Table 1.
Clinical evaluation of endothelin antagonists in cancer*
| Compound (target receptor) | Study population and intervention | Trial status | Results and conclusions |
|---|---|---|---|
| Bosentan (Dual competitive ETA/ETB) | Phase II, metastatic melanoma (monotherapy; n = 35) (Kefford et al., 2007) | Completed | •Stable disease seen in six patients at 12 weeks |
| •No treatment responses | |||
| Phase II, metastatic melanoma (in combination with dacarbazine, placebo-controlled; n = 80) (Kefford et al., 2010) | Completed | •No difference in time to progression seen at 12 months | |
| YM598 (Selective ETA) | Phase II, prostate cancer (monotherapy) | Terminated | |
| Phase II, prostate cancer (in combination with mitoxantrone and prednisone) | Terminated | ||
| Atrasentan (Selective ETA) | Phase III, metastatic prostate cancer (placebo-controlled, monotherapy; n = 809) (Carducci et al., 2007) | Completed | •No reduction in disease progression |
| •Study design and prior assumption of progression rates may have limited the ability to define clinical benefit | |||
| Phase III, non-metastatic prostate cancer (placebo-controlled, monotherapy; n = 941) (Nelson et al., 2008) | Completed | •No statistically significant difference in time to progression | |
| •Large regional differences in TTP suggest trial conduct may have influenced results | |||
| Phase III, prostate cancer with bone metastases (in combination with docetaxel and prednisone) | Ongoing | (data not yet available) | |
| Phase II, hormone-refractory prostate cancer (double-blind, randomized monotherapy; n = 288) (Carducci et al., 2003) | Completed | •Trend towards prolongation of disease | |
| •Statistically significant delay in PSA | |||
| Phase II, hormone-naive prostate cancer (monotherapy) | Completed | (data not yet available) | |
| Phase II, prostate cancer with bone metastases (in combination with zoledronic acid; n = 44) (Michaelson et al., 2006) | Completed | •No evidence of additive or synergistic effects of combination therapy | |
| Phase I-II, metastatic prostate cancer (in combination with docetaxel; n = 31) (Armstrong et al., 2008) | Completed | •Survival comparable to that seen with docetaxel and prednisone, but rate of PSA decline lower than expected | |
| Phase I-II, NSCLC (in combination with paclitaxel and carboplatin; n = 44) (Chiappori et al., 2008) | Completed | •Lack of positive response data may reflect deficiencies in clinical trial design and low dose | |
| Phase II, renal carcinoma (monotherapy; n = 94) (Manola et al., 2007) | Completed | •6-month progression-free rates did not support use as first-line monotherapy | |
| Phase I, malignant glioma (monotherapy; n = 25) (Phuphanich et al., 2008) | Completed | •Primarily a safety study, but two partial responses observed | |
| Zibotentan (specific ETA) | Phase III, prostate cancer with bone metastases (monotherapy) | Completed | (data not yet available) |
| Phase III, non-metastatic prostate cancer (monotherapy) | Recruiting | (data not yet available) | |
| Phase III, prostate cancer, metastatic (in combination with docetaxel) | Ongoing | (data not yet available) | |
| Phase II, prostate cancer with bone metastases (placebo-controlled, monotherapy; n = 312) (James et al., 2010) | Complete | •No statistically significant improvement in TTP, but overall survival extended versus placebo | |
| Phase II, prostate cancer, metastatic, patients previously treated with chemotherapy (monotherapy; n = 24) | Ongoing | (data not yet available) | |
| Phase II, NSCLC (in combination with pemetrexed) | Completed | (data not yet available) | |
| Phase I, metastatic prostate cancer (in combination with docetaxel; n = 31) (Trump et al., 2010) | Completed | •Activity observed with the combination, meriting further evaluation | |
| Phase I, advanced solid malignancies in elderly Chinese patients (monotherapy) | Recruiting | (data not yet available) |
*
Not including planned clinical trials. ETA, endothelin A receptor; ETB, endothelin B receptor; NSCLC, non-small-cell lung cancer; PSA, prostate-specific antigen; TTP, time to tumour progression.