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A first-in-human phase I clinical trial of CXR1002 in patients (pts) with advanced cancer.
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2011
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First-in-human PhaseCancer ManagementEr StressPharmacotherapyPim Kinase InhibitionPre-clinical PharmacologyOncologyMetronomic TherapyClinical TrialsDrug MonitoringRadiation OncologyCancer ResearchMolecular OncologyRadiologyHealth SciencesTherapeutic Drug MonitoringPharmacokinetic ModelingAmmonium SaltCancer TreatmentPharmacologyAdvanced CancerClinical PharmacologyMedicinePharmacokinetics
3063 Background: CXR1002, an ammonium salt of perfluorooctanoic acid, is a lipid mimetic that causes ER stress and inhibits PIM kinases. Aims of this study were to assess the tolerability, safety and pharmacokinetics (PK) and to identify the recommended phase II dose (RP2D) of CXR1002 administered orally once weekly. Methods: Sequential cohorts of pts with advanced refractory solid tumors were enrolled. Cohort 1 received a single dose of CXR1002 followed by once weekly dosing commenced 6 weeks (wks) later. Subsequent cohorts received CXR1002 once wkly. Dose escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. Plasma levels of CXR1002 were determined by LC-MS/MS at the following time-points: pre-dose, 2, 3, 4, 24 hours post-dose for the first 6 wks then 6 wkly. Exploratory PD analyses included: serum leptin; plasma lipids, glucose and insulin. Results: 41 pts have been enrolled (23M / 18F); median age 63 (range 36-75); PS < 2; colorectal (n=16); pancreatic (n=5); other (n=20). CXR1002 was administered at 10 dose levels [mg (pts entered/evaluable)]: 50 (4/3), 100 (3/3), 200 (3/3), 300 (4/3), 450 (3/3), 600 (8/6), 750 (3/3), 950 (4/3), 1000 (3/3), 1200 (6/6). Median duration of therapy was 6.5 wks (range 0-40). DLT (grade 5 renal failure / grade 4 transaminitis; possibly drug-related) occurred in 1 pt at the 600mg dose. Protocol-defined MTD was not reached and the RP2D of 1,000mg wkly was based on tolerability of common cumulative drug-related toxicities, primarily: fatigue, nausea, vomiting, and diarrhea. Cmax was reached 1.5 hours after administration of a single dose of CXR1002 and maintained at a constant level over a 6 wk sampling period. CXR1002 was cumulative with wkly dosing with increased exposure seen with increasing dose level and duration. Reductions in LDL-cholesterol consistent with a PD effect were observed. Stable disease >12 wks was observed in 8 pts including pts with anaplastic thyroid (40 wks), pancreatic (35 wks), and cervical cancer (34 wks). Conclusions: The RP2D of CXR1002 when administered orally once wkly is 1,000mg. An expansion phase at this dose level will investigate biomarkers of PIM kinase inhibition. CXR1002 exhibits unusual PK with an extremely long t1/2.