Table 1.
Overview of studies investigating hypoxia-activated drugs (pHAPs) in pancreatic cancer (2000-Current).
| HAP | Author | Chemotherapy | XRT | Study | Sample Size | Limitations | Summary of Applicable Findings |
|---|---|---|---|---|---|---|---|
| TH-302 | Weiss, et al. [28] | No | No | Phase I clinical trial | 57 | Only 2 pancreatic patients in the study | TH-302 was well tolerated during the first phases of monotherapy investigations with only mild concern regarding high-grade skin and mucosal toxicities above 240 mg/m2. |
| Borad, et al. [77] | Yes | No | Phase I/II clinical study | 46 | No full publication of results. No XRT | Overall response rate of 21% and median PFS time of 5.9 months across advanced pancreatic cancer patients. | |
| Sun, et al. [78] | No | No | In vitro | Monotherapy study | TH-302 antitumour activity was reported as dose-dependent. | ||
| Meng, et al. [79] | No | No | In vivo | Monotherapy study | TH-302 requires more severe hypoxia for to produce higher rates of anti-tumour activity. | ||
| Borad, et al. [27] | Yes | No | Phase II clinical trial (NCT01144455) |
229 | No XRT | First randomised Phase II clinical trial to demonstrate the potential outcomes of combining TH-302 with gemcitabine. Demonstrated improved tumour response and PFS (median 5.6 vs 3.6 months) compared to gemcitabine alone. | |
| Sun, et al. [80] | Yes | No | In vitro | No XRT | TH-302, gemcitabine and nab-paclitaxel were assessed as tolerable and providing favourable anti-tumour activity. | ||
| Wojtkowiak, et al. [81] | No | No | In vitro and in vivo | Monotherapy study | Identified biomarkers which may predict a significant decrease in tumour growth with TH-302. | ||
| Lohse, et al. [23] | No | Yes | In vitro | No chemotherapy | Reduced tumour growth rates demonstrate a strong predictor of OS for clinical application and efficacy of the treatment combination. | ||
| Van Cutsem, et al. [33] | Yes | No | Phase III ‘MAESTRO’ clinical trial (NCT01746979) | 693 | No full publication of results. No overall survival benefit with the treatment combination of TH-302 with gemcitabine (median of 8.7 months compared to 7.6 months for gemcitabine alone) | Treatment combination demonstrated favourable signs of antitumour activity regarding patient PFS (median of 5.5 months compared to 3.7 months for gemcitabine alone) and higher objective response rate. | |
| Hajj, et al. [30] | No | Yes | In vitro | Single-fraction 15 Gy | Combination produced significant growth delay compared to either TH-302 or XRT treatments alone. | ||
| Clofibrate | Xue, et al. [82] | No | Yes | In vivo | No chemotherapy Single-fraction 4 Gy |
Reduction in the affinity of haemoglobin for oxygen and thus acting as a radiosensitiser for pancreatic xenografts. | |
| Papaverine | Benej, et al. [25] | No | Yes | In vivo | No chemotherapy. | Significantly enhances tumour response to XRT in terms of LC and OS. | |
| PR-350 | Shibamoto, et al. [83] | No | Yes | In vitro and in vivo | Large amount required, therefore not predicted to have a high radiosensitising effect in clinical studies | Effective radiosensitiser in pancreatic cancer cell lines and xenografts. | |
| Sunamura, et al. [84] | No | Yes | Phase III clinical trial | 48 | Intraoperative XRT | PR-350 group showed higher survival rates and more effective control than the group that did not receive the radiosensitizer. | |
| Karasawa, et al. [85] | No | Yes | Phase III clinical trial | 47 | Intraoperative XRT No chemotherapy |
No difference in short-term survival. | |
| Metformin | Lipner, et al. [86] | No | No | In vitro | Monotherapy study. | All tested pancreatic cell lines were resistant to metformin. | |
| Benej, et al. [25] | No | Yes | In vivo | Metformin required 24 hours to reach full mitochondrial inhibition and clinical effectiveness | Papaverine was more suitable radiosensitiser, taking only 30 min to reach clinical effectiveness (similar to Atovaquone). | ||
| OXY111A | Limani, et al. [87] | No | No | Ib/IIa clinical trial (NCT02528526) |
69 | Study last updated at recruiting in 2015 | Pending results. Study aims to assess the safety, tolerability, and efficacy of the HAP. |
| PR-104 | Patterson, et al. [88] | Yes | Yes | In vitro | Single-fraction 10 Gy | Clinical benefit adding PR-104 to standard gemcitabine and XRT care. | |
| McKeage, et al. [89] | Yes | Phase Ib clinical trial (NCT00459836) |
42 | 4 patients with pancreatic cancer, remaining 3 had other diseases | PR-104 combined with docetaxel results in dose-limiting toxicities. |
HAP: hypoxia activated prodrug, PFS: progression-free survival, LC: local control, OS: overall survival, XRT: photon radiation therapy, Gy: Gray.