RESUMO
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations. METHODS: In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing. FINDINGS: Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths. INTERPRETATION: Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations. FUNDING: Pfizer/Medivation.
Assuntos
Antineoplásicos/uso terapêutico , Reparo do DNA/genética , Ftalazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Análise de SobrevidaRESUMO
We have developed an automated assay to enumerate and characterize circulating multiple myeloma cells (CMMC) from peripheral blood of patients with plasma cell disorders. CMMC show expression of genes characteristic of myeloma and fluorescence in situ hybridisation results on CMMC correlated well with bone marrow results. We enumerated CMMC from over 1000 patient samples including separate cohorts of newly diagnosed multiple myeloma and high/intermediate risk smouldering multiple myeloma (SMM) with clinical follow-up data. In newly diagnosed myeloma patient samples, CMMC counts correlated with other clinical measures of disease burden, including the percentage of bone marrow plasma cells, serum M protein, and International Staging System stage. CMMC counts decreased significantly from baseline when a remission was achieved due to treatment (P < 0·001). Patients with CMMC counts ≥100 at remission showed reduced survival relative to patients with CMMC counts <100. Patients with undetectable CMMC in remission showed further overall survival benefits. In the SMM cohort, there was a trend toward higher CMMC in patients with higher-risk myeloma precursor states. Significantly higher CMMC counts were observed between intermediate/high risk SMM patients that progressed versus those without progression (P = 0·031). CMMC allow a non-invasive means of monitoring tumour biology and may have use as a prognostic test for patients with plasma cell disorders.
Assuntos
Contagem de Células , Mieloma Múltiplo/diagnóstico , Neoplasias de Plasmócitos/diagnóstico , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Medula Óssea/patologia , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Citometria de Fluxo/métodos , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Neoplasias de Plasmócitos/sangue , Neoplasias de Plasmócitos/genética , Neoplasias de Plasmócitos/mortalidade , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study. METHODS: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response. RESULTS: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response. CONCLUSION: The results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Mutação em Linhagem Germinativa , Terapia Neoadjuvante , Ftalazinas , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Proteína BRCA2/genética , Proteína BRCA1/genética , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Biomarcadores Tumorais/genética , Idoso , Perda de HeterozigosidadeRESUMO
PURPOSE: In this Phase 1, multicenter, open-label study, intetumumab (CNTO 95), a fully human anti-αv integrin monoclonal antibody was evaluated for safety, pharmacokinetics, and pharmacodynamic activity in patients with melanoma or angiosarcoma. PATIENTS AND METHODS: Patients with histologically-confirmed inoperable melanoma or angiosarcoma refractory to standard treatment were allocated to treatment with 10 mg/kg or 20 mg/kg intetumumab, administered once every 3 weeks for up to four cycles unless unacceptable toxicity or disease progression occurred. Extended dosing was available for patients who responded with stable disease or better. RESULTS: Eight patients received 10 mg/kg and 11 received 20 mg/kg intetumumab. Baseline patient characteristics were comparable between treatment groups; 18 patients had metastatic malignant melanoma and one had angiosarcoma. No dose-limiting toxicities were observed. Headache was the most common adverse event across both dose groups. Vomiting, nausea and chills were more common, and uveitic reactions lasted longer, in patients treated with 20 mg/kg compared with 10 mg/kg intetumumab. No patient developed antibodies to intetumumab. Intetumumab drug exposure as assessed by area under the curve and maximum serum concentration appeared to increase approximately dose-proportionally from 10 to 20 mg/kg, while volume of distribution remained constant for both doses. Stable disease was observed in two patients with metastatic malignant melanoma (one in each dose group) for at least 6 weeks. CONCLUSIONS: In patients with metastatic malignant melanoma and angiosarcoma in this study, intetumumab demonstrated manageable toxicity, was well tolerated, and presented approximately dose-proportional pharmacokinetics for the 10 mg/kg and 20 mg/kg doses.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Hemangiossarcoma/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Biomarcadores Tumorais/sangue , Feminino , Genes ras/genética , Hemangiossarcoma/genética , Hemangiossarcoma/metabolismo , Humanos , Integrinas/sangue , Masculino , Melanoma/genética , Melanoma/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismoRESUMO
Angiogenesis is a major component of the pathogenesis of various ocular diseases, including age-related macular degeneration (AMD). CNTO95 is a fully human monoclonal antibody against alpha(nu) integrins that has shown antiangiogenic properties in cynomolgus macaques and rats. Because angiogenesis inhibitors may have the potential to treat AMD, a proof-of-concept study was conducted in a macaque model of laser-induced choroidal neovascularization. In the course of this study, transient, intense anterior chamber ocular inflammation was observed within 24 hours following the first intravitreal or intravenous administration of the human monoclonal antibody. These animals had no outward signs of ocular toxicity or discomfort. Additional ocular safety studies demonstrated that the inflammation following intravenous administration of CNTO95 was not due to a contaminant in the vehicle, not due to endotoxin, and not a nonspecific reaction in the macaques from administration of a human monoclonal antibody. The anterior chamber ocular inflammation noted following the first dose did not recur with subsequent CNTO95 dosing. In repeated-dose toxicology studies, histopathological examination of the eyes revealed no ocular toxicity. The reason for the ocular inflammation following intravenous dosing remains unresolved but may be a secondary manifestation of a first-dose systemic infusion reaction.
Assuntos
Inibidores da Angiogênese/toxicidade , Câmara Anterior/efeitos dos fármacos , Anticorpos Monoclonais/toxicidade , Cadeias alfa de Integrinas/imunologia , Uveíte/induzido quimicamente , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Animais , Câmara Anterior/patologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Bevacizumab , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/fisiopatologia , Modelos Animais de Doenças , Feminino , Injeções Intravenosas , Macaca fascicularis , Degeneração Macular/complicações , Degeneração Macular/tratamento farmacológico , Degeneração Macular/fisiopatologia , Masculino , Testes de Toxicidade , Uveíte/patologia , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/patologiaRESUMO
PURPOSE: CNTO 95 is a fully human anti-alphav integrin monoclonal antibody that inhibits macaque and rodent angiogenesis and inhibits human tumor growth in rodents. The purpose of these studies was to evaluate the preclinical safety of long-term administration of CNTO 95 in cynomolgus macaques. EXPERIMENTAL DESIGN: The in vitro binding profiles of CNTO 95 to human and macaque tissues and the in vivo binding to macaque tissues was evaluated by immunohistochemistry. The preclinical safety of CNTO 95 (10 and 50 mg/kg, i.v.) was evaluated in macaques treated once per week for up to 6 months. Safety was evaluated by clinical observations, ophthalmic and physical examinations (including heart rate, blood pressure, and electrocardiogram), clinical pathology (including coagulation parameters), and comprehensive anatomic pathology. The effect of CNTO 95 (50 mg/kg, i.v.) on incisional wound healing was evaluated in macaques. RESULTS: The tissue binding studies showed that CNTO 95 bound with mild to moderate intensity to macaque and human endothelial cells, epithelial cells, and vascular smooth muscle cells in most normal tissues examined. CNTO 95 showed strong to intense staining to the positive control tissue, human placenta. Despite the widespread binding to normal tissues, treatment of cynomolgus macaques with CNTO 95 produced no signs of toxicity and no histopathologic changes in any of the tissues examined (including ovaries and bone growth plates). CNTO 95 did not impair wound healing. CONCLUSION: These studies show that CNTO 95 is safe and, unlike some other angiogenesis inhibitors, does not seem to inhibit normal physiologic angiogenesis.
Assuntos
Anticorpos Monoclonais/química , Integrina alfaV/química , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Aorta/metabolismo , Área Sob a Curva , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Feminino , Humanos , Sistema Imunitário , Imuno-Histoquímica , Macaca fascicularis , Masculino , Miócitos de Músculo Liso/citologia , Neovascularização Patológica , Placenta/metabolismo , Ligação Proteica , Fatores de Tempo , CicatrizaçãoAssuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Monitorização Fisiológica , Neoplasias/tratamento farmacológico , Células Neoplásicas Circulantes , Anticorpos Monoclonais/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Sensibilidade e EspecificidadeRESUMO
The prolonged survival of donor hematopoietic stem cells is crucial to the success of bone marrow transplantation. The anti-apoptotic gene Bcl-xL has been shown to promote survival of cells of the erythroid, myeloid and lymphoid lineages. To evaluate a potential therapeutic role for Bcl-xL, we used a retroviral vector to express Bcl-xL in donor cells used for murine bone marrow transplantation. We find that Bcl-xL expression in bone marrow cells facilitates hematopoietic reconstitution (as assessed by total cellularity) without altering cell differentiation. Most importantly, cells reconstituted with Bcl-xL are able to achieve high levels of donor chimerism even in non-ablative conditioning protocols in a syngeneic model of transplantation. Thus, expression of Bcl-xL by donor cells during bone marrow transplantation may provide a means to minimize host conditioning and toxicity while still achieving therapeutic degrees of mixed chimerism.
Assuntos
Transplante de Medula Óssea/métodos , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Transplante de Células-Tronco/métodos , Células-Tronco/metabolismo , Animais , Western Blotting , Sobrevivência Celular , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Retroviridae/genética , Condicionamento Pré-Transplante , Proteína bcl-XRESUMO
The application of TCR transgenic mice to transplantation immunology is hampered by the limited lines available. Recently, we reported CD4+ T cell receptor (TCR) transgenic mice specific for I-Abm12 expressed on B6.C.H-2bm12 mice. Here, we characterized rejection of skin and vascularized cardiac allografts in these mice, which we term ABM (for anti-bm12). In vivo proliferative experiments reveal that all CD4 T cells in ABM mice react to bm12 antigens. Surprisingly, while ABM mice have accelerated (compared to B6 recipients) rejection of bm12 skin allografts, they, like B6 recipients, fail to acutely reject bm12 cardiac allografts. This is not due to lack of immunogenicity of bm12 hearts, as these grafts are acutely rejected by primed ABM recipients, although not by primed B6 recipients. Lastly, long-term surviving bm12 grafts in ABM recipients are relatively free from chronic rejection (compared with B6 recipients), which may be due to skewing of the CD4 repertoire towards direct alloreactivity, and consequent lack of CD4 mediated indirect allorecognition as evidenced by the lack of IgG deposition in those grafts. The results indicate that a complex interplay between responder frequency, priming and repertoire dictates the occurrence, or lack thereof, of acute and chronic rejection.