RESUMEN
Mitazalimab is an agonistic human monoclonal antibody targeting CD40, a target for anti-tumor immunotherapy. This phase 1, dose-escalation study evaluated the safety, dose-limiting toxicities (DLTs), pharmacokinetic and pharmacodynamic profile of mitazalimab. Adults with advanced solid malignancies received mitazalimab intravenously once every-2-weeks. Dose-escalation was pursued with and without pre-infusion corticosteroids for mitigation of infusion-related reactions (IRRs). In all, 95 patients were enrolled in 7 cohorts (n = 50, 75-2000 µg/kg) with corticosteroids and in 5 cohorts (n = 45, 75-1200 µg/kg) without corticosteroids. Two patients experienced DLTs (transient Grade-3 headache; Grade-3 drug-induced liver injury [Hy's law]). The most frequently reported (≥ 25%) treatment-emergent adverse events were fatigue (44.2%), pyrexia (38.9%), pruritus (38.9%), chills (27.4%), and headache (26.3%). IRRs were reported in 51.6% of patients; pruritus (30.5%; with corticosteroids [36.0%], without corticosteroids [24.4%]) was the most frequent. Following the first infusions of 600 µg/kg and 2000 µg/kg, mitazalimab was rapidly cleared from the systemic circulation with mean terminal half-life of 11.9 and 24.1 h, respectively. Pharmacokinetics appeared to exhibit target-mediated drug disposition at the tested doses. Mitazalimab treatment induced higher levels of selected chemokines and transient reduction of B-cells, T-cells, and NK cells. One patient (renal cell carcinoma) displayed partial response lasting 5.6 months. Stable disease was reported by 35 (36.8%) patients, persisting for ≥ 6 months in 9 patients. Mitazalimab has a manageable safety profile with acceptable pharmacokinetic and pharmacodynamic properties. Future clinical development will evaluate combination with existing treatment options. Trial registration NCT02829099 (ClinicalTrials.gov; July 7, 2016).
Asunto(s)
Anticuerpos Monoclonales , Neoplasias , Adulto , Humanos , Administración Intravenosa , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Relación Dosis-Respuesta a Droga , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antígenos CD40RESUMEN
BACKGROUND: Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma. METHODS: In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. FINDINGS: From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. INTERPRETATION: Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. FUNDING: Janssen.
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Antígenos CD20/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma no Hodgkin/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenina/análogos & derivados , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antígenos CD20/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Ensayos Clínicos Controlados no Aleatorios como Asunto , Piperidinas , Prednisona/efectos adversos , Prednisona/uso terapéutico , Pronóstico , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Rituximab , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéutico , Adulto JovenRESUMEN
We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; pâ¯=â¯0.065; complete response 37.5% vs. 0%; pâ¯=â¯0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; pâ¯=â¯0.055), KLHL14 (30.0% vs. 0%; pâ¯=â¯0.046), and LRP1B (30.0% vs. 6.2%; pâ¯=â¯0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; pâ¯=â¯0.047) and ROS1 (0% vs. 50.0%; pâ¯=â¯0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.
RESUMEN
To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Using the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (registered on www.clinicaltrials.gov as NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib+nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3, day 1. Overall, 172 ctDNA samples from 67 patients were analyzed by the LyV4.0 ctDNA Cancer Personalized Profiling Deep Sequencing Assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved in 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired the C481S BTK mutation implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.
Asunto(s)
ADN Tumoral Circulante , Linfoma de Células B Grandes Difuso , Adenina/análogos & derivados , ADN Tumoral Circulante/genética , Humanos , Nivolumab/uso terapéutico , Piperidinas , PirimidinasRESUMEN
INTRODUCTION: This unplanned post-hoc analysis was based on data from the phase Ib DBL1002 study (NCT01569750) and evaluated the association between molecular biomarkers and clinical response to combined treatment with ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) subtypes. METHODS: DLBCL subtyping was conducted using immunohistochemistry. Next-generation sequencing using immunoglobulin H primers assessed minimal residual disease (MRD). A quantitative assay evaluated Bruton's tyrosine kinase (BTK) occupancy by ibrutinib in peripheral blood mononuclear cells. Targeted DNA sequencing examined genetic variants by DLBCL subtype. Secreted protein expression was evaluated with a SomaLogic analyte panel. RESULTS: Among 21 patients with DLBCL (median age 53.5 years), 17 achieved a complete response (CR) and 4 a partial response (PR). Of the 11 subtyped patients, 9 had a CR (5/7 germinal center B-cell-like [GCB] and 4/4 non-GCB) and 2 had a PR (both GCB). Nine of 12 patients tested for MRD achieved early (cycle 2 day 1) MRD negativity; most had a CR. There was near-complete BTK occupancy at 4 h postdose. Mutation analysis (n = 19) revealed variants including CREBBP, KMT2D, LRP1B, BCL2, and TNFRSF14; only 1 CD79B and TP53 each; no CARD11 or MYD88. CONCLUSIONS: In this study, first-line ibrutinib plus R-CHOP benefited patients with DLBCL, with good overall response rate and early MRD negativity. With a caveat of small sample size, our results showed that a favorable genetic profile and younger patient age may be important to beneficial clinical outcome with ibrutinib plus R-CHOP in DLBCL.
Asunto(s)
Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Piperidinas/uso terapéutico , Adenina/farmacología , Adenina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas/farmacología , Prednisona/farmacología , Prednisona/uso terapéutico , Pronóstico , Rituximab/farmacología , Rituximab/uso terapéutico , Vincristina/farmacología , Vincristina/uso terapéuticoRESUMEN
BACKGROUND: Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. METHODS: We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing. FINDINGS: Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]). INTERPRETATION: The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. FUNDING: Janssen R&D.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Seguridad , Adenina/análogos & derivados , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas , RecurrenciaRESUMEN
The maximum tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/week) plus subcutaneous bortezomib (1.3 mg/m(2)) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was determined. No dose-limiting toxicities were reported in 6/8 mg groups except ventricular fibrillation (Grade 4 cardiac arrest, n = 1 [10 mg] cycle 6) and clinically significant cardiac toxicities (Grade 3 QTc prolongation, Grade 3 atrial fibrillation, n = 2 [12 mg]). Thrombocytopenia (n = 11), asthenia (n = 10), and diarrhea (n = 12) were most common adverse events. Overall, 88.2% patients achieved treatment response, median duration of response, and median progression-free survival were 9.4 and 8.2 months, respectively. The MTD of quisinostat was established as 10 mg thrice weekly oral dose with bortezomib + dexamethasone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Monitoreo de Drogas , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ácidos Hidroxámicos/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Mieloma Múltiple/mortalidad , Células Neoplásicas Circulantes , Recurrencia , Retratamiento , Resultado del TratamientoRESUMEN
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi). EXPERIMENTAL DESIGN: In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titration design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clinical efficacy were evaluated at each schedule. RESULTS: Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs observed were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 months). CONCLUSIONS: The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule.