Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer

Abstract

Background: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload.Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. Methods: Patients initiated CRLX101 dosed at RP2D (15 mg/m 2 ) on days 1 and 15 of a 28-day cycle.Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. Results: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drugrelated toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m 2 . Conclusions: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.

The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy

“…The established dose for CRLX101 concluded from phase I clinical trial is 15 mg/m 2 to be given intravenously every 2 weeks 124 . The preferential safety profile of CRLX101 was also confirmed in a pilot trial using the same recommended dose in patients with chemotherapy-refractory gastroesophageal cancer 125,128 . SN38, 5) is the multiarmed PEG backbone linked form of SN38.…”

Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors

“…NLG207 is well tolerated, with over 300 patients spanning multiple tumor histologies (e.g., non-small-cell lung cancer, advanced ovarian cancer, and metastatic renal cell carcinoma) receiving at least one dose via numerous clinical trials [9][10][11][12][13][14]. In the majority of studies, NLG207 has been administered at a dose of 15 mg/m 2 via intravenous infusion every 2 weeks, with once weekly and 12 mg/m 2 dosing strategies also investigated [1].…”

“…Despite improvements in CPT delivery, commonly reported adverse events (AEs) of NLG207 included fatigue, myelosuppression, and, notably, bladder-associated toxicity [ 9 , 10 , 12 – 14 ]. In response to hemorrhagic cystitis occurring early in phase I dose escalation, hydration strategies have been successfully implemented pre- and post-NLG207 infusion to dilute accumulated CPT concentrations in the bladder; however, a low frequency of subsequent patients receiving NLG207 still reported low-grade cystitis, dysuria, and hematuria [ 14 ].…”

<p>Phytochemical-Based Nanomedicine for Advanced Cancer Theranostics: Perspectives on Clinical Trials to Clinical Use</p>

“…Recent reports demonstrated in a phase-II trial that nanocamptothecin drug conjugate has a better toxicity profile in locally advanced rectal cancer and gastroesophageal cancer patients. 74,75 Curcumin Liposome [Lipocurc™] Liposomal nano-formulation of phyto-compounds such as curcumin polyphenol containing DMPC (14:0-1, 2-dimyristoyl-sn-glycero-3-phosphocholine) and DMPG (14:0-1, 2-dimyristoyl-sn-glycero-3-phosphorylglycerol), possess potential anticancer effects. When infused intravenously, the liposomal carrier increased curcumin plasma levels significantly in a dose-dependent manner in cancer patients.…”