Anti-cancer drugs
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Multicenter Study
Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia.
Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. ⋯ Repeated-measures analysis detected no statistical significance (P≥0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL.
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Multicenter Study
Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas.
This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). ⋯ In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.
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Restoration of p53 function triggers cell death and eliminates tumors in vivo. Identification of p53-reactivating small molecules such as PRIMA-1 holds promise for effective new anticancer therapies. Here, we investigated the effects of small molecule PRIMA-1 on cell viability and expression of p53-regulated genes and proteins in the acute promyelocytic leukemia-derived NB4 cell line. ⋯ Moreover, protein expression of nuclear factor-κB-regulated antiapoptotic (Bcl-2 and XIAP) and proliferative (c-Myc) gene products was decreased. Importantly, PRIMA-1 did not show any significant apoptotic effect in normal human peripheral blood mononuclear cells. These in-vitro studies imply that p53 reactivation by small compounds may become a novel anticancer therapy in acute promyelocytic leukemia.
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Pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), in patients with locally advanced rectal cancer, occurs in 15-27% of patients. Because blood cell counts and albumin are a direct indicator of the host environment, a response to nCRT might be predicted by these markers. This study was carried out to determine whether the neutrophil to albumin ratio (NAR) was predictive of pCR in veteran patients. ⋯ Overall survival between nonresponders and pCR patients at 1, 5, and 10 years was 96, 62, and 44% versus 93, 85, and 61%, P=0.13, and disease-free survival was 95, 60, and 47% versus 93, 85, and 61%, P=0.17; respectively. Our study shows that the pre-nCRT NAR is an independent predictor of pCR. These findings should be applied to other cohorts to determine its validity and reliability for use as a potential predictor of pCR.
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In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. ⋯ No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine kinase inhibitors.