RESUMO
CD47 is frequently overexpressed on tumor cells and is an attractive therapeutic target. The mechanism by which anti-CD47 immunotherapy eliminates cutaneous lymphoma has not been explored. We utilized CRISPR/Cas-9 CD47 knock-out, depletion of NK cells, and mice genetically deficient in IFN-γ to elucidate the mechanism of anti-CD47 therapy in a murine model of cutaneous T cell lymphoma (CTCL). CD47 was found to be a crucial factor for tumor progression since CD47 KO CTCL exhibited a delay in tumor growth. The treatment of CD47 WT murine CTCL with anti-CD47 antibodies led to a significant reduction in tumor burden as early as four days after the first treatment and accompanied by an increased percentage of cytotoxic NK cells at the tumor site. The depletion of NK cells resulted in marked attenuation of the anti-tumor effect of anti-CD47. Notably, the treatment of CD47 WT tumors in IFN-γ KO mice with anti-CD47 antibodies was efficient, demonstrating that IFN-γ was not required to mediate anti-CD47 therapy. We were able to potentiate the therapeutic effect of anti-CD47 therapy by IFN-α. That combination resulted in an increased number of cytotoxic CD107a + IFN-γ-NK1.1 cells and intermediate CD62L + NKG2a-NK1.1. Correlative data from a clinical trial (clinicaltrials.gov, NCT02890368) in patients with CTCL utilizing SIRPαFc to block CD47 confirmed our in vivo observations.
Assuntos
Micose Fungoide , Neoplasias Cutâneas , Animais , Antígeno CD47 , Humanos , Interferon gama , Células Matadoras Naturais , Camundongos , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. METHODS: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). RESULTS: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. CONCLUSIONS: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058707.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
AIM: To evaluate treatment patterns of diffuse large B-cell lymphoma (DLBCL). PATIENTS & METHODS: First-line and relapsed/refractory treatment patterns and survival outcomes following first-line therapy in adult patients newly diagnosed with DLBCL were evaluated. RESULTS: A total of 1436 DLBCL patients initiated treatment and mainly received a combination regimen versus monotherapy (92.1 vs 7.9%). Patients who received monotherapy were older with more comorbidities and had shorter progression-free survival than patients receiving combination therapy (median: 31.3 vs 55.8 months). In the second-line setting (n = 164), rituximab-based combination regimens were most common; 25% underwent stem cell transplantation, and were younger with fewer comorbidities. CONCLUSION: These results illustrate the need for new treatment options for patients unable to tolerate initial combination therapy and transplant-ineligible patients who require salvage therapy.
Assuntos
Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia/terapia , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bases de Dados Factuais/estatística & dados numéricos , Resistencia a Medicamentos Antineoplásicos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Indução de Remissão/métodos , Estudos Retrospectivos , Rituximab/uso terapêutico , Terapia de Salvação/métodos , Terapia de Salvação/estatística & dados numéricos , Transplante de Células-Tronco/estatística & dados numéricos , Análise de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
AIM: Evaluate healthcare costs and utilization of treated diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) patients. MATERIALS & METHODS: Adults with newly diagnosed DLBCL and FL between 1 January 2008 and 31 October 2015 were identified in the Optum™ claims database. Healthcare costs and utilization were assessed from diagnosis date until end of follow-up. RESULTS: A total of 1267 DLBCL- and 1595 FL-treated patients were identified. Mean per-patient, per-month cost during follow-up was US$11,890 for DLBCL and US$10,460 for FL. Healthcare costs and utilization decreased from year 1 to 2 following diagnosis, due to a decrease in chemotherapy services, inpatient admissions and other outpatient services. CONCLUSION: The economic burden of treated DLBCL and FL is considerable, especially in the first year following diagnosis.
Assuntos
Efeitos Psicossociais da Doença , Linfoma Folicular/economia , Linfoma Difuso de Grandes Células B/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Custos de Cuidados de Saúde , Humanos , Pacientes Internados , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.
Assuntos
Compostos de Boro/uso terapêutico , Drogas em Investigação/uso terapêutico , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Administração Oral , Adulto , Idoso , Área Sob a Curva , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacocinética , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Fadiga/induzido quimicamente , Feminino , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Recidiva Local de Neoplasia , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/farmacocinética , Indução de Remissão , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
In patients with chronic myeloid leukemia, BCR-ABL mutations contribute to resistance to tyrosine kinase inhibitor therapy. We examined the occurrence of treatment-emergent mutations and their impact on response in patients from the ENESTnd phase 3 trial. At the 3-year data cutoff, mutations were detected in approximately twice as many patients (21) on imatinib 400 mg once daily as on nilotinib (11 patients each on nilotinib 300 mg twice daily and nilotinib 400 mg twice daily). The majority of mutations occurred in patients with intermediate or high Sokal scores. Most mutations (14 [66.7%]) emerging during imatinib treatment were imatinib-resistant and nilotinib-sensitive. Incidence of the T315I mutation was low (found in 3, 2, and 3 patients on nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib, respectively) and mostly occurred in patients with high Sokal scores. Of the patients with emergent mutations, 1 of 11, 2 of 11, and 7 of 21 patients on nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib, respectively, progressed to accelerated phase/blast crisis (AP/BC) on treatment. Overall, nilotinib led to fewer treatment-emergent BCR-ABL mutations than imatinib and reduced rates of progression to AP/BC in patients with these mutations. (Clinicaltrials.gov NCT00471497).
Assuntos
Benzamidas/efeitos adversos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação/efeitos dos fármacos , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Crise Blástica/epidemiologia , Crise Blástica/genética , Crise Blástica/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Seguimentos , Frequência do Gene , Humanos , Mesilato de Imatinib , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure.
Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Benzamidas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Tolerância a Medicamentos/fisiologia , Seguimentos , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60-120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.
Assuntos
Linfoma Difuso de Grandes Células B , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Resultado do Tratamento , Quinase Syk , Linfoma Difuso de Grandes Células B/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The preferentially expressed antigen in melanoma (PRAME) is expressed in several hematologic malignancies, but either is not expressed or is expressed at only low levels in normal hematopoietic cells, making it a target for cancer therapy. PRAME is a tumor-associated antigen and has been described as a corepressor of retinoic acid signaling in solid tumor cells, but its function in hematopoietic cells is unknown. PRAME mRNA expression increased with chronic myeloid leukemia (CML) disease progression and its detection in late chronic-phase CML patients before tyrosine kinase inhibitor therapy was associated with poorer therapeutic responses and ABL tyrosine kinase domain point mutations. In leukemia cell lines, PRAME protein expression inhibited granulocytic differentiation only in cell lines that differentiate along this lineage after all-trans retinoic acid (ATRA) exposure. Forced PRAME expression in normal hematopoietic progenitors, however, inhibited myeloid differentiation both in the presence and absence of ATRA, and this phenotype was reversed when PRAME was silenced in primary CML progenitors. These observations suggest that PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. Lastly, these observations suggest that PRAME is a target for both prognostic and therapeutic applications.
Assuntos
Antígenos de Neoplasias/biossíntese , Diferenciação Celular , Regulação Leucêmica da Expressão Gênica , Granulócitos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Inativação Gênica , Granulócitos/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Células-Tronco Neoplásicas/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/metabolismo , Tretinoína/farmacologiaRESUMO
Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRPαFc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits.
RESUMO
BACKGROUND: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. METHODS: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 µg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. FINDINGS: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. INTERPRETATION: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. FUNDING: Trillium Therapeutics.
Assuntos
Antígeno CD47/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoglobulina G/uso terapêutico , Micose Fungoide/tratamento farmacológico , Síndrome de Sézary/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Antígeno CD47/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Micose Fungoide/imunologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Síndrome de Sézary/imunologia , Neoplasias Cutâneas/imunologiaRESUMO
PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. PATIENTS AND METHODS: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). RESULTS: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. CONCLUSIONS: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
Assuntos
Antígeno CD47/antagonistas & inibidores , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoglobulina G/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoglobulina G/administração & dosagem , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
The Karpas-620 human myeloma cell line (HMCL) expresses high levels of Cyclin D1 (CCND1), but has a der(8)t(8;11) and a der(14)t(8;14), and not a conventional t(11;14). Fluorescent in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) studies suggest that der(14)t(11;14) from a primary translocation underwent a secondary translocation with chromosome 8 to generate der(8)t(8;[14];11) and der(14)t(8;[11];14). Both secondary derivatives share extensive identical sequences from chromosomes 8, 11, and 14, including MYC and the 3' IgH enhancers. Der(14), with MYC located approximately 700 kb telomeric to the 3'IGH enhancer, expresses MYC. By contrast, der(8), with both CCND1 and MYC repositioned near a 3'IGH enhancer, expresses CCND1, which is telomeric of the enhancer, but not MYC, which is centromeric to the enhancer. The secondary translocation that dysregulated MYC resulted in extensive regions from both donor chromosomes being transmitted to both derivative chromosomes, suggesting a defect in DNA recombination or repair in the myeloma tumor cell.
Assuntos
Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 8/genética , Ciclina D1/metabolismo , Elementos Facilitadores Genéticos , Mieloma Múltiplo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação Genética , Animais , Hibridização Genômica Comparativa , Ciclina D1/genética , Dosagem de Genes/genética , Humanos , Hibridização in Situ Fluorescente , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , RNA/metabolismoRESUMO
The aim of this phase 1 study was to determine the effects of sapanisertib on the heart rate-corrected QT (QTc) interval in patients with advanced solid tumors. Adult patients with advanced solid tumors were enrolled to receive a single sapanisertib 40-mg dose. Blood samples for pharmacokinetic analysis were collected and electrocardiogram readings were recorded at baseline and up to 48 hours after dosing. Patients could continue to receive sapanisertib 30 mg once weekly in 28-day cycles for up to 12 months. The primary objective was to characterize the effect of a single dose of sapanisertib (40 mg) on the QT interval. Secondary objectives were to evaluate safety, tolerability, and pharmacokinetics. Following a single sapanisertib 40-mg dose in 44 patients, the maximum least squares mean (upper bound of 1-sided 95% confidence interval) changes from time-matched baseline were 7.1 milliseconds (11.4 milliseconds) for individual rate-corrected QT interval at 24 hours after dosing, and 1.8 milliseconds (5.6 milliseconds) for Fridericia-corrected QTc at 1 hour post-dose. There was no sapanisertib plasma concentration-dependent increase in the change from time-matched baseline individual rate-corrected QTc interval or Fridericia-corrected QTc. The most common adverse events following sapanisertib 30 mg once-weekly dosing were nausea (80%), fatigue (61%), vomiting (57%), and decreased appetite (45%). A single sapanisertib 40 mg dose did not produce clinically relevant effects on QTc interval in patients with advanced solid tumors. The safety profile of sapanisertib 30 mg once weekly was favorable, and no new safety signals were observed (NCT02197572, clinicaltrials.gov).
Assuntos
Antineoplásicos/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Feminino , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/epidemiologia , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , SegurançaRESUMO
PURPOSE: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. PATIENTS AND METHODS: Patients received continuous, once-daily oral TAK-659, 60-120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. RESULTS: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (T max â¼2 hours) with a long terminal half-life (â¼37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). CONCLUSIONS: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.
Assuntos
Drogas em Investigação/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirrolidinonas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Esquema de Medicação , Drogas em Investigação/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirrolidinonas/efeitos adversos , Quinase Syk/antagonistas & inibidores , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresRESUMO
AIM: Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are common types of non-Hodgkin's lymphoma, and real-world evidence continues to be lacking for healthcare costs and utilization among DLBCL and FL patients. Our study aims to describe medical and pharmacy costs and health resource utilization and to characterize longitudinal treatment patterns among these patients. METHODS: A retrospective observational study was performed among adult patients with DLBCL or FL using the US MarketScan (Truven) administrative claims data from 1 January 2007 to 31 December 2015. Diagnoses of DLBCL and FL were based upon ICD-9 codes. Identifications of treatment lines involved 30 lymphoma-specific anticancer systemic agents. Direct healthcare costs and utilizations were computed in the 1-year postdiagnosis period. Generalized linear models with a gamma link were used to compare healthcare costs between therapies with and without rituximab. RESULTS: A total of 2767 DLBCL and 5989 FL patients received frontline therapy. The majority received treatment within 3 months after initial diagnosis (DLBCL 79.9% and FL 62.4%) and were treated with rituximab or bendamustine either alone or in combination (DLBCL 67.4% and FL 84.7%). The total healthcare costs were US $15,555 and $10,192 per patient per month within 1 year following their initial diagnosis for DLBCL and FL, respectively. The medical costs were nearly twice as much as the drug costs for DLBCL patients. Both DLBCL and FL patients receiving rituximab had higher pharmacy costs but lower medical costs (p < 0.001). During the first year following initial diagnosis, the resource utilization (per patient per month) of DLBCL patients included 0.21 inpatient admissions, 0.26 radiation therapy, 2.63 outpatient or office visits, 0.18 emergency room visits, 0.06 intensive care unit admissions and 0.10 stem cell transplantation. FL patients occupied less health resources than DLBCL patients. CONCLUSION: The healthcare costs and health resources utilized were considerable in non-Hodgkin's lymphoma, especially DLBCL patients.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/economia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pesquisa Comparativa da Efetividade , Feminino , Gastos em Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Humanos , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/economia , Rituximab/uso terapêutico , Estados Unidos , Adulto JovemRESUMO
Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is highly heterogeneous and current trials are investigating new approaches to improve outcomes. Limited data on response endpoints can confound estimation of a treatment effect when designing studies of novel agents in this setting, which can hinder study sample size calculations, especially if a net estimate is required for a 'physician's choice' comparator arm. Here we estimate complete response rate (CRR), overall response rate (ORR), and extrapolate durable response rates (DRR; CR/partial response lasting ≥16 weeks) for such a comparator arm from published ORRs in DLBCL. CRR, ORR, and DRR (if reported) were obtained from published clinical trials for approved single-agent therapies in patients with relapsed/refractory aggressive non-Hodgkin lymphoma after ≥2 prior therapies. Meta-analyses were performed to estimate CRR, ORR, and DRR based on ORR data reported from these studies. Published data from studies of eight monotherapies were included. Meta-analyses using fixed and random effects models showed a pooled estimate for a CRR of 12% (95% confidence interval [CI]: 9-15) and 11% (95% CI: 8-15), respectively, an ORR of 30% (95% CI: 25-35) and 30% (95% CI: 24-36), respectively, and a DRR of 14% (95% CI: 11-18; same for fixed and random effects models). Bayesian meta-analysis estimated a pooled DRR of 14% (95% credible interval: 11-19). CRR estimates for a physician's choice comparator arm in patients with relapsed/refractory DLBCL were 11-12%; DRR estimates were 14% regardless of methodology. Lack of consistency in reported data and choice of endpoints can be addressed using meta-analytic approaches.
RESUMO
In diffuse large B-cell lymphoma (DLBCL), predictive modeling may contribute to targeted drug development by enrichment of the study populations enrolled in clinical trials of DLBCL investigational drugs to include patients with lower likelihood of responding to standard of care. In clinical practice, predictive modeling has the potential to optimize therapy choices in DLBCL. The objectives of this study were to create a model for predicting health outcomes in patients with DLBCL treated with standard of care and determine informative predictors of health outcomes for patients with DLBCL. This was a retrospective observational study using data extracted from the IMS Health Database between September 2007 and April 2015. Patients were ⩾18 years of age with a DLBCL diagnosis. The index date was the date of the first DLBCL diagnosis. Patients were followed until outcome occurrence, defined as progression to a later line of therapy after ⩾60 days from the end of a previous therapy or stem cell transplantation. Patients were categorized into three cohorts depending on the post-index observation period: ⩽1 year, ⩽3 years, or ⩽5 years. Lasso logistic regression (LASSO), Naive Bayes, gradient-boosting machine (GBM), random forest (RF), and neural network models were performed for each cohort. The best-performing algorithms were predictive models based on GBM and observation periods ⩽1 and ⩽3 years after index date. Informative predictors included myocardial imaging, DLBCL stage IV, bronchiolar and renal disease, a chemotherapy regimen, and exposure to diphenhydramine and vasoprotectives on or before the first DLBCL diagnosis. These predictive models may be applied to targeted drug development and have the potential to optimize therapy choices in DLBCL. They were generated efficiently using a large number of independent variables readily available in standard insurance claims or electronic health record data systems.
RESUMO
TAK-117 (also known as MLN1117 or serabelisib) is an orally available inhibitor of phosphoinositide 3-kinase alpha being developed for treatment of solid tumors. This clinical study in healthy subjects assessed the relative bioavailability of a TAK-117 tablet compared with a capsule formulation (part 1) and the effect of food (part 2) and intragastric pH modulation (part 3) on TAK-117 pharmacokinetics. In part 1, subjects received single doses of 900 mg TAK-117 under fasting conditions as capsules and tablets on 2 different occasions in random order. In part 2, subjects received a single dose of 600 mg TAK-117 under fed (high-fat meal) or fasted conditions on 2 different occasions in random order. In part 3, subjects received a single dose of 900 mg TAK-117 alone and in combination with lansoprazole in a fixed sequence. Blood samples were collected up to 72 hours after each TAK-117 dose. The geometric mean ratios (90% confidence intervals) for the area under the TAK-117 plasma concentration-time curves were 1.53 (0.93-2.51) for tablets versus capsules, 1.50 (1.00-2.25) for fed versus fasted, and 0.02 (0.01-0.04) for TAK-117 plus lansoprazole compared with TAK-117 alone. The most common adverse event was nausea, the incidence of which was reduced when TAK-117 was administered with food despite the increased systemic exposure. The incidence of all adverse events was reduced when TAK-117 was administered with lansoprazole, which was consistent with the substantial reduction in bioavailability. Intersubject variability of TAK-117 was high. Careful management of intragastric pH-modulatory concomitant medications and food intake may be required.
Assuntos
Benzoxazóis/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Imidazóis/farmacocinética , Morfolinas/farmacocinética , Piridinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Benzoxazóis/administração & dosagem , Benzoxazóis/efeitos adversos , Disponibilidade Biológica , Cápsulas/farmacocinética , Esquema de Medicação , Drogas em Investigação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Jejum/sangue , Feminino , Voluntários Saudáveis , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Comprimidos/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Few studies have evaluated real-world treatment patterns and survival in follicular lymphoma (FL). This study evaluated these outcomes among newly diagnosed patients with FL in routine clinical care. PATIENTS AND METHODS: A retrospective study was conducted in newly diagnosed patients with FL from Humedica, a large United States electronic medical record database, from January 1, 2008 to July 31, 2015. Patients were followed from treatment initiation until death, loss to follow-up, or end of study (September 30, 2015). Treatment patterns were assessed in the follow-up period. Progression-free survival (PFS) and overall survival (OS) at 2 years were evaluated in the overall population using Kaplan-Meier analyses. OS was also compared between patients with and without evidence of disease progression within 2 years following first-line therapy (ie, early progressors vs. non-early progressors). RESULTS: A total of 1346 patients were included in the study, with most patients receiving rituximab-based regimens. Fewer early progressors received rituximab-based regimens. Across all lines, combination therapies predominated, particularly bendamustine + rituximab. Following first-line therapy, OS was 86.9% at 2 years, and median OS was not reached. Two-year PFS after first-line therapy was 64.6%, and median PFS was 48.1 months (95% confidence interval, 39.4-58.4 months). OS at 2 years was 76.8% among early progressors versus 90.4% among non-early progressors (P < .001); the median OS was not reached in both groups. CONCLUSION: In routine clinical practice, rituximab-based regimens predominated; however, utilization of these regimens differed among early and non-early progressors. The assessment of survival outcomes also highlights the negative impact of early progression on OS in the rituximab-era.