Table 3.
Clinical trials with combinations including FTIs*
| Drugs | Disease | Phase | Patients (median age) | Clinical response and number of patients‡ | FT activity or prenylation | Response rate (%) | Other comments |
|---|---|---|---|---|---|---|---|
| Tipifarnib + capecitabine | Advanced solid tumours | I | 41 (57) | 5 PR and 11 SD | FT ↓§ and HDJ2 ↓ | 12.2 | No correlation between FT ↓ and response |
| Tipifarnib + doxorubicin + cyclophosphamide | Advanced breast cancer | I and II | 32 (51) | 7 CR | FT ↓ by 55–100% | 21.9 | |
| Stage IIB–IIIC breast cancer | II | 44 (51) | 11 CR | Median FT ↓ by 91% | 25 | ||
| Tipifarnib + etoposide | AML | I | 84 (77) | 20 CR | p-S6 ↓ | 23.4 | |
| Tipifarnib + gemcitabine | Advanced solid tumours | I | 19 (59) | 2 PR | HDJ2 ↓ | 10.5 | |
| Tipifarnib + gemcitabine | Advanced pancreatic cancer | III | 341 (61) | 6 CR, 6 PR, 53 SD, and 28 PD and MD | ND | 1.8 | MS: 193 days. 6-month survival: 53%. 1-year survival: 27% |
| 347‖ (62) | 8 CR, 8 PR, 52 SD, and 30 PD and MD | ND | 2.3 | MS: 182 days. 6-month survival: 49%. 1-year survival: 24% | |||
| Tipifarnib + gemcitabine + cisplatin | Advanced solid tumours | I | 27 (58) | 1 CR and 8 PR | Prelamin A ↓ | 33.3 | |
| Advanced solid tumours | I | 31 (58) | 8 PR and 12 SD | ND | 25.8 | Phase II trial recommended | |
| Tipifarnib + idarubicin + cytarabine | AML and MDS | I/II | 95 (50) | 61# CR and 9 PR | ND | 74 | MS: 17 months |
| 108¶ (52) | 65# | 70 | MS: 13 months | ||||
| Tipifarnib + imatinib | CML | I | 25 (62) | 17 PR | ND | 68 | 11 patients withdrew (lack of response) |
| Tipifarnib + irinotecan | Solid tumours | I | 35 (52) | 3 PR, 14 SD, and 13 PD and MD | ND | 8.6 | |
| Tipifarnib + letrozole | Advanced breast cancer | II | 74 (60) | 3 CR, 19 PR, 29 SD, and 23 PD and MD | ND | 29.7 | No improvement by tipifarnib |
| 39‖ (61) | 1 CR, 14 PR, 15 SD, and 9 PD and MD | ND | 38.5 | ||||
| Tipifarnib + sorafenib | Advanced solid tumours | I | 43 (56) | 3 PR, 15 SD, and 20 PD and MD | 25% of patients with >50% FT ↓ | 7.0 | |
| Tipifarnib + tamoxifen | Metastatic breast cancer | I | 12 (50) | 2 PR and 1 SD | FT ↓ 42–54% | 16.7 | |
| Lonafarnib + carboplatin + paclitaxel | Advanced NSCLC | III | 308 (unknown) | NA | NA | OS: 144 days. TTP: 137 days | |
| 308‖ (unknown) | NA | OS: 168 days. TTP: 152 days | |||||
| Lonafarnib + docetaxel | Advanced solid tumours | I | 29 | 1 CR and 6 SD | 3.4 | Response (CR + SD) correlates with low FNTB mRNA levels | |
| Lonafarnib + gemcitabine | Advanced bladder cancer | II | 31 (64) | 1 CR and 9 PR | ND | 32.3 | MS: 11.5 months. TTP: 7 months |
| Lonafarnib + imatinib | CML | I | 23 (55) | 6 CR and 2 PR | ND | 34.7 | |
| Lonafarnib + paclitaxel | Solid tumours | I | 21 (60) | 6 PR | ND | 28.6 | 6 patients previously treated |
| BMS-214662 + cisplatin | Advanced solid tumours | I | 23 (57) | 15 SD | Short-lived FT ↓ | 0 | No objective response |
| BMS-214662 + paclitaxel | Advanced solid tumours | I | 26 (60) | 2? PR | Short-lived FT ↓ | ≤7.7 | |
| BMS-214662 + paclitaxel + carboplatin | Advanced solid tumours | I | 30 (58) | 3 PR and 8 SD | Short-lived FT ↓ and HDJ2 ↓ | 10.0 | No correlation between dose and HDJ2 ↓ |
| L-778,123 + radiotherapy | Advanced solid tumours | I | 7 (59) | 5 CR, 1 PR, and 6 PD and MD | ND | 85.7 | No RAS mutations |
| Advanced pancreatic cancer | I | 10 (59) | 1 PR, 5 SD, and 4 PD and MD | HDJ2 ↓ | 10.0 | 3 out of 4 patients examined have KRAS mutations |
AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; CR, complete response; FNTB, farnesyltransferase β-subunit; FT, farnesyltransferase; FTIs, FT inhibitors; GGTI, geranylgeranyltransferase 1 inhibitor; HI, haematological improvement; MD, metastatic disease; MDS, myelodysplastic syndrome; MS, median survival; NA, not applicable; ND, not determined; NSCLC, non-small-cell lung cancer; OS, overall survival; p, phosphorylated; PD, progressive disease; PR, partial response; S6, ribosomal protein S6; SD, stable disease; TTP, median time to progression.
See Supplementary information S5 (table) for a table with references. This table only considers FTIs because, to our knowledge, only one GGTI, GGTI-2418, is currently in clinical trials. Studies that did not evaluate tumour response are not included. Median ages are rounded to the closest integer. The number of evaluable patients is stated whenever possible. The response rate was calculated by dividing the sum of complete and partial responses by the number of evaluable patients.
PR includes haematological improvement.
Downward arrows indicate a reduction of enzyme activity (in the case of FT) or a reduction in farnesylation (in the case of HDJ2 or prelamin A).
This patient cohort received a placebo instead of the FTI.
This patient cohort received idarubicin plus cytarabine (referred to by the authors as a historical control).
As the reference only provides percentage response rates, the patient numbers were calculated.