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[This corrects the article DOI: 10.1371/journal.pone.0222259.].

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Purpose Galunisertib, a TGF-ß inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.

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Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/terapia , Quimioradioterapia , Glioma/terapia , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Temozolomida/administración & dosificación , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Femenino , Glioma/inmunología , Glioma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Quinolinas/efectos adversos , Subgrupos de Linfocitos T/efectos de los fármacos , Temozolomida/efectos adversos

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BACKGROUND: Transforming growth factor beta (TGF-ß) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-ßRI/ALK5 inhibitor galunisertib. METHODS: This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-ß1, E-cadherin, selected miRNAs, and other plasma proteins were monitored. RESULTS: The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-ß1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-ß1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036). CONCLUSIONS: Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-ß1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results.

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Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Pirazoles/farmacología , Pirazoles/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/sangre , Biomarcadores de Tumor/sangre , Cadherinas/sangre , Carcinoma Hepatocelular/sangre , Estudios de Cohortes , Femenino , Humanos , Neoplasias Hepáticas/sangre , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Factor de Crecimiento Transformador beta1/análisis , Resultado del Tratamiento , alfa-Fetoproteínas/análisis

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PURPOSE: Overactivation of TGF-ß signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-ß receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. PATIENTS AND METHODS: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. RESULTS: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%). CONCLUSIONS: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.

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Antineoplásicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Pronóstico , Estudios Prospectivos , Factores de Riesgo

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PURPOSE: To evaluate the exposure-overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP). METHODS: Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS. RESULTS: The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22-84 years, weight: 39-126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5-2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure-OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer. CONCLUSIONS: This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.

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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígeno CA-19-9/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Adulto Joven , Gemcitabina

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BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-ß1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP). METHODS: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-ß1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS). RESULTS: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-ß1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2). CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-ß1 levels (vs no response) correlated with longer survival. TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.

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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/farmacología , Quinolinas/farmacología

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PURPOSE: Galunisertib, the first small molecule transforming growth factor beta (TGFß) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking. METHODS: In the Phase 1b/2 JBAJ study, 156 patients were randomized 2:1 to galunisertib + gemcitabine (N = 104) or placebo + gemcitabine (N = 52). Clinical outcome data were integrated with baseline markers and pharmacodynamic markers while patients were on treatment, including circulating proteins using a multi-analyte panel, T cell subset evaluation, and miRNA profiling. RESULTS: Baseline biomarkers associated with overall prognosis regardless of treatment included CA19-9 and TGF-ß1. In addition, IP-10, FSH, MIP-1α, and PAI-1 were potential predictive proteins. Baseline proteins that were changed during treatment included amphiregulin, CA15-3, cathepsin D, P-selectin, RAGE, sortilin, COMP, eotaxin-2, N-BNP, osteopontin, and thrombospondin-4. Plasma miRNA with potential prognostic value included miR-21-5p, miR-301a-3p, miR-210-3p, and miR-141-3p, while those with potential predictive value included miR-424-5p, miR-483-3p, and miR-10b-5p. CONCLUSIONS: Galunisertib + gemcitabine resulted in improvement of overall survival, and 4 proteins (IP-10, FSH, MIP-1α, PAI-1) were potentially predictive for this combination treatment. Future studies should also include baseline evaluation of miR-424-5p, miR-483-3p, and miR-10b-5p. TRIAL REGISTRATION: Clinicaltrials.gov NCT01373164.

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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , MicroARNs/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Biomarcadores de Tumor/sangre , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Método Doble Ciego , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Neoplasias Pancreáticas/patología , Pronóstico , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Tasa de Supervivencia , Gemcitabina

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Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Sorafenib/administración & dosificación , Distribución Tisular

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BACKGROUND: Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined. METHODS: This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers. RESULTS: Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit. CONCLUSIONS: Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.

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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores de Tumor/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Placebos , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Gemcitabina

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Transforming growth factor-ß (TGFß) is an important driver of tumor growth via intrinsic and extrinsic mechanisms, and is therefore an attractive target for developing cancer therapeutics. Using preclinical models, we characterized the anti-tumor activity of a small molecule inhibitor of TGFß receptor I (TGFßRI), galunisertib (LY2157299 monohydrate). Galunisertib demonstrated potent and selective inhibition of TGFßRI with corresponding inhibition of downstream signaling via inhibition of SMAD phosphorylation (pSMAD). Galunisertib also inhibited TGFß-induced pSMAD in vivo, which enabled a pharmacokinetic/pharmacodynamic profile in Calu6 and EMT6-LM2 tumors. Galunisertib demonstrated anti-tumor activity including inhibition of tumor cell migration and mesenchymal phenotype, reversal of TGFß-mediated immune-suppression, and tumor growth delay. A concentration-effect relationship was established with a dosing schedule to achieve the optimal level of target modulation. Finally, a rat model demonstrated a correlation between galunisertib-dependent inhibition of pSMAD in tumor tissues and in PBMCs, supporting the use of PBMCs for assessing pharmacodynamic effects. Galunisertib has been tested in several clinical studies with evidence of anti-tumor activity observed in subsets of patients. Here, we demonstrate that galunisertib inhibits a number of TGFß-dependent functions leading to anti-tumor activity. The enhanced understanding of galunisertib provides rationale for further informed clinical development of TGFß pathway inhibitors.

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Galunisertib, a Transforming growth factor-ßRI (TGF-ßRI) kinase inhibitor, blocks TGF-ß-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-ß-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2⁺ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H⁺ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3⁺ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4⁺ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.

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Biomarcadores de Tumor/metabolismo , Glioblastoma/tratamiento farmacológico , Lomustina/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/sangre , Relación CD4-CD8 , Citocinas/sangre , Femenino , Factores de Transcripción Forkhead/sangre , Factores de Transcripción Forkhead/metabolismo , Glioblastoma/sangre , Glioblastoma/patología , Humanos , Isocitrato Deshidrogenasa/metabolismo , Lomustina/efectos adversos , Lomustina/uso terapéutico , Masculino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Proteína Smad2/metabolismo , Análisis de Supervivencia

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OBJECTIVE: Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor ß (TGFß) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations. METHODS: Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. RESULTS: Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-∞) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. CONCLUSIONS: In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation.

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BACKGROUND: The combination of galunisertib, a transforming growth factor (TGF)-ß receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma. METHODS: Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity. RESULTS: One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS. CONCLUSIONS: Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms. CLINICAL TRIAL REGISTRATION: NCT01582269, ClinicalTrials.gov.

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Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Lomustina/uso terapéutico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Supervivencia sin Enfermedad , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Humanos , Estimación de Kaplan-Meier , Lomustina/efectos adversos , Lomustina/farmacocinética , Masculino , Persona de Mediana Edad , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Resultado del Tratamiento

RESUMEN

Transforming growth factor-beta (TGF-ß) signaling regulates a wide range of biological processes. TGF-ß plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-ß signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-ß receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

Asunto(s)

Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Esquema de Medicación , Cardiopatías/inducido químicamente , Estructura Molecular , Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/patología , Fosforilación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/química , Pirazoles/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/química , Quinolinas/farmacocinética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Smad2/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

BACKGROUND: Glioblastoma (GB) treatment remains challenging because of recurrence and poorly defined treatment options after first-line therapy. To better understand real-world application of treatment paradigms and their impact on outcomes, we describe patterns of treatment, outcomes, and use of cancer-related healthcare resource for glioblastoma in the USA. METHODS: A retrospective, online chart-abstraction study was conducted; each participating oncologist contributed ≤5 charts. Patients were ≥18 years with biopsy-confirmed primary or secondary newly diagnosed GB on or after 1 January 2010, had received first- and second-line therapies, and had information collected for ≥3 months after initiation of second-line therapy or until death. Assessments were descriptive and included Kaplan- Meier analyses from initiation to end of second-line therapy, disease progression, or death. RESULTS: One hundred sixty physicians contributed information on 503 patient charts. During first-line therapy, patients most commonly underwent temozolomide monotherapy (76.5%). During second-line therapy, patients most commonly underwent bevacizumab monotherapy (58.1%). Median duration of second-line therapy was 130 days; median time to disease progression was 113 days. Median survival was 153 days. Use of supportive care was observed to be numerically higher in first- compared with second-line therapy except for anti-depressants, growth factors, and stimulants. Frequently used resources included corticosteroids (78.8% of patients in first-line and 62.6% in second-line therapies), anti-epileptics (45.8% and 41.5%) and narcotic opioids (45.3% and 41.4%). CONCLUSIONS: Most GB patients received temozolomide during first-line therapy and bevacizumab monotherapy or combination therapy during second-line therapy. Use of supportive care appeared to be higher in first- compared with second-line therapy for some agents.

RESUMEN

Purpose Transforming growth factor-beta (TGF-ß) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-ß signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15%) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation.

Asunto(s)

Neoplasias/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Proteínas ADAM , Adulto , Anciano , Anticonvulsivantes/farmacología , Área Bajo la Curva , Recuento de Células Sanguíneas , Quimiocina CCL22 , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Lomustina , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/farmacología , Pirazoles , Quinolinas , Receptor Tipo I de Factor de Crecimiento Transformador beta , Proteína Smad2/biosíntesis , Proteínas Supresoras de Tumor

RESUMEN

PURPOSE: TGFß signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGFß signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer. EXPERIMENTAL DESIGN: Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria. RESULTS: In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥ 6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ≥ 6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events. CONCLUSIONS: On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation.

Asunto(s)

Antineoplásicos/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Quinolinas/farmacología , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Resultado del Tratamiento , Adulto Joven

RESUMEN

Transforming growth factor-beta (TGF-ß) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-ß signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-ß inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-ß inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Ecocardiografía Doppler , Electrocardiografía , Femenino , Cardiopatías/sangre , Cardiopatías/inducido químicamente , Cardiopatías/diagnóstico por imagen , Humanos , Lomustina/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias/enzimología , Neoplasias/patología , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/efectos adversos , Quinolinas/efectos adversos , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Medición de Riesgo , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , España , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven

RESUMEN

Transforming growth factor ß (TGF-ß) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-ß ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TßM1 is a humanized mAb optimized for neutralizing activity against TGF-ß1. The objective of this clinical trial was to assess the safety and tolerability of TßM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤ 2 on the ECOG scale were administered TßM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TßM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TßM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-ß1 expression signature in patients' whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study.

Asunto(s)

Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas de Neoplasias/biosíntesis , Neoplasias/inmunología , Neoplasias/patología , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores

RESUMEN

AIMS: To identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor ß (TGF-ß) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations. METHODS: The model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-ß RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg. RESULTS: No medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l⁻¹ h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients. CONCLUSIONS: A therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development.

Asunto(s)

Pirazoles/farmacocinética , Quinolinas/farmacocinética , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adulto , Anciano , Biomarcadores , Estudios de Cohortes , Descubrimiento de Drogas , Femenino , Glioblastoma/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Pirazoles/farmacología , Quinolinas/farmacología