---|---|---|---|---|---|---|---|---|
Gd 3 | Gd 4 | Gd 3 | Gd 4 | Gd 3 | Gd 4 | Gd 3 | Gd 4 | |
Leucopenia | 2 | - | 3 | 1 | 4 | 6 | 3 | - |
Neutropenia | 2 | 1 | 3 | 1 | 3 | 6 | 2 | 1 |
Thrombocytopenia | - | 3 | - | - | 2 | 4 | - | 2 |
Anaemia | 1 | - | - | - | 3 | - | 1 | - |
Any haematological toxicity | 4 | 3 | 1 | 5 | 7 | 1 | 3 |
Tumour response
Hypoxia imaging
Pharmacokinetics
PR104 Dose | Patients | AUC/PR-104 dose (100*h.m2.L-1)a
| |||||
---|---|---|---|---|---|---|---|
Level | mg/m2
| (n) | PR104G | PR104H | PR-104M | PR-104S1 | |
Group A PR104 + gemcitabine | 1 | 140 | 3 | 1.51 ± 0.63 | 0.12 ± 0.02 | 0.022±0.002 | 0.021±0.006 |
2 | 275 | 6 | 1.18 ± 0.30 | 0.16 ± 0.03 | 0.015±0.002 | 0.020±0.006 | |
Group B PR104 + docetaxel 60 | 1 | 200 | 3 | 0.86 ± 0.29 | 0.20 ± 0.06 | 0.016±0.003 | 0.010±0.003 |
2 | 400 | 3 | 1.63 ± 0.73 | 0.12 ± 0.03 | 0.016±0.002 | 0.042±0.022 | |
Group C PR104 + docetaxel 60 + GCSF | 1 | 200 | 3 | 0.47 ± 0.26 | 0.07 ± 0.01 | 0.021±0.003 | 0.022±0.004 |
2 | 400 | 3 | 1.75 ± 0.57 | 0.11 ± 0.03 | 0.012±0.001 | 0.017±0.002 | |
3 | 550 | 3 | 1.56 ± 0.38 | 0.16 ± 0.04 | 0.025±0.007 | 0.045±0.012 | |
4 | 770 | 6 | 2.56 ± 0.67 | 0.07 ± 0.01 | 0.012±0.002 | 0.062±0.019 | |
5 | 1100 | 6 | 2.76 ± 1.68 | 0.09 ± 0.01 | 0.010±0.001 | 0.019±0.030 | |
Group D PR104 + docetaxel 75 + GCSF | 1 | 770 | 6 | 1.16 ± 0.18 | 0.035 ± 0.005 | 0.009±0.001 | 0.022±0.006 |
n/a | 675 | 7 | 1.02 ± 0.24 | 0.06 ± 0.01 | 0.011 ± 0.002 | 0.042 ± 0.015 | |
1100 | 10 | 2.35 ± 0.85 | 0.09 ± 0.01 | 0.015± 0.002 | 0.041 ± 0.009 |
Cmax (mg/L) | AUC (mg/L*hr) | t1/2(hr) | |
---|---|---|---|
Gemcitabine | 20.8 ± 10.6 | 4.87 ± 1.69 | 0.21 ± 0.06 |
Difluorodeoxyuridine | 30.8 ± 9.56 | 219 ± 57.6 | 12.2 ± 2.34 |