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1.
Clin Cancer Res ; 28(17): 3695-3708, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35511938

RESUMEN

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/uso terapéutico , Linfocitos T CD4-Positivos/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Nivolumab/administración & dosificación , Estudios Prospectivos
2.
Life Sci ; 109(1): 20-9, 2014 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-24931905

RESUMEN

AIMS: The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease. MAIN METHODS: We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131. KEY FINDINGS: The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies. SIGNIFICANCE: RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans.


Asunto(s)
Fármacos Gastrointestinales/química , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Gastrointestinales/tratamiento farmacológico , Ghrelina/química , Ghrelina/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Complicaciones de la Diabetes/tratamiento farmacológico , Perros , Vaciamiento Gástrico/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Gastroparesia/tratamiento farmacológico , Hormona del Crecimiento/metabolismo , Humanos , Ileus/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Ratones , Ratas , Ratas Sprague-Dawley
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