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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Satraplatin (JM216, BMY-45594, BMS-182751) was developed with the intention of producing the first orally active platinum-based chemotherapeutic agent. Had it been successful, this would have been a significant improvement on clinical convenience compared to the other platinum analogues which have to be administered intravenously. Satraplatin was first disclosed in the literature in 1993, and evaluated in the 2000s, in patients with advanced prostate cancer who had failed previous chemotherapy. Structurally, it contains a cyclohexane ring which makes it more hydrophobic compared to other analogues such as cisplatin or oxaliplatin, with the possibility of improving cell membrane transport. Satraplatin has been manufactured in the US by Spectrum Pharmaceuticals and the German company GPC Biotech AG under the proposed trade name OrplatnaTM. It has also been used experimentally in the treatment of lung and ovarian cancers. Another potential advantage over related platinum analogues is that it maintains effectiveness in cisplatin-resistant cell lines.
Developing and Validating Prognostic Models of Clinical Outcomes
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Susan Halabi, Lira Pi, Chen-Yen Lin
We provide an example to illustrate the application of a random forest. Our motivation was to develop and validate predictive models of ≥30% and ≥50% PSA decline from baseline in men who were enrolled on the TROPIC trial. The TROPIC trial was a randomized, open-label, multicenter, phase III trial of 755 men with mCRPC previously treated with a docetaxel-containing regimen [25]. Participants were randomly assigned to receive either 12 mg/m2 mitoxantrone plus 10 mg oral prednisone daily or cabazitaxel 25 mg/m2 plus prednisone. PSA decline was defined per the PSA Working Group 2 [65]. We followed a similar logic as presented in Figure 17.1 for building a prognostic model and validating it. We planned to utilize a subset of 488 men who were randomized on the SPRAC trial and who were previously treated with docetaxel for external validation [26]. The SPARC trial was a double-blind, placebo-controlled study comparing the efficacy and safety of satraplatin plus prednisone versus placebo plus prednisone in mCRPC men previously treated with one cytotoxic regimen [26]. We considered 14 variables that were common in the two trials TROPIC and SPARC (external validation set): arm, race, age, body mass index (BMI), time on hormone, years since diagnosis, pain, ECOG performance status (ECOG PS), presence of measurable disease, site of metastases (that is, lymph nodes, bone, visceral), time from docetaxel use to second line chemotherapy <6 months, hemoglobin, PSA, and alkaline phosphatase. We used the random forest not solely as a variable-selection method, but also to impute the missing data as seven out of 14 variables had missing values. To impute the missing values of the variables, the random forest is called with the complete case data. The proximity matrix from the random forest, based on the frequency that pairs of data points are in the same terminal nodes, is used to update the imputation of the missing values. For continuous predictors, the imputed value is the weighted average of the non-missing observations, where the weights are the proximities. For categorical predictors, the imputed value is the category with the largest average proximity. In our analyses, we considered both complete cases and imputed datasets. Of the 14 variables, the random forest procedure selected seven as significant in predicting ≥30% and ≥50% decline in PSA. The significant predictors of PSA decline were: age, body mass index (BMI), years on hormone therapy, years since initial diagnosis, hemoglobin (HGB), alkaline phosphatase (ALK) and PSA (Figure 17.5). The importance of the selected variable is indicated as they are in the far right position in Figure 17.5. Unfortunately the model for ≥30% PSA decline had poor performance in the imputed and complete case (Table 17.5). Despite the low misclassification rates for ≥50% PSA decline, the area under the curve was low, indicating potential independence between the outcomes and the covariates.
Protein kinase inhibitors for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Vincent Chau, Ravi A. Madan, Jeanny B. Aragon-Ching
Additional studies combined bevacizumab with other anti-neoplastic agents in order to overcome resistance mechanisms. In a phase II study, 60 patients with mCRPC were given docetaxel, bevacizumab, thalidomide, and prednisone [41]. In this trial, 90% had 50% PSA declines. Median time to progression was 18.3 months, and median OS was 28.2 months. A second phase II study tested docetaxel, bevacizumab, lenalidomide, and prednisone in mCRPC [42]. Of 61 evaluable patients, 57 (93%) showed PSA declines of >30%, of which 55 (90%) showed PSA decline of >50% and 33 (54%) showed PSA decline of >90%. Another group tested bevacizumab with satraplatin, which is an oral platinum agent, in mCRPC patients who were previously treated with docetaxel [43]. Median time to progression was 7.0 months (90% CI, 4.7–8.5 months) and median OS was 11.2 months (90% CI, 9.1–16.4 months). Grade 3–4 toxicities include pulmonary embolism and thrombocytopenia. Lastly, bevacizumab, docetaxel, and everolimus along with maintenance therapy with bevacizumab/everolimus were given to patients with mCRPC [44]. This combination was determined to be safe in the phase IB portion of this trial, and median PFS was 8.9 months (95% CI, 7.4–10.6 months) and median OS was 21.9 months (95% CI, 18.4–30.3 months) in the phase II portion of this study. Together, these data suggest that bevacizumab does not have single-agent activity in mCRPC but can be combined with other agents for potential benefit. However, randomized controlled trials are need before further conclusions can be made.
Pharmacokinetics and tissue distribution in rats of a novel anticancer platinum compound LLC-1903
Published in Xenobiotica, 2020
Yingxue Li, Fanzhuo Meng, Zhijian Chen, Fuguo Han, Donglin He, Yanli Hao, Anli Gao, Jing Jiang, Zhao Wang, Weiping Liu, Qingfei Liu
Traditionally, Pt-based drugs are Pt(II) complexes, but the use of Pt(IV) compounds as prodrugs might improve the pharmacological properties of Pt-based drugs in vivo. After reduction by glutathione, ascorbate or cellular proteins, Pt(IV) compounds can transform into active Pt(II) complexes (Wexselblatt & Dan, 2012). Also, photoactivatable Pt(IV) compounds and thermogelling polymer-Pt (IV) conjugates were also reported, providing new ideas for Pt compounds delivery and enhancing selectivity and cytotoxicity against tumor cells (Kasparkova et al., 2015; Shen et al., 2015). Tetraplatin, iproplatin and satraplatin were main Pt(IV) compounds but failed to pass clinic trails due to their toxicity or lack of superiority compared to cisplatin (Wheate et al., 2010). Just like Pt(II) complexes, Pt(IV) complexes could also be modified with bioactive ligands. It was found that Pt(IV)–(D)−1-methyltryptophan conjugates induced the apoptosis of cisplatin-resistant human ovarian cancer cells, and inhibited an immunosuppressive enzyme called indoleamine-2,3-dioxygenase, which promotes T-cell proliferation and reduces tumor tolerance (Awuah et al., 2015; Engel et al., 2012).
Issues and promises of bevacizumab in prostate cancer treatment
Published in Expert Opinion on Biological Therapy, 2018
Vittore Cereda, Vincenzo Formica, Mario Roselli
More recently, in a small phase II clinical trial, 31 docetaxel-pretreated mCRPC patients with extensive visceral involvement were enrolled and treated with 80 mg/m2 of orally administered satraplatin on day 1–5 plus bevacizumab 10 mg/kg on day 1 and 15 mg/kg on day 15 in a 35-day cycle schedule. The results were negative: only 17% of patients had a major PSA decline with 15% of partial radiographic responses. Median PFS was 7 months and median OS was 11.2 months. The safety profile was manageable [44].