Table 2:
Detailed evaluation of the clinical pharmacology of vorinostat in the regulation of autophagy.
| Details of clinical trial | Drug entity | Cancer type | Clinical pharmacology properties and their relevance | Autophagy-associated molecular mechanisms of action | Reference |
|---|---|---|---|---|---|
| Phase I clinical trial (NCT01023737*) | Hydroxychloroquine (HCQ) (400–1000) and vorinostat (300) mg/m2/day | Patients with advanced or malignant solid tumors (colorectal and renal) | Evaluation of safety, tolerability, drug response rate, progression-free survival and anti-tumor activity. | Inhibition of autophagy by HCQ in combination with vorinostat critically regulated autophagy, resulting in inhibition of cancer progression with minimal toxicity. | – |
| Phase I clinical trial | HCQ and oral ingestion of vorinostat (400 mg/m2, once a day for 21 d) | Colorectal, soft tissue sarcoma, ovarian cancer, melanoma, NSCLC, renal cell carcinoma, prostate, breast and bladder cancers | Evaluation of minimal dose-related (MDR) toxicity at maximum tolerated dose (MTD), Cmax of 768 and 786 μg/L, AUC of 3387 and 2410 μg × hr/L, median half time of 2.06 h and 1.3 h and median Vd/f of 304–309 L. | Enhanced expression of cathepsin D (CTSD), which is responsible for the onset of HCQ-vorinostat-regulated autophagy-mediated apoptosis. Accumulation of autophagic vacuoles (AVs). Enhanced expression of CDKN1A, SQSTM1 (p62) and MAP1LC3B. | 57 |
| Early phase clinical trial | HCQ (600) and oral ingestion of vorinostat (400) mg/m2, once a day for 21 d) | Advanced and refractory metastatic colorectal cancer | Evaluation of median overall survival (6.7 months), median progression-free survival (2.8 months) and minimal drug-related adverse toxicity. | Enhanced CTSD and p62 level. | 58 |
| Phase II randomized, therapeutic clinical trial (NCT02316340*) | HCQ (600 mg/m2) and oral ingestion of vorinostat (400 mg/m2, once a day for 28 days) | Chemorefractory metastatic colorectal cancer | Evaluation of enhanced anti-tumor efficacy, overall survival and median progression-free survival | Autophagy inhibition leading to enhanced tumor immunity (decreased expression of IL-1b, IL-6, IL-10, IL-2, IFN-γ and TNF-α). | – |
| Phase II clinical trial (NCT00882206*) | Vorinostat (230 mg/m2, oral gavage, twice a day), intravenous injection of decitabine (15 mg/m2), prednisone (40 mg/m2, twice a day for 8 days), vincristine (1.5 mg/m2), doxorubicin (60 mg/m2), Pegasparaginase (2,500 IU/m2) and intrathecal cytarabine (70 mg for 14 d) | Relapsed and refractory acute lymphoblastic leukemia (ALL) | Evaluation of enhanced chemo-sensitization and identification of 32 differentially methylated genes in the responding groups as compared to non-responding ALL patients | Hypomethylation of cell death (apoptosis and autophagy) and transcription-regulating genes, such as SQSTM1, MAP3K5, SIRT1, DNAJB6, BTAF1 and UB2E1. | – |
*
The NCT reference codes identify the clinical trials, and details of these clinical trials can be found in ClinicalTrials.gov.