RESUMO
A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty-four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid-study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose-dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP-10, IL10, IL1-RA). Most patients (51/54; 94%) experienced ≥1 treatment-emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti-tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Citocinas , Lipídeo A/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor 4 Toll-Like/agonistas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. PATIENTS AND METHODS: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. RESULTS: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). CONCLUSION: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. IMPLICATIONS FOR PRACTICE: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias , Anticorpos Monoclonais Humanizados , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Estudos ProspectivosRESUMO
PURPOSE: Interest in Toll-like receptor (TLR) agonists for cancer treatment has been renewed after promising preliminary clinical data in combination with checkpoint inhibitors. This first-in-human study assessed the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of intravenous GSK1795091, a synthetic TLR4 agonist, in healthy volunteers as a precursor to evaluation in patients with cancer. METHODS: Healthy participants were randomized (1:3; double-blinded manner) to receive placebo or a single intravenous injection of GSK1795091 at doses of 7-100 ng. The primary objective was to evaluate the safety and tolerability of GSK1795091; secondary and exploratory objectives were to characterize GSK1795091 PK and PD properties. FINDINGS: Forty participants received study treatment (10 received placebo and 30 received GSK1795091). Overall, 3 of the 10 participants (30%) who received placebo and 16 of the 30 (53%) who received GSK1795091 experienced ≥1 adverse event (AE). The most common AEs were influenza-like illness, headache, back pain, and increased body temperature. One participant experienced late-occurring AEs (alanine aminotransferase and aspartate aminotransferase increases), considered possibly related to GSK1795091. No serious AEs were reported. GSK1795091 PK properties were characterized by dose proportional increase in exposure. Transient and dose-dependent changes in induced cytokine and chemokine concentrations and immune cell counts were observed 1-4 h after GSK1795091 administration and returned to baseline within 24 h. IMPLICATIONS: Intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. These results supported the design and initiation of a repeat-dose study of intravenous GSK1795091 in combination with other immunotherapies in patients with advanced cancer. ClinicalTrials.gov identifier: NCT02798978.
Assuntos
Antineoplásicos , Glicolipídeos , Receptor 4 Toll-Like/agonistas , Adulto , Alanina Transaminase/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Aspartato Aminotransferases/sangue , Dor nas Costas/induzido quimicamente , Temperatura Corporal/efeitos dos fármacos , Citocinas/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Glicolipídeos/administração & dosagem , Glicolipídeos/efeitos adversos , Glicolipídeos/farmacocinética , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Imunoterapia , Infusões Intravenosas , Contagem de Leucócitos , Masculino , Pessoa de Meia-IdadeRESUMO
NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686-95. ©2018 AACR.See related commentary by Wilson and Politi, p. 676This article is highlighted in the In This Issue feature, p. 663.
Assuntos
Afatinib/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias/tratamento farmacológico , Neuregulina-1/genética , Proteínas de Fusão Oncogênica/genética , Afatinib/farmacologia , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Terapia de Alvo Molecular , Neoplasias/genética , Ligação Proteica/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais/farmacocinética , Macrófagos/imunologia , Compostos Radiofarmacêuticos/farmacocinética , Receptor ErbB-3/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Linhagem Celular Tumoral , Feminino , Óxido Ferroso-Férrico/química , Humanos , Imuno-Histoquímica , Marcação por Isótopo , Macrófagos/citologia , Macrófagos/patologia , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Radioisótopos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/uso terapêutico , Receptor ErbB-3/metabolismo , Distribuição Tecidual , Transplante Heterólogo , Zircônio/químicaRESUMO
Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC50 = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC50 = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.
Assuntos
Anticolesterolemiantes/farmacocinética , Indanos/farmacologia , Mucosa Intestinal/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Fenilpropionatos/farmacologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Rosuvastatina Cálcica/farmacocinética , Adulto , Idoso , Animais , Anticolesterolemiantes/sangue , Células CHO , Cricetulus , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Absorção Intestinal , Pessoa de Meia-Idade , Rosuvastatina Cálcica/sangue , Especificidade por SubstratoRESUMO
INTRODUCTION: Pharmacokinetic drug interactions resulting from the inhibition of drug elimination mechanisms are of concern in drug development due to the clinical risk associated with elevated drug concentrations. Advances in understanding the mechanistic basis of these drug interactions has resulted in the widespread application of mechanistic in vitro assays and the conduct of clinical drug interaction studies to predict and quantify the risks in drug development. AREAS COVERED: The authors investigate co-medication prescriptions in target patient populations and characterize the mechanistic basis and clinical impact of known co-medication drug interactions. This has enabled identification of critical mechanistic in vitro studies and provided options to manage co-medication use in clinical studies. Furthermore, they demonstrate, for the pharmaceutical scientist, how improved understanding of the drug interactions risks associated with key medications in a target therapeutic area, can help prioritize the conduct of in vitro data and optimize the timing of the clinical drug interaction studies required to characterize drug interaction risks. EXPERT OPINION: This approach provides a more targeted strategy to drug interaction data generation, as routine application of assays may provide limited impact on drug progression decisions. Assessing co-medications in the target patient population enables early discharge of the safety risks associated with drug interactions and reduced investment in drug interaction studies.
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Desenho de Fármacos , Interações Medicamentosas , Farmacocinética , Ensaios Clínicos como Assunto/métodos , Tomada de Decisões , Quimioterapia Combinada , Humanos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , RiscoRESUMO
Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short-acting calcium-sensing receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur. Chronic administration of SB-423557 did not increase parathyroid cell proliferation in rats. In healthy human volunteers, single doses of intravenous SB-423562 and oral SB-423557 elicited transient elevations of endogenous PTH concentrations in a profile similar to that observed with subcutaneously administered PTH. Both agents were well tolerated in humans. Transient increases in serum calcium, an expected effect of increased parathyroid hormone concentrations, were observed post-dose at the higher doses of SB-423557 studied. These data constitute an early proof of principle in humans and provide the basis for further development of this class of compound as a novel, orally administered bone-forming treatment for osteoporosis.
Assuntos
Etanolaminas/farmacologia , Naftalenos/farmacologia , Osteogênese/efeitos dos fármacos , Hormônio Paratireóideo/sangue , Fenilpropionatos/farmacologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Administração Oral , Animais , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Cálcio/sangue , Proliferação de Células/efeitos dos fármacos , Cães , Esquema de Medicação , Etanolaminas/administração & dosagem , Etanolaminas/química , Etanolaminas/farmacocinética , Haplorrinos , Humanos , Masculino , Naftalenos/administração & dosagem , Naftalenos/química , Naftalenos/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Glândulas Paratireoides/citologia , Glândulas Paratireoides/efeitos dos fármacos , Fenilpropionatos/administração & dosagem , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
P-glycoprotein (P-gp) and CYP3A have considerable overlap in inducers in vitro. Characterizing P-gp induction in vivo and potential coregulation with CYP3A are important goals for predicting drug interactions. This study examined P-gp expression in mouse tissues and potential coinduction with CYP3A following oral treatment with 1 of 7 prototypical inducing agents for 5 days. P-gp expression in brain or liver was not induced by any treatment as determined by Western blot, whereas dexamethasone, pregnenolone-16alpha-carbonitrile (PCN), St. John's wort (SJW), and rifampin induced hepatic CYP3A expression. In intestine, rifampin and SJW induced P-gp expression 3.7- and 1.6-fold and CYP3A 3.5- and 2.4-fold, respectively, whereas dexamethasone and PCN induced CYP3A only. These observations suggest that P-gp in mouse small intestine is inducible by some, but not all, CYP3A inducers, whereas P-gp expression in liver or brain is not readily induced. Intriguingly, rifampin and SJW, both activators of the human pregnane X receptor (PXR), induced CYP3A in both liver and intestine but induced P-gp only in intestine, whereas PCN, an activator of murine PXR, did not induce P-gp in any tissue. Rifampin disposition was evaluated, and hepatic exposure to rifampin was comparable to intestine; in contrast, brain concentrations were low. Overall, these observations demonstrate that P-gp induction in vivo is tissue-specific; furthermore, there is a disconnect between P-gp induction and CYP3A induction that is tissue- and inducer-dependent, suggesting that PXR activation alone is insufficient for P-gp induction in vivo. Tissue-specific factors and inducer pharmacokinetic/pharmacodynamic properties may underlie these observations.