Introduction
Materials and methods
Patient eligibility
Study design and treatment
Docetaxel (every 21 days) (mg/m2) | Sunitinib (once-daily dose) (mg) | Patients (N) | DLTs (n/N) | |
---|---|---|---|---|
Schedule 4/2 | ||||
Dose level 0a
| 60 | 25 | 4 | None |
Dose level 1 | 60 | 37.5 | 6 | Grade 3 muscular weakness (n = 1) Grade 3 febrile neutropenia (n = 1) |
Schedule 2/1b
| ||||
Dose level 0a
| 60 | 25 | 9 | Grade 4 febrile neutropenia (n = 1) Grade 4 neutropenia (n = 1) |
Dose level 1 | 60 | 37.5 | 3 | None |
Dose level 2 | 60 | 50 | 3 | None |
Dose level 3a | 75 | 50 | 2 | Grade 3 febrile neutropenia (n = 1) Grade 4 neutropenia (n = 1) |
Dose level 3bc
| 75 | 37.5 | 23 | Grade 3 gastrointestinal hemorrhage (n = 1) Grade 4 febrile neutropenia (n = 1) |
Study endpoints and assessments
Statistical methods
Results
Patient characteristics
Schedule 4/2 (N = 10) | Schedule 2/1 | ||
---|---|---|---|
All patients (N = 40) | MTDa only (n = 23) | ||
Age in years | |||
Median (range) | 57 (46–72) | 56 (26–74) | 55 (37–73) |
<65, n (%) | 7 (70) | 33 (83) | 18 (78) |
≥65, n (%) | 3 (30) | 7 (18) | 5 (22) |
Sex, n (%) | |||
Male | 8 (80) | 20 (50) | 7 (30) |
Female | 2 (20) | 20 (50) | 16 (70) |
ECOG performance status, n (%) | |||
0 | 2 (20) | 8 (20) | 4 (17) |
1 | 8 (80) | 32 (80) | 19 (83) |
Primary tumor types, n (%) | |||
RCC | 7 (70) | 3 (8) | 0 |
NSCLC | 1 (10) | 17 (43) | 11 (48) |
Adenocarcinoma | 0 | 7 (18) | 3 (13) |
Squamous cell carcinoma | 0 | 3 (8) | 2 (9) |
Bronchioloalveolar carcinoma | 0 | 1 (3) | 1 (4) |
Other/NOS | 1 (10) | 6 (15) | 5 (22) |
Other tumor typeb
| 2 (20) | 20 (50) | 12 (52) |
Previous cancer-related surgery | 10 (100) | 40 (100) | 23 (100) |
Outcome | |||
Partial/complete resection | 1 (10)/6 (60) | 2 (5)/19 (48) | 1 (4)/9 (39) |
Not applicable | 3 (30) | 19 (48) | 13 (57) |
Previous radiotherapy | 5 (50) | 11 (28) | 6 (26) |
Previous systemic therapy | 10 (100) | 32 (80) | 17 (74) |
Number prior systemic therapies | |||
1 | 2 (20) | 6 (15) | 3 (13) |
≥2 | 8 (80) | 26 (65) | 14 (61) |
Schedule 4/2 dose levelsa 0–1 (N = 10) | Schedule 2/1 dose levelsa 0–3b | ||
---|---|---|---|
All patients (N = 40) | MTD only dose level 3b (n = 23) | ||
Median cycles started (range) | 2 (1–3) | 4 (1–6) | 4 (1–6) |
Treatment interruption for sunitinib, n (%) | |||
Adverse event | 3 (30) | 11 (28) | 9 (39) |
Other | 0 | 0 | 0 |
Dose reduction for sunitinib, n (%) | 1 (10) | 5 (13) | 4 (17) |
Reason for treatment discontinuation, n (%) | |||
Adverse event | 6 (60) | 5 (13) | 4 (17) |
Consent withdrawn | 1 (10) | 2 (5) | 1 (4) |
Lack of antitumor activity | 2 (20) | 16 (40) | 8 (35) |
Sponsor decision | 0 | 3b (8) | 1 (4) |
Patient completed study per protocol | 1 (10) | 14 (35) | 9 (39) |
Safety and tolerability
Schedule 4/2
Determination of MTD
Other safety findings
Adverse event | Schedule 4/2 (N = 10) | Schedule 2/1 (N = 40) | ||
---|---|---|---|---|
Grade 3 n (%) | Grade 4 n (%) | Grade 3 n (%) | Grade 4 n (%) | |
Neutropenia | 1 (10.0) | 5 (50.0) | 4 (10.0) | 20 (50.0) |
Fatigue | 2 (20.0) | 0 | 8 (20.0) | 0 |
Febrile neutropenia | 2 (20.0) | 1 (10.0) | 1 (2.5) | 3 (7.5) |
Hyperglycemia | 1 (10.0) | 0 | 4 (10.0) | 0 |
Hypophosphatemia | 4 (40) | 0 | 0 | 0 |
Leukopenia | 0 | 0 | 3 (7.5) | 1 (2.5) |
Hypokalaemia | 0 | 0 | 3 (7.5) | 0 |
Dyspnea | 0 | 0 | 1 (2.5) | 1 (2.5) |
Diarrhea | 0 | 0 | 3 (7.5) | 0 |
Hemaglobin decrease | 1 (10.0) | 0 | 1 (2.5) | 0 |
Hypersensitivity | 0 | 0 | 2 (5.0) | 0 |
Infection (NOS) | 1 (10.0) | 0 | 1 (2.5) | 0 |
Nausea | 1 (10.0) | 0 | 1 (2.5) | 0 |
Pyrexia | 0 | 0 | 2 (5.0) | 0 |
Schedule 2/1
Determination of MTD
Other safety findings
Adverse event | Schedule 2/1 MTD (N = 23) | |||
---|---|---|---|---|
Grade 1 n (%) | Grade 2 n (%) | Grade 3 n (%) | Grade 4 n (%) | |
Neutropenia | 0 | 2 (8.7) | 0 | 15 (65.2) |
Fatigue | 4 (17.4) | 7 (30.4) | 5 (21.7) | 0 |
Febrile neutropenia | 0 | 0 | 1 (4.3) | 2 (8.7) |
Hyperglycemia | 1 (4.3) | 4 (17.4) | 3 (13.0) | 0 |
Leukopenia | 0 | 1 (4.3) | 1 (4.3) | 1 (4.3) |
Hypokalaemia | 0 | 0 | 3 (13.0) | 0 |
Diarrhea | 5 (21.7) | 6 (26.1) | 2 (8.7) | 0 |
Pyrexia | 7 (30.4) | 4 (17.4) | 2 (8.7) | 0 |
Pharmacokinetics
Mean (SD) sunitinib alone | Mean (SD) docetaxel + sunitinib | Geometric mean ratio (combination/drug alone) | |
---|---|---|---|
(a) Sunitinib, SU12662,c and total drugd
| |||
Schedule 4/2 Dose level 0, n = 3 Sunitinib | |||
AUC0–24 (ng*h/mL)
| 721.2 (289.0) | 548.0 (164.7) | 0.78 |
C
max (ng/mL)
| 36.4 (15.7) | 27.8 (7.4) | 0.79 |
T
max (h)
a
| 6.0 (4.0, 6.0) | 4.0 (4.0, 4.0) | NA |
SU12662 | |||
AUC0–24 (ng*h/mL)
| 294.0 (195.0) | 299.9 (132.7) | 1.10 |
C
max (ng/mL)
| 13.3 (8.3) | 14.4 (7.2) | 1.14 |
T
max (h)
a
| 4.0 (4.0, 12.0) | 4.0 (2.0, 4.0) | NA |
Total drug | |||
AUC0–24 (ng*h/mL)
| 1,015.5 (478.7) | 848.3 (288.7) | 0.86 |
C
max (ng/mL)
| 49.1 (23.8) | 42.1 (14.2) | 0.89 |
T
max (h)
a
| 4.0 (4.0, 6.0) | 4.0 (4.0, 4.0) | NA |
Schedule 4/2 Dose level 1, n = 5 Sunitinib | |||
AUC0–24 (ng*h/mL)
| 1,166.8 (303.6) | 1,020.4 (263.9) | 0.88 |
C
max (ng/mL)
| 60.1 (15.1) | 51.9 (12.9) | 0.87 |
T
max (h)
a
| 8.0 (2.0, 8.0) | 4.0 (4.0, 4.0) | NA |
SU12662 | |||
AUC0–24 (ng*h/mL)
| 341.9 (110.9) | 366.8 (137.5) | 1.06 |
C
max (ng/mL)
| 16.3 (4.6) | 17.7 (7.2) | 1.05 |
T
max (h)
a
| 6.0 (2.0, 12.0) | 4.0 (1.0, 12.0) | NA |
Total drug | |||
AUC0–24 (ng*h/mL)
| 1,508.9 (381.7) | 1,387.4 (346.7) | 0.92 |
C
max (ng/mL)
| 75.6 (17.1) | 69.5 (18.3) | 0.91 |
T
max (h)
a
| 8.0 (2.0, 8.0) | 4.0 (4.0, 4.0) | NA |
Schedule 2/1 Dose level 3bb, n = 10 Sunitinib | |||
AUC0–24 (ng*h/mL)
| 297.2 (89.0) | 312.9 (88.4) | 1.05 |
C
max (ng/mL)
| 17.8 (5.9) | 19.7 (7.4) | 1.09 |
T
max (h)
a
| 5.0 (4.0, 12.0) | 7.0 (2.0, 12.0) | NA |
SU12662 | |||
AUC0–24 (ng*h/mL)
| 58.0 (22.3) | 62.7 (32.4) | 0.99 |
C
max (ng/mL)
| 3.4 (1.3) | 4.1 (1.9) | 1.16 |
T
max (h)
a
| 5.0 (4.0, 24.0) | 7.0 (2.0, 24.0) | NA |
Total drug | |||
AUC0–24 (ng*h/mL)
| 355.3 (105.5) | 374.2 (103.7) | 1.06 |
C
max (ng/mL)
| 21.0 (7.0) | 23.4 (8.9) | 1.10 |
T
max (h)
a
| 5.0 (4.0, 12.0) | 8.0 (2.0, 24.0) | NA |
(b) Docetaxel PK parametersd
| |||
Schedule 4/2 Dose level 1, n = 5 Docetaxel | |||
AUClast (ng*h/mL)
| 2,290.4 (596.1) | 3,415.4 (1,102.8) | 1.47 |
AUCinf (ng*h/mL)
| 2,552.7 (649.4) | 3,692.8 (1,099.8) | 1.43 |
C
max (ng/mL)
| 2,100.0 (571.9) | 3,098.0 (984.2) | 1.46 |
t
1/2 (h)
| 19.6 (10.6) | 21.3 (7.4) | NA |
T
max (h)
a
| 0.5 (0.5, 1.0) | 0.5 (0.4, 1.0) | NA |
Schedule 2/1 Dose level 3b, n = 8 Docetaxel | |||
AUClast (ng*h/mL)
| 2,712.5 (731.9) | 3,056.5 (303.7) | 1.16 |
AUCinf (ng*h/mL)
| 2,961.5 (766.6) | 3,235.9 (298.5) | 1.12 |
C
max (ng/mL)
| 2,581.3 (535.6) | 3,180.0 (495.5) | 1.24 |
t
1/2 (h)
| 15.7 (9.9) | 17.7 (7.9) | NA |
T
max (h)
a
| 0.6 (0.5, 1.0) | 0.8 (0.5, 1.0) | NA |