Introduction
Materials and methods
Study drug
Patients
Study design and dose escalation
Curcumin DLs | Other | DL 1 | DL 2 | DL 3 | DL 4 | DL 5 | DL 6 | DL 6a | All |
(mg/m2) | 120 | 100 | 120 | 150 | 190 | 240 | 300 | 300 |
–
|
Duration of infusion | |||||||||
(h) | 24 | 8 | 8 | 8 | 8 | 8 | 8 | 6 | – |
Number of patients | |||||||||
n
| 1 | 4 | 7 | 4 | 3 | 3 | 4 | 6 | 32 |
Gender | |||||||||
Male | |||||||||
n (%) | 1 | 4 (100) | 5 (71) | 2 (50) | 1 (33) | 2 (67) | 4 (100) | 4 (67) | 23 (72) |
Female | |||||||||
n (%) | 0 | 0 (0) | 2 (29) | 2 (50) | 2 (67) | 1 (33) | 0 (0) | 2 (33) | 9 (28) |
Age (years) | |||||||||
Median | 65.2 | 63.7 | 58.2 | 72.8 | 61.8 | 60.6 | 67.0 | 60.3 | 62.7 |
Range | 65.2 | 50.4–68.9 | 42.6–69.8 | 66.7–84.5 | 48.2–62.2 | 58.6–69.4 | 57.0–76.9 | 48.0–72.9 | 42.6–84.5 |
Number of previous treatment regimes | |||||||||
2 | |||||||||
n | 1 |
–
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–
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–
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–
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–
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–
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–
| 1 |
3 | |||||||||
n |
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–
| 1 | 1 | 1 |
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–
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–
| 3 |
4 | |||||||||
n |
–
| 2 | 1 | 4 |
–
| 1 | 1 | 1 | 10 |
5 | |||||||||
n |
–
| 1 | 5 | 5 |
–
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–
| 2 | 1 | 14 |
6 | |||||||||
n |
–
| 1 | 2 |
–
| 1 |
–
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–
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–
| 4 |
7 | |||||||||
n |
–
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–
| 1 |
–
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–
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–
| 1 | 1 | 3 |
8 | |||||||||
n |
–
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–
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–
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–
| 1 | 1 |
–
| 2 | 4 |
9 | |||||||||
n |
–
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–
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–
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–
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–
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–
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–
| 1 | 1 |
10 | |||||||||
n |
–
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–
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–
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–
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–
| 1 |
–
|
–
| 1 |
ECOG score | |||||||||
0 | |||||||||
n | 1 |
–
| 2 | 1 | 1 | 1 |
–
| 3 | 9 |
1 | |||||||||
n |
–
| 4 | 3 | 3 | 1 | 1 | 2 | 2 | 16 |
2 | |||||||||
n |
–
|
–
| 2 |
–
| 1 | 1 | 2 | 1 | 7 |
Mean treatment duration | |||||||||
(days) | 15 | 31 | 33.3 | 27.5 | 38.3 | 38.3 | 26.8 | 54.2 | 35.8 |
Safety assessments
Pharmacokinetic assessments
Efficacy assessments
Results
Patients
Adverse events (AEs)
DL | Patient | AE (preferred term) | Timing | Grade | SAE | Relationship | Outcome |
---|---|---|---|---|---|---|---|
1 | 002 | Red blood cell abnormality | Cycle 1 | n.a. | No | Definite | Recovered |
003 | Platelet count decreased | Cycle 1 | 2 | No | Probable | Recovered with sequelae | |
Platelet count decreased | Cycle 2 | 2 | No | Probable | Recovered with sequelae | ||
004 | Pyrexia | Cycle 1 | 1 | No | Probable | Recovered | |
Productive cough | Cycle 1 | 1 | No | Probable | Recovered | ||
Pyrexia | Cycle 2 | 1 | No | Probable | Recovered | ||
Chills | Cycle 5 | 2 | No | Probable | Recovered | ||
Pyrexia | Cycle 5 | 1 | No | Probable | Recovered | ||
5 | 023 | Hypertrichosis | Cycle 4 | 1 | No | Probable | Recovered |
6a | 028 | Anemia | Cycle 3 | 2 | No | Probable | Ongoing after final examination |
028 | Haemolysis | Cycle 4 | 3 | No | Definite | Recovered with sequelae | |
029 | Anemia | Cycle 4 | 3 | No | Definite | Ongoing after final examination | |
030 | Infusion-related reaction | Cycle 7 | 2 | No | Probable | Recovered | |
031 | Face edema | Cycle 1 | 2 | Yes | Probable | Recovered | |
032 | Anemia | Cycle 1 | 3 | Yes | Probable | Recovered | |
032 | Anemia | Cycle 2 | 2 | No | Definite | Recovered |
DLT and recommended phase 2 dose
Pharmacokinetics of curcumin and THC
Patient |
C
max (ng/mL) |
T
max (h) | AUC0−Tlast (ng h/mL) |
C
last (ng/mL) |
T
last (h) |
---|---|---|---|---|---|
DL 3: 150 mg/m2, 8 h infusion | |||||
17 | 66.1 | 6.0 | 270 | 66.1 | 6.0 |
DL 4: 190 mg/m2, 8 h infusion | |||||
18 | 54.7 | 2.0 | 231 | 26.4 | 6.0 |
19a | 3885.1 | 6.0 | 13,752 | 251.2 | 8.8 |
20 | 64.1 | 6.0 | 254 | 64.1 | 6.0 |
Mean | 59.4 | 4.0 | 243 | 45.3 | 6.0 |
SD | 6.7 | 2.8 | 16 | 26.7 | 0 |
SE | 4.7 | 2.0 | 12 | 18.8 | 0 |
%CV | 11 | 71 | 7 | 59 | 0 |
DL 5: 240 mg/m2 8 h infusion | |||||
22 | 824.2 | 4.0 | 3077 | 61.9 | 8.5 |
23 | 469.4 | 2.0 | 2325 | 310.4 | 6.7 |
Mean | 646.8 | 3.0 | 2701 | 186.2 | 7.6 |
SD | 250.9 | 1.4 | 532 | 175.7 | 1.3 |
SE | 171.4 | 1.0 | 376 | 124.3 | 0.9 |
%CV | 39 | 48 | 20 | 94 | 17 |
DL 6: 300 mg/m2, 8 h infusion | |||||
24 | 3484.4 | 2.0 | 17,351 | 12.9 | 7.8 |
25 | 1212.3 | 4.0 | 5174 | 319.1 | 8.0 |
26 | 1051.4 | 4.0 | 4374 | 807.1 | 6.0 |
27 | 815.8 | 4.3 | 3674 | 11.3 | 8.9 |
Mean | 1641 | 3.6 | 7643 | 287.6 | 7.7 |
SD | 1239.7 | 1.1 | 6501 | 375.4 | 1.2 |
SE | 715.7 | 0.6 | 3753 | 216.7 | 0.7 |
%CV | 76 | 30 | 85 | 131 | 16 |
DL 6a: 300 mg/m2, 6 h infusion | |||||
28 | 2351.2 | 4.0 | 9701 | 10.4 | 6.5 |
29 | 1261.8 | 5.8 | 5780 | 24.9 | 6.4 |
30 | 1672.7 | 2.0 | 6915 | 286.2 | 6.4 |
31 | 1367.6 | 4.0 | 6669 | 10.6 | 6.2 |
32 | 767.2 | 5.9 | 2448 | 13.8 | 6.4 |
33 | 1147.7 | 4.0 | 5168 | 790.2 | 5.8 |
Mean | 1428 | 4.3 | 6113 | 189.4 | 6.3 |
SD | 540.1 | 1.4 | 2378 | 313.8 | 0.2 |
SE | 220.5 | 0.6 | 971 | 128.1 | 0.1 |
%CV | 38 | 34 | 39 | 166 | 4 |
Patient |
C
max (ng/mL) |
T
max (h) | AUC0−Tlast (ng h/mL) |
C
last (ng/mL) |
T
last (h) | AUC0−Tlast THC/AUC0−Tlast curcumin |
---|---|---|---|---|---|---|
DL 3: 150 mg/m2, 8 h infusion | ||||||
17 | 16.1 | 4 | 59 | 10.3 | 6.0 | 0.218 |
DL 4: 190 mg/m2, 8 h infusion | ||||||
18 | 7.7 | 4.0 | 22 | 7.7 | 4.0 | 0.096 |
19a | 396.1 | 8.1 | 1656 | 11.8 | 8.8 | 0.122 |
20 | 6.6 | 6.0 | 31 | 6.6 | 6.0 | 0.121 |
Mean | 7.2 | 5.0 | 27 | 7.2 | 5.0 | 0.109 |
SD | 0.7 | 1.4 | 6 | 0.7 | 1.4 | 0.018 |
SE | 0.5 | 1.0 | 4 | 0.5 | 1.0 | 0.012 |
%CV | 10 | 28 | 23 | 10 | 28 | 16 |
DL 5: 240 mg/m2 8 h infusion | ||||||
22 | 24.3 | 2.0 | 102 | 14.3 | 6.0 | 0.033 |
23 | 63.3 | 2.0 | 271 | 28.2 | 6.7 | 0.116 |
Mean | 43.8 | 2.0 | 186 | 21.2 | 6.4 | 0.075 |
SD | 27.6 | 0 | 119 | 9.9 | 0.5 | 0.059 |
SE | 19.5 | 0 | 84 | 7.8 | 0.3 | 0.042 |
%CV | 63 | 0 | 64 | 47 | 7 | 79 |
DL 6: 300 mg/m2, 8 h infusion | ||||||
24 | 108.3 | 2.0 | 359 | 48.2 | 6.0 | 0.021 |
25 | 75.2 | 3.8 | 407 | 28.6 | 7.6 | 0.079 |
26 | 75.6 | 2.0 | 426 | 5.3 | 8.5 | 0.097 |
27 | 38.5 | 2.3 | 187 | 5.1 | 8.6 | 0.051 |
Mean | 74.4 | 2.5 | 344 | 21.8 | 7.7 | 0.062 |
SD | 28.5 | 0.8 | 109 | 20.8 | 1.2 | 0.033 |
SE | 16.5 | 0.5 | 63 | 12.0 | 0.7 | 0.019 |
%CV | 38 | 34 | 32 | 95 | 16 | 54 |
DL 6a: 300 mg/m2, 6 h infusion | ||||||
28 | 110.4 | 2.0 | 497 | 6.9 | 6.8 | 0.051 |
29 | 35.1 | 4.0 | 155 | 5.2 | 6.8 | 0.027 |
30 | 80.1 | 2.0 | 385 | 5.2 | 7.3 | 0.056 |
31 | 67.6 | 2.5 | 332 | 6.0 | 6.0 | 0.050 |
32 | 70.7 | 5.9 | 321 | 8.4 | 6.6 | 0.131 |
33 | 58.3 | 5.8 | 264 | 5.7 | 6.2 | 0.051 |
Mean | 70.3 | 3.7 | 326 | 6.2 | 6.6 | 0.061 |
SD | 24.9 | 1.8 | 115 | 1.2 | 0.5 | 0.036 |
SE | 10.2 | 0.7 | 47 | 0.5 | 0.2 | 0.015 |
%CV | 35 | 49 | 35 | 20 | 7 | 59 |