5 research outputs found
First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas
Antibodies; Combination; NeoplasmAnticossos; Combinació; NeoplàsiaAnticuerpos; Combinación; NeoplasiaBackground GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.
Methods Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10–1500 mg) or GWN323+spartalizumab (GWN323 10–750 mg+spartalizumab 100–300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.
Results Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.
Conclusions GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.This study was supported by Novartis Oncology
Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study
Futibatinib; Advanced solid tumors; AberrationsFutibatinib; Tumores sólidos avanzados; AberracionesFutibatinib; Tumors sòlids avançats; AberracionsFutibatinib, a highly selective, irreversible FGFR1–4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1–3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement–positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy.
Significance:
This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1–4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population
Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study
Antibody–drug conjugate; Dose-escalation study; Tusamitamab ravtansineConjugado anticuerpo-fármaco; Estudio de escalada de dosis; Tusamitamab ravtansinaConjugat anticossos-fàrmac; Estudi d'escalada de dosi; Tusamitamab ravtansinaTusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors.
Patients and methods
Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria.
Results
Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2.
Conclusions
Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.This work was supported by Sanofi, France (no grant number)
Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials
Immunotherapy; Phase 1 trials; Prognostic modelInmunoterapia; Ensayos de fase 1; Modelo pronósticoImmunoteràpia; Assajos de fase 1; Model pronòsticPurpose
Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline.
Methods
Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application.
Results
We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3–12.7) for ICIs cohort and 7.7 m (95% CI, 6.6–8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS – ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64–0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%–90%).
Conclusions
PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/CE07/50610001). Cellex Foundation for providing research facilities and equipment. This work was supported by the Accelerator Award (UpSMART) from Fundacion Científica – Asociacion Espanola Contra el Cancer (FC -AECC)/ Associazione Italiana per la Ricerca sul Cancro (AIRC) /Cancer Research United Kingdom (CRUK)
Caracterización del mecanismo de acción de los pan-inhibidores selectivos del receptor del factor de crecimiento fibroblástico e identificación de potenciales biomarcadores predictivos de respuesta mediante la utilización de xenoinjertos derivados de pacientes con alteraciones en esta vía molecular.
En càncer, la desregulació de la via del FGFR:FGF s'ha associat a un creixement tumoral descontrolat, una angiogènesi aberrant i una major capacitat de metastatització. En aquest context, en l'última dècada s'ha fet un gran esforç per desenvolupar fàrmacs dirigits contra aquesta diana terapèutica. Les dades d'eficàcia incipients amb la primera generació d'inhibidors de la via, fàrmacs multi-tirosina quinasa (MTKI), han estat més aviat limitats, amb un percentatge significatiu d'efectes secundaris no desitjats -off target-. Per aquest motiu, s'estan desenvolupant nous inhibidors més selectius i potents del FGFR (FGFRinh), però encara existeix controvèrsia sobre quines d'aquestes alteracions podrien ser els millors biomarcadors predictius de resposta al bloqueig amb FGFRinh.
Amb aquest projecte de tesi, pretenem contribuir a la definició d'una estratègia terapèutica òptima per als pacients amb alteracions de la via del FGFR: FGF, mitjançant una millor selecció d'aquells que més poden beneficiar-se d'aquests FGFRinh. Amb aquest objectiu, aquesta memòria per a la defensa de tesi consta de dos estudis principals. El primer es tracta d'un estudi retrospectiu d'una cohort de pacients amb càncer avançat, pre-seleccionats per ser portadors de tumors amb aberracions en els gens del FGFR i FGFs detectades dins del programa de pre-screening VHIO, i inclosos en assaigs fase 1 on s'estava testant un FGFRinh. Es presenten les dades de l'anàlisi exploratori de biomarcadors realitzat després de la correlació estadística de les dades clínic-patològiques i d'eficàcia als FGFRinh disponibles. La majoria d'aquests estudis partien de la hipòtesi que qualsevol alteració molecular en la via del FGFR:FGF podia servir com a biomarcador predictiu de resposta als FGFRinh, sense importar el subtipus tumoral. No obstant això, amb aquest anàlisi retrospectiu pretenem identificar entre els responedors a un subgrup de pacients portadors d'una alteració específica FGFR:FGF comuna. El nostre objectiu és delimitar amb més precisió quins d'aquests determinants moleculars són en realitat biomarcadors fiables i discernir si, en realitat, estan al mateix nivell en relació a la predicció de resposta en els diferents contextos histològics (p.ex. alteracions a nivell de l'ADN -amplificacions, mutacions, traslocacions- versus nivell mRNA versus proteïna).
El segon estudi en canvi, es tracta d'un estudi prospectiu amb l'objectiu de generar una col·lecció de mostres de pacients amb càncer avançat seleccionats molecularment per les seves alteracions en els gens de la via FGFR: FGF. Es presenten dades sobre el desenvolupament del protocol investigacional FGFR 360º RESISTANCE, la plataforma traslacional implementada per obtenir mostres seriades (biòpsies tumorals pre-, en curs i post-tractament, plasma i fins i tot autòpsies en calent) en diferents moments de la malaltia d'aquests pacients. Aquest valuós repositori de mostres ha servit per generar xenoinjerts derivats de pacients (PDXs), utilitzats en el nostre laboratori per validar in vivo algunes de les hipòtesis prèviament observades, així com integrar el coneixement obtingut de l'anàlisi molecular de les mostres més rellevants d'alguns responedors inusuals seleccionats.
La presentació de cadascún d'aquests estudis s'acompanya d'una discussió dels resultats obtinguts, així com un sumari final de les conclusions assolides i les futures línies de recerca associades.En cáncer, la desregulación de la vía del FGFR:FGF se ha asociado a un crecimiento tumoral descontrolado, una angiogénesis aberrante y una mayor capacidad de metastatización. En este contexto, en la última década se ha realizado un gran esfuerzo en desarrollar fármacos dirigidos contra esta diana terapéutica. Los datos de eficacia incipientes con la primera generación de inhibidores de la vía, fármacos multi-tirosina quinasa (MTKI), han sido más bien limitados, con un significativo porcentaje de efectos secundarios no deseados –off target-. Por este motivo, se están desarrollando nuevos inhibidores más selectivos y potentes del FGFR (FGFRinh), pero aún existe controversia sobre cuáles de estas alteraciones podrían ser los mejores biomarcadores de predicción de respuesta al bloqueo con FGFRinh.
Con este proyecto de tesis, pretendemos contribuir a la definición de una estrategia terapéutica óptima para los pacientes con alteraciones de la vía del FGFR:FGF, mediante una mejor selección de aquéllos que más pueden beneficiarse de estos FGFRinh. Con tal objetivo, esta memoria para la defensa de tesis consta de dos estudios principales. El primero se trata de un estudio retrospectivo de una cohorte de pacientes con cáncer avanzado, pre-seleccionados por ser portadores de tumores con aberraciones en los genes del FGFR y FGFs detectadas dentro del programa de pre-screening VHIO, e incluidos en ensayos fase 1 dónde se estaba testando un FGFRinh. Se presentan los datos del análisis exploratorio de biomarcadores realizado tras la correlación estadística de los datos clínico-patológicos y de eficacia a los FGFRinh disponibles. La mayoría de estos estudios partían de la hipótesis de que cualquier alteración molecular en la vía del FGFR:FGF podía servir como biomarcador predictivo de respuesta a los FGFRinh, independientemente del subtipo tumoral. Sin embargo, con este análisis retrospectivo pretendemos identificar entre los respondedores a un subgrupo de pacientes portadores de una alteración específica común FGFR:FGF. Nuestro objetivo es delimitar con mayor precisión cuáles de estos determinantes moleculares son en realidad biomarcadores fiables y discernir si, en realidad, están al mismo nivel en relación a la predicción de respuesta en los distintos contextos histológicos (p.ej. alteraciones a nivel del ADN –amplificaciones, mutaciones, translocaciones- versus nivel mRNA versus proteína).
El segundo estudio en cambio, se trata de un estudio prospectivo cuyo objetivo es generar una colección de muestras de pacientes con cáncer avanzado seleccionados molecularmente por sus alteraciones en los genes de la vía FGFR:FGF. Se presentan datos sobre el desarrollo del protocolo investigacional FGFR 360º RESISTANCE, la plataforma traslacional implementada para obtener muestras seriadas (biopsias tumorales pre-, en curso y post- tratamiento, plasma e incluso autopsias en caliente) en diferentes momentos de la enfermedad de estos pacientes. Este valioso repositorio de muestras ha servido para generar xenoinjertos derivados de pacientes (PDXs), utilizados en nuestro laboratorio para validar in vivo algunas de las hipótesis previamente observadas, así como integrar el conocimiento obtenido del análisis molecular de las muestras más relevantes de algunos respondedores inusuales seleccionados.
La presentación de cada uno de estos estudios se acompaña de una discusión de los resultados obtenidos, así como un sumario final de las conclusiones alcanzadas y las futuras líneas de investigación asociadas.Among cancers, deregulation of the FGFR:FGF pathway has been widely associated with uncontrolled tumoral growth, aberrant angiogenesis and increased metastatic dissemination rates. In this context, several efforts have been done during the last decade in order to develop targeted agents against this molecular pathway. However, early efficacy data seen with first-generation FGFR inhibitors, namely multi-tyrosin kinase inhibitors (MTKI), has been limited, with a significant proportion of off-target effects. Hence, more potent and selective second-generation FGFR inhibitors (FGFRinh) are currently under development, although there is a lack of consensus regarding which FGFR:FGF molecular alteration could represent a reliable predictive biomarker of response to FGFR blockade.
With this thesis project, we aim to contribute in the definition of an optimal therapeutic strategy for patients whose tumours harbour FGFR:FGF pathway alterations, by better selecting those patients more likely to respond to FGFRinh. With this purpose, this thesis encompasses two principal studies. The first study is a retrospective study performed in a cohort of refractory FGFR:FGF-aberrant cancer patients, pre-selected within the molecular pre-screening program at VHIO, and treated with novel FGFRinh in ongoing phase 1 clinical trials. Here we present the biomarker exploratory analysis, statistically correlating the clinic-pathological characteristics of these patients with the efficacy signals observed. The vast majority of these studies were based on the hypothesis that any molecular alteration in the FGFR:FGF pathway could serve as predictive biomarker to FGFRinh, independently of the tumor subtype. However, this retrospective analysis is seeking to identify a subgroup of patients sharing a common molecular alteration of the FGFR:FGF pathway among the responders. Our aim is to delineate more precisely which of these molecular determinants are actually reliable biomarkers and to discern if, in fact, they are at the same level in terms of predicting response in different histological contexts (eg. DNA alterations, amplifications, mutations, translocations- versus mRNA versus protein).
The second study instead is a prospective study whose objective is to generate a valuable collection of biological samples from advanced cancer patients, molecularly-selected by their FGFR:FGF gene alterations. Here we present the results of the development of the investigational protocol FGFR 360º RESISTANCE, the traslational platform implemented to obtain serial patient samples (tumoral biopsies pre-/on-/post-treatment, blood samples and warm autopsies, if feasible) at different timepoints of their disease. This valuable repository of samples has served to generate patient-derived xenografts (PDXs), used for validating in vivo some of our previous observed hypothesis, as well as to integrate the molecular knowledge acquired from deep-sequencing the most relevant samples from selected unusual responders.
The presentation of each one of these two studies is accompanied by a discussion of the results obtained, together with a final summary of the conclusions reached and the future lines of research associated.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin