Antitumor activity of IT-101 in various s.c. human xenograft models in nude mice
| Model . | n . | Agent . | Schedule . | Dose (mg/kg) . | Median TTE . | TGD (%) . | Log-rank significance . | . | CR . | TFS . | TR . | BWLmax (%) . | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| . | . | . | . | . | . | . | vs UT . | vs CPT-11 . | . | . | . | . | |
| LS174T (colon) | 8 | UT | — | — | 24.6 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 37.1 | 51 | * | — | 0 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 25.8 | 62.0 | 152 | † | * | 0 | 0 | 0 | 12.1 (5) | ||
| 8 | IT-101 | qwk × 3 | 25.8 | 71.0 | 189 | ne | ne | 0 | 2 | 2 | 15.9 (18) | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 69.0 | 180 | † | † | 0 | 0 | 0 | 4.7 (11) | ||
| HT29 (colon) | 8 | UT | — | — | 36.6 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 52.0 | 42 | ns‡ | — | 0 | 0 | 0 | — | ||
| 16 | IT-101 | qd × 1 | 20.7 | 32.0 | — | ne§ | ne | 0 | 0 | 5 | 20.9 (5) | ||
| 8 | IT-101 | qwk × 3 | 12.9 | 60.0 | 64 | † | * | 0 | 0 | 0 | 2.5 (11) | ||
| H1299 (NSCLC) | 8 | UT | — | — | 45.6 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 91.0 | 100 | * | — | 1 | 1 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 25.8 | 91.5 | 101 | * | ns | 4 | 4 | 0 | 4.2 (4) | ||
| 8 | IT-101 | qwk × 2 | 25.8 | 14.0 | — | ne | ne | 4 | 3 | 4 | 23.4 (12) | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 92.0 | 102 | † | ns∥ | 8 | 8∥ | 0 | 8.0 (19) | ||
| MDA-MB-231 (breast) | 8 | UT | — | — | 21.4 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 41.1 | 92 | ns | — | 0 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 25.8 | 17.2 | — | ne | ne | 0 | 0 | 4 | 14.2 (5) | ||
| 8 | IT-101 | qwk × 3 | 25.8 | 38.0 | 78 | ne | ne | 0 | 0 | 5 | 9.1 (5) | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 68.6 | 221 | * | ¶ | 1 | 1 | 0 | — | ||
| H69 (SCLC) | 8 | UT | — | — | 21.2 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 67.0 | 216 | † | — | 1 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 16.1 | 59.0 | 178 | † | ns | 1 | 1 | 0 | — | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 95.0 | 348 | † | * | 2 | 0 | 0 | — | ||
| 8 | IT-101 | qwk × 3 | 9.7 | 38.9 | 183 | † | ns | 0 | 0 | 0 | — | ||
| Panc-1 (pancreatic) | 8 | UT | — | — | 48.8 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 58.6 | 20 | ns | — | 0 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 20.7 | 64.1 | 31 | ns | ns | 0 | 0 | 1 | 12.7 (5) | ||
| 8 | IT-101 | qwk × 3 | 20.7 | 91.0 | 86 | ¶ | ¶ | 4 | 1 | 0 | 13.5 (5) | ||
| 8 | IT-101 | qwk × 3 | 12.9 | 91.0 | 86 | ¶ | * | 3 | 1 | 0 | — | ||
| Model . | n . | Agent . | Schedule . | Dose (mg/kg) . | Median TTE . | TGD (%) . | Log-rank significance . | . | CR . | TFS . | TR . | BWLmax (%) . | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| . | . | . | . | . | . | . | vs UT . | vs CPT-11 . | . | . | . | . | |
| LS174T (colon) | 8 | UT | — | — | 24.6 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 37.1 | 51 | * | — | 0 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 25.8 | 62.0 | 152 | † | * | 0 | 0 | 0 | 12.1 (5) | ||
| 8 | IT-101 | qwk × 3 | 25.8 | 71.0 | 189 | ne | ne | 0 | 2 | 2 | 15.9 (18) | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 69.0 | 180 | † | † | 0 | 0 | 0 | 4.7 (11) | ||
| HT29 (colon) | 8 | UT | — | — | 36.6 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 52.0 | 42 | ns‡ | — | 0 | 0 | 0 | — | ||
| 16 | IT-101 | qd × 1 | 20.7 | 32.0 | — | ne§ | ne | 0 | 0 | 5 | 20.9 (5) | ||
| 8 | IT-101 | qwk × 3 | 12.9 | 60.0 | 64 | † | * | 0 | 0 | 0 | 2.5 (11) | ||
| H1299 (NSCLC) | 8 | UT | — | — | 45.6 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 91.0 | 100 | * | — | 1 | 1 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 25.8 | 91.5 | 101 | * | ns | 4 | 4 | 0 | 4.2 (4) | ||
| 8 | IT-101 | qwk × 2 | 25.8 | 14.0 | — | ne | ne | 4 | 3 | 4 | 23.4 (12) | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 92.0 | 102 | † | ns∥ | 8 | 8∥ | 0 | 8.0 (19) | ||
| MDA-MB-231 (breast) | 8 | UT | — | — | 21.4 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 41.1 | 92 | ns | — | 0 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 25.8 | 17.2 | — | ne | ne | 0 | 0 | 4 | 14.2 (5) | ||
| 8 | IT-101 | qwk × 3 | 25.8 | 38.0 | 78 | ne | ne | 0 | 0 | 5 | 9.1 (5) | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 68.6 | 221 | * | ¶ | 1 | 1 | 0 | — | ||
| H69 (SCLC) | 8 | UT | — | — | 21.2 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 67.0 | 216 | † | — | 1 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 16.1 | 59.0 | 178 | † | ns | 1 | 1 | 0 | — | ||
| 8 | IT-101 | qwk × 3 | 16.1 | 95.0 | 348 | † | * | 2 | 0 | 0 | — | ||
| 8 | IT-101 | qwk × 3 | 9.7 | 38.9 | 183 | † | ns | 0 | 0 | 0 | — | ||
| Panc-1 (pancreatic) | 8 | UT | — | — | 48.8 | — | — | — | 0 | 0 | 0 | — | |
| 8 | CPT-11 | qwk × 3 | 100 | 58.6 | 20 | ns | — | 0 | 0 | 0 | — | ||
| 8 | IT-101 | qd × 1 | 20.7 | 64.1 | 31 | ns | ns | 0 | 0 | 1 | 12.7 (5) | ||
| 8 | IT-101 | qwk × 3 | 20.7 | 91.0 | 86 | ¶ | ¶ | 4 | 1 | 0 | 13.5 (5) | ||
| 8 | IT-101 | qwk × 3 | 12.9 | 91.0 | 86 | ¶ | * | 3 | 1 | 0 | — | ||
NOTE: See Materials and Methods for statistical methods. Irinotecan (CPT-11) was included as a positive internal control.
Irinotecan (CPT-11) was administered i.p.; IT-101 was administered i.v.; IT-101 dose is in camptothecin equivalents.
UT, untreated control group. TTE, time to end point (days); 1,500 mm3 (LS174T and MDA-MB-231); 1,200 mm3 (H1299, H69, and Panc-1); 1,000 mm3 (HT29). TGD, percent tumor growth delay versus control group: [(T − C) / C] × 100. CR, number of animals classified as complete responders. TFS, number of animals classified as tumor-free survivors. TR, number of treatment-related deaths. BWLmax, percent maximum mean body weight loss (numbers in parentheses indicate days after drug dosing when BWLmax was observed). NSCLC, non–small-cell lung cancer. SCLC, small-cell lung cancer.
Log-rank test is equivalent to Mantel-Haenszel test; P < 0.01.
Log-rank test is equivalent to Mantel-Haenszel test; P < 0.001.
Log-rank test is equivalent to Mantel-Haenszel test; ns, not significant (P ≥ 0.05).
Log-rank test is equivalent to Mantel-Haenszel test; ne, nonevaluable.
Fisher's exact test comparing complete versus non–complete responders showed IT-101 to be significantly more effective than irinotecan (P < 0.001).
Log-rank test is equivalent to Mantel-Haenszel test; P < 0.05.