Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung

Abstract

The standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E). Most patients have chemosensitive disease at the outset, but disease frequently relapses and limits survival. Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat. The primary objective was to determine the maximum tolerated dose of the combination of belinostat (B) with C+E. Belinostat was administered as a 48-h continuous intravenous infusion on days 1–2; cisplatin was administered as a 1-h intravenous infusion on day 2; and etoposide was administered as a 1-h intravenous infusion on days 2, 3, and 4. Twenty-eight patients were recruited in this single-center study. The maximum tolerated dose was belinostat 500 mg/m2/24 h, cisplatin 60 mg/m2, and etoposide 80 mg/m2. The combination was safe, although some patients were more susceptible to adverse events. Hematologic toxicities were most commonly observed. Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more than three copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance. DNA damage peaked at 36 h after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 h after the end of infusion. The combination of B + C + E is safe and active in SCLC and other neuroendocrine cancers. Future phase II studies should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of adverse events.

Comparison of tumor related signaling pathways with known compounds to determine potential agents for lung adenocarcinoma

“…After analyzing these five pathways in CMap, several known compounds were identified. Unsurprisingly, many among the top 10 have been studied for the treatment of LUAD, including etoposide, irinotecan, resveratrol, and daunorubicin . This finding confirms that several well‐known anti‐cancer drugs used in LUAD treatment fulfill their function by targeting the five aforementioned signaling pathways.…”

A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

“…The study design and other details of this trial (NCT00926640) have been previously reported [4–6]. This trial was approved by the Institutional Review Board of the National Cancer Institute, and informed consent was obtained from all patients enrolled (Table S1).…”

“…Platelet counts were obtained at several points throughout cycle 1, per protocol-mandated patient monitoring. All patients enrolled on this study were genotyped for UGT1A1 , as described previously [4–6]. …”

“…A phase I Clinical trial (NCT00926640) infused belinostat over 48 h, along with cisplatin and etoposide, and demonstrated that this combination was safe and effective in patients with small cell lung cancer or other neuroendocrine cancers (39% objective response rate [4]). Belinostat is predominantly metabolized via uridine glucuronyltransferases, specifically UGT1A1, and patients with lower function alleles of UGT1A1 , namely UGT1A1 * 28 (extra TA in promotor region conferring lower expression) and UGT1A1*60 (–3279 T>G in promotor region conferring lower expression), had slower belinostat clearance [5, 6].…”

Assessment of DNA Damage Induction in Farm Animals After the FNPP Accident

“…Though DNA DSBs had been detected by experimental methods such as the comet assay and pulsed-field gel electrophoresis previously, γ-H2AX is sensitive enough to detect radiation exposure equivalent to several mGy, and the operation is simple; therefore, it is widely used as a marker of DNA DSB [6,9,10]. Recently, the γ-H2AX assay is used as a method of monitoring in vivo DNA DSB level for clinical trials of novel anticancer drugs and for assessment of exposure dose of cancer patients who received radiation therapy [11][12][13][14][15][16][17]. Present when this manuscript is being written (June 2018), more than 40 clinical trials using the γ-H2AX assay seem to be performed in the United States (https://clinicaltrials.gov/).…”