Table 1.
Selected ongoing phase II and III clinical trials of novel targeted therapies for men with metastatic CRPC
| Target/pathway | Agent | Phase | Treatment arm(s) | 1ary end point | Identifier |
|---|---|---|---|---|---|
| AR-directed approaches | |||||
| CYP17 (androgen synthesis) | Orteronel | III | Randomized trial: orteronel 400 mg orally twice daily vs placebo orally twice daily (post-docetaxel) | Overall survival | NCT01193257 |
| III | Randomized trial: orteronel 400 mg orally twice daily vs placebo orally twice daily (pre-docetaxel) | Overall survival and progression-free survival (co-primary) | NCT01193244 | ||
| TOK-001 | I/II | Single-arm trial: TOK-001 650–2600 mg orally daily (dose escalation) (pre-docetaxel) | Phase I: Safety Phase II: ≥50% PSA ↓ |
NCT00959959 | |
| AR | MDV3100 | III | Randomized trial: MDV3100 160 mg orally daily vs placebo orally daily (post-docetaxel) | Overall survival | NCT00974311 |
| III | Randomized trial: MDV3100 160 mg orally daily vs placebo orally daily (pre-docetaxel) | Overall survival and progression-free survival (co-primary) | NCT01212991 | ||
| ARN-509 | I/II | Single-arm trial: ARN-509 30–300 mg orally daily (dose escalation) (pre- and post-docetaxel) | Phase I: Safety Phase II: Time to PSA progression (≥25% ↑) |
NCT01171898 | |
| Immunotherapies | |||||
| CTLA-4 (immune checkpoint) | Ipilimumab | III | Randomized trial: bone irradiation, then ipilimumab 10 mg/kg i.v. every 3 weeks vs placebo i.v. every 3 weeks (post-docetaxel) | Overall survival | NCT00861614 |
| III | Randomized trial: ipilimumab 10 mg/kg i.v. every 3 weeks vs placebo i.v. every 3 weeks (pre-docetaxel) | Overall survival | NCT01057810 | ||
| Other targeted therapies | |||||
| VEGF-R (angiogenesis) | Sorafenib | II | Single-arm trial: sorafenib 400 mg orally twice daily (post-docetaxel) | Time to disease progression | NCT00414388 |
| II | Single-arm trial: sorafenib 400 mg orally twice daily plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | ≥50% PSA ↓ | NCT00589420 | ||
| Cediranib | II | Randomized trial: cediranib 20 mg orally daily plus dasatinib 100 mg orally daily vs cediranib 20 mg orally daily (post-docetaxel) | Progression-free survival | NCT01260688 | |
| Ramucirumab | II | Randomized trial: cixutumumab (see below) 6 mg/kg i.v. every 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks vs ramucirumab 6 mg/kg i.v. every 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks (post-docetaxel) | Progression-free survival | NCT00683475 | |
| VEGF-Trap (angiogenesis) | Aflibercept | III | Randomized trial: aflibercept 6 mg/kg i.v. plus docetaxel 75 mg/m2 i.v. every 3 weeks vs placebo i.v. plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | Overall survival | NCT00519285 |
| mTOR (angiogenesis) | Temsirolimus | II | Single-arm trial: temsirolimus 25 mg i.v. every 1 week, plus anti-androgen upon progression (post-docetaxel) | Change in circulating tumor cell counts over time | NCT00887640 |
| Everolimus | II | Single-arm trial: everolimus 10 mg orally daily plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | Objective response rate | NCT00459186 | |
| II | Single-arm trial: everolimus 5 mg orally daily plus carboplatin AUC =5 i.v. every 3 weeks (post-docetaxel) | Time to disease progression | NCT01051570 | ||
| Ridaforolimus | II | Single-arm trial: ridaforolimus 50 mg i.v. every 1 week (post-docetaxel) | Objective response rate | NCT00110188 | |
| PI3K (angiogenesis) | BKM-120 | II | Single-agent trial: BKM-120 100 mg orally daily (post-docetaxel) | Progression-free survival | Being planned |
| S100A9 (angiogenesis) | Tasquinimod | III | Randomized trial: tasquinimod 1 mg orally daily vs placebo daily (pre-docetaxel) | Progression-free survival | NCT01234311 |
| Clusterin (apoptosis) | Custirsen | III | Randomized trial: custirsen 640 mg i.v. every 1 week plus docetaxel 75 mg/m2 i.v. every 3 weeks vs docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | Overall survival | NCT01188187 |
| III | Randomized trial: custirsen 640 mg i.v. every 1 week plus docetaxel 75 mg/m2 i.v. every 3 weeks vs placebo i.v. every 1 week plus docetaxel 75 mg/m2 i.v. every 3 weeks (post-docetaxel) | Improvement in pain | NCT01083615 | ||
| Survivin (apoptosis) | YM-155 | II | Single-arm trial: YM-155 5 mg/m2 i.v. daily over 7 days (post-docetaxel) | ≥50% PSA ↓ | NCT00257478 |
| II | Single-arm trial: YM-155 5 mg/m2 i.v. daily over 7 days plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | Objective response rate | NCT00514267 | ||
| LY2181308 | II | Randomized trial: LY2181308 750 mg i.v. every 1 week plus docetaxel 75 mg/m2 i.v. every 3 weeks vs docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | Progression-free survival | NCT00642018 | |
| IGF-1R (cell nutrition) | Cixutumumab | II | Randomized trial: cixutumumab 6 mg/kg i.v. every 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks vs ramucirumab (see above) 6 mg/kg i.v. every 1 week plus mitoxantrone 12 mg/m2 i.v. every 3 weeks (post-docetaxel) | Progression-free survival | NCT00683475 |
| II | Single-arm study: cixutumumab 6 mg/kg i.v. every 1 week plus temsirolimus 25 mg i.v. every 1 week | Time to disease progression | NCT01026623 | ||
| Figitumumab | II | Single arm trial: figitumumab 20 mg/kg i.v. every 3 weeks plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre- and post-docetaxel) | Objective response rate | NCT00313781 | |
| Src kinase (bone regulation) | Dasatinib | III | Randomized trial: dasatinib 100 mg orally daily plus docetaxel 75 mg/m2 i.v. every 3 weeks vs placebo orally daily plus docetaxel 75 mg/m2 i.v. every 3 weeks (pre-docetaxel) | Overall survival | NCT00744497 |
| Saracatinib | II | Randomized trial: saracatinib 175 mg orally daily vs zoledronate 4 mg i.v. every 4 weeks (pre- or post-docetaxel) | Change in bone resorption parameters | NCT00558272 | |
| KX2-391 | II | Single-arm trial: KX2-391 40 mg orally twice daily (pre-docetaxel) | Time to disease progression | NCT01074138 | |
| HDAC (epigenetics) | Panobinostat | II | Single-arm trial: panobinostat 15 mg/m2 i.v. on days 1 and 8 of a 21-day cycle (post-docetaxel) | Progression-free survival | NCT00667862 |
| DNMT (epigenetics) | Azacitidine | II | Single-arm study: azacitidine 150 mg/m2 i.v. on days 1–5 of a 21-day cycle plus docetaxel 75 mg/m2 i.v. every 3 weeks (post-docetaxel) | Objective response rate | NCT00503984 |
| PARP (DNA repair) | Olaparib | II | Single-arm study: olaparib 400 mg orally twice daily (pre- or post-docetaxel) | Objective response rate | NCT01078662 |
| Veliparib | II | Single-arm study: veliparib 40 mg orally twice daily on days 1–7 of a 28-day cycle plus temozolomide 150 mg/m2 orally on days 1–5 of a 28-day cycle (post-docetaxel) | ≥30% PSA ↓ | NCT01085422 | |
Abbreviations: AR, androgen receptor; AUC, area under the curve; CRPC, castration-resistant prostate cancer; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CYP17; cytochrome P450 17; DNMT, DNA methyltransferase; HDAC, histone deacetylase; IGF-1R, insulin-like growth factor receptor-1; i.v., intravenous; mTOR, mammalian target of rapamycin; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; VEGF-R, vascular endothelial growth factor receptor.