RESUMEN
This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8+ and Ki67+CD8+ T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
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Linfocitos T CD8-positivos , Neoplasias , Humanos , Linfocitos T CD8-positivos/metabolismo , Neoplasias/patología , Fibroblastos/patologíaRESUMEN
Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Receptores de Hialuranos/genética , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Progresión de la Enfermedad , Femenino , Humanos , Receptores de Hialuranos/inmunología , Receptores de Hialuranos/metabolismo , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Proyectos Piloto , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Distribución Tisular , Circonio/farmacocinéticaRESUMEN
RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML).Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg.Forty-four patients (median age, 69 years) were enrolled. One dose-limiting toxicity occurred (grade 3 hemolysis exacerbation) after one 1200 mg dose (twice-weekly cohort). The majority of adverse events were mild/moderate. Infusion-related reactions occurred in 64% of patients mainly during cycle 1. Two patients experienced grade 3 drug-induced aseptic meningitis. Pharmacokinetics increased supraproportionally, suggesting a target-mediated drug disposition (TMDD) at ≥ 1200 mg. Two patients achieved complete response with incomplete platelet recovery or partial response, respectively. One patient had stable disease with hematologic improvement.RG7356 was generally safe and well tolerated. Maximum tolerated dose was not reached, but saturation of TMDD was achieved. The recommended dose for future AML evaluations is 2400 mg every other week.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. EXPERIMENTAL DESIGN: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. RESULTS: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. CONCLUSIONS: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR.
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Benzamidas/uso terapéutico , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Mutación/genética , Neoplasias/tratamiento farmacológico , Oxazinas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/farmacocinética , Fosfatidilinositol 3-Quinasa Clase I , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/patología , Oxazinas/farmacocinética , Selección de Paciente , Fosfatidilinositol 3-Quinasas/genética , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Distribución Tisular , Adulto JovenRESUMEN
PURPOSE: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. EXPERIMENTAL DESIGN: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)]. RESULTS: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C(max) occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma. CONCLUSION: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.
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Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Resultado del TratamientoRESUMEN
The olfactory system in both vertebrates and invertebrates can recognize and distinguish thousands of chemical signals. Olfactory receptors are responsible for the early molecular events in the detection of volatile compounds and the perception of smell. Recently, candidate olfactory receptor genes have been identified in several organisms, but their characterization is far from been completed due to the difficulty to functionally express them in heterologous systems. To circumvent such difficulty, we expressed a mammalian olfactory gene, rat I7, in the nematode. We generated transgenic worms expressing I7 in AWA or AWB chemosensory neurons and performed behavioural assays using different concentrations of the rat I7 receptor agonist octanal. Pure octanal was repellent for wild-type worms whereas a 1:10 dilution was attractant. Expression of I7 in AWB neurons counteracted the volatile attraction to diluted octanal observed in control wild-type worms. Furthermore, expression of I7 in AWA neurons counteracted the volatile avoidance to pure octanal observed in wild-type worms. These results indicate that it is possible to functionally express mammalian olfactory receptors in providing a research tool to efficiently search for specific olfactory receptor ligands and to extend our understanding of the molecular basis of olfaction.