Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 Ã signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m 2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.
A phosphorothioate oligonucleotide, OL(1)p53, can be administered systemically without complications. This type of modified oligonucleotide can be administered without complete degradation, as it was recovered from the urine intact. This oligonucleotide may be useful in combination with currently available chemotherapy agents for the treatment of malignancies.
A synthetic phosphorothioate oligonucleotide was administered systemically to five patients with either relapsed or refractory acute myelogenous leukemia (AML), or myelodysplastic syndrome (MDS). Patients received a 10-day continuous intravenous infusion of this compound, which is complementary to p53 mRNA. No major toxicity attributable to a dose of 0.05 mg/kg/hr was observed. A range of approximately 9 to 18% of the administered dose was recovered in the urine as intact oligonucleotide. Evaluation of malignant cells recovered from bone marrow and peripheral blood at intervals before, during, and after treatment reveals no enhanced growth potential following oligonucleotide administration. Hence, a phosphorothioate oligonucleotide complementary to p53 mRNA can be administered at this dose level to humans without major toxicity. Higher doses need to be evaluated for toxicity and potential clinical efficacy.
Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
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