Table 4.
Clinical Trials Involving PDE-is. Studies that tested the efficacy of PDE-is at preventing side effects of therapy (i.e., ED after radical prostatectomy) are not included.
| Completed Clinical Studies | |||||
|---|---|---|---|---|---|
| Phosphodiesterase Inhibitor | Cancer Type | Combination Treatment | Compared with | Effect | Reference |
| Tadalafil | T1-T4 Oral Squamous Cell Carcinoma | Surgery | Surgery Alone | Myeloid-derived suppressor cells and regulatory T cells were reduced in the blood and tumor, although effect was maximized at the intermediate dose |
[281]. |
| Tadalafil | Primary or Secondary Stage III or IV Head and Neck Squamous Cell Carcinoma | Anti-MUC1 Vaccine/ Anti-Influenza Vaccine |
Vaccine Alone/Tadalafil Alone | There were no significant adverse effects of combination therapy. Immunohistochemical analysis shows decreased immune cell exclusion from inside the tumor |
NCT02544880 (Active, non-recruiting) [282] |
| Tadalafil | Invasive head and neck squamous cell carcinoma | None | Placebo | An increase of ex vivo T cell expression and reduction in myeloid-derived suppressor cells were noted, suggesting reversal of tumor mediated immune suppression |
[283] |
| Tadalafil | Invasive head and neck squamous cell carcinoma | None | Placebo | One patient in the tadalafil arm died, although no other adverse events were reported in either treatment group | NCT01697800 |
| Exisulind (PDE-2/5i) | Stage IIIB/IV or recurrent non-squamous cell lung cancer | Carboplatin and Gemcitabine |
None | Median progression-free survival was 4.7 months while median overall survival was 9.0 months. Combination therapy was well tolerated with the goal of the primary endpoint being met |
[284] |
| Exisulind (PDE-2/5i) | Metastatic breast cancer | Capecitabine | Capecitabine alone | In pretreated patients with other therapies, the addition of exisulind is similar to that of capecitabine alone | [285] |
| Exisulind (PDE-2/5i) | Solid Malignancy | Docetaxel | None | Combination therapy was well tolerated |
[285,286] |
| Exisulind (PDE-2/5i) | Castration-resistant prostate cancer | Docetaxel | None | Overall survival and progression-free survival were similar to other studies of chemotherapy alone |
[287] |
| Exisulind (PDE-2/5i) | Metastatic castration-resistant prostate cancer | Docetaxel | None | Low likelihood of benefit of exisulind to docetaxel therapy |
[288] |
| CP-461 (PDE-2/5i) | Advanced Solid Malignancy | Usual Treatment | None | Four of 21 patients displayed stable disease and CP461 was well tolerated | [288,289] |
| Roflumilast (PDE-4i) | Advanced B-cell malignancy | prednisone | None | PI3K activity was suppressed in over 75% of patients, with 66% exhibited partial response or disease stability | [290] |
| Theophylline (non-selective PDE-i) | Metastatic castration-resistant prostate cancer | Abiraterone/prednisone | Combination Therapy with Dextromethorphan |
One subject in the theophylline group experienced a grade 3 increase in alkaline phosphatase | NCT01017939 |
| RA-233( Dipyridamole derivative) | Non-small cell lung carcinoma, small cell lung carcinoma, extensive colon adenocarcinoma | Multiple | Combination Therapy Alone |
RA-233 significantly extended median survival in only this with NSCLC limited to 1 hemithorax |
[291] |
| Dipyridamole ( platelet PDE-5/6i |
stage II or III unresectable adenocarcinoma of the pancreas | 5-Fluorouracil, leucovorin, mitomycin C | None | Median Survival of 13.8 months and an overall response rate of 26%. Six patients underwent curative resection, 2 of whom did not experience disease recurrence |
[292] |
| Aminophylline/ theophylline |
B Cell Chronic Lymphocytic Leukemia | None | None | Dose-dependent and time-dependent apoptosis was noted in 45% of patients, who experienced a longer progression-free survival time |
[293] |
| Ongoing Clinical Studies without Posted Results | |||||
| Drug | Cancer Type | Combination Treatment | Compared with | Completed | Clinical Trial Number |
| Sildenafil | IIIB or IV non-small cell lung cancer | paclitaxel/carboplatin | Combination Therapy Alone |
Yes | NCT00752115 |
| Sildenafil | Advanced solid tumors | Regorafenib | None | Yes | NCT02466802 |
| Sildenafil | Kidney Cancer | Surgery after treatment | Placebo and Surgery |
Yes | NCT01950923 |
| Sildenafil | Waldenstrom’s Macroglobulinemia | None | None | Yes | NCT00165295 |
| Sildenafil | WHO Grade III or IV Brain Glioma | Valproic Acid/sorafenib | None | Active-Not Recruiting | NCT01817751 |
| Tadalafil | Refractory hepatocellular carcinoma and pancreatic/colorectal cancer with liver metastasis | Oral vancomycin/nivolumab |
None | Recruiting | NCT03785210 |
| Tadalafil | Recurrent or Metastatic Head and Neck Cancer | Pembrolizumab | None | Recruiting | NCT03993353 |
| Tadalafil | Resectable Head and Neck Cancer | Nivolumab/surgery | Combination Therapy Alone |
Active-Not Recruiting | NCT03238365 |
| Aminophylline (non-selective PDE-i) |
Bladder Cancer | BCG Vaccine | None | Yes | NCT01240824 |
| pentoxifylline (non-selective PDE-i) |
grade IV astrocytoma/glioblastoma multiforme | hydroxyurea/radiotherapy | Combination Therapy Alone |
Yes | NCT00019058 |
| Dipyridamole | Stage III/IV ovarian carcinoma refractory to platinum chemotherapy | Intraperitoneal methotrexate |
Unknown | Unknown | NCT00002487 |
| Thymoquinone (PDE-1i) | Premalignant oral Lesions | None | Placebo | Yes | NCT03208790 |
| Vesnarinone (PDE-3i) |
Kaposi Sarcoma | None | Unknown | Yes | NCT00002131 |
| PBF-999 (PDE-10i) | Advanced metastatic solid tumor | Usual Treatment | None | Recruiting | NCT03786484 |