Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Abstract

Background Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. Procedure Satraplatin was administered orally once daily on days 1–5 of a 28-day cycle at dose level (DL) 1 (60 mg/m2/dose), and DL2 (80 mg/m2/dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. Results Nine patients received 1–15 cycles (median=2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (6–15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. Conclusions The MTD of oral satraplatin in children with solid tumors was 60 mg/m2/dose daily × 5 days every 28 days, which is lower than the adult recommended dose of 80–120 mg/m2/dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicity was observed.

Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update

“…There were 54 phase I (69%) and 24 phase II clinical trials (31%) . Half evaluated conventional chemotherapeutics ( n = 40) and 35% ( n = 27) targeted therapies (Table ).…”

Reduction Process of Tetraplatin in the Presence of Deoxyguanosine Monophosphate (dGMP): A Computational DFT Study

“…[1,2] Especially,s quare-planar Pt II complexes like cisplatin (cisdiamminedichloroplatinum(II), approved as an anticancer drug first in 1978), oxaliplatin ([(1R,2R)-cyclohexane-1,2-diamine]-(ethanedioato-O,O')platinum(II)), and carboplatin (cisdiammine-(cyclobutane-1,1-dicarboxylate-O,O')platinum(II)) are currentlyt he most frequently used cytostatic metallodrugs. However,n ew agents are still being searched forb ecause there are al arge number of negative side effects of the contemporary drugs,w hicha re also resistant to some types of tumors.N owadays, the attention is particularly focusedo n complexes of Pt IV , [3,4] Ru II , [5,6] Ir III , [7] Au, [8,9] and some others. [10] These compounds are usuallyp repared in af orm of "prodrugs", which must be first activatedi na no rganism.…”

“…This property enables for example, oral administration of Pt IV complexes like satraplatin (bis(acetate)amminedichloro(cyclohexylamine)platinum(IV)), which is still under clinical testing. [3] The hydration process (which means replacement of someo ft he chloro ligands by water molecules) is as tandard mechanism of activation for generally all chloro-ligand-containing complexes. However,t his process occurs with av ery low probability in the case of Pt IV complexes.…”

Nanomaterials as nanocarriers: a critical assessment why these are multi-chore vanquisher in breast cancer treatment

“…Cisplatin an anti-tumour drug, induces apoptosis through the binding of DNA [165]. FDA has approved drug "Oxaliplatin" that exhibit similar therapeutic results as cisplatin, with no expressive acquisition of multidrug resistance due to immunogenic response dependent of the toll-like receptors [166]. Satraplatin, being more lipophilic has enhanced anticancer pharmacokinetic properties, is in advanced clinical trial phases.…”