RESUMO
BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).
Assuntos
Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Sarcoma Alveolar de Partes Moles , Adolescente , Adulto , Criança , Humanos , Recém-Nascido , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Peso Corporal , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Administração IntravenosaRESUMO
BACKGROUND: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. METHODS: Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. RESULTS: Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. CONCLUSION: Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. CLINICALTRIALS.GOV IDENTIFIER: NCT03233204. IRB approved: initial July 24, 2017.
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Reparo do DNA , Neoplasias , Ftalazinas , Piperazinas , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ftalazinas/uso terapêutico , Ftalazinas/efeitos adversos , Ftalazinas/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversosRESUMO
BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (nâ =â 7) and prior BRAF inhibitor therapy (nâ =â 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).
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Mutação , Proteínas Proto-Oncogênicas B-raf , Vemurafenib , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêutico , Vemurafenib/administração & dosagem , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pré-Escolar , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.
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Compostos de Anilina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Sorafenibe , Humanos , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time. METHODS: We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion of overall response (complete response and partial response) and complete response rate in the study periods of 2000-05, 2006-12, and 2013-2019, and evaluated their trends over time. We also analysed cancer type-specific and investigational agent-specific response, and analysed the trend of response in each cancer type over time. Univariate associations of overall response rates with patients' baseline characteristics (age, sex, performance status, BMI, albumin concentration, and haemoglobin concentration), enrolment period, investigational agents, and trial design were assessed using risk ratio based on the modified Poisson regression model. FINDINGS: We analysed 465 protocols that enrolled 13â847 patients using 261 agents. 144 (31%) trials used a monotherapy and 321 (69%) used combination therapies. The overall treatment-related death rate was 0·7% (95% CI 0·5-0·8) across all periods. Risks of treatment-related deaths did not change over time (p=0·52). All on-treatment death risk during the study period was 8·0% (95% CI 7·6-8·5). The most common grade 3-4 adverse events were haematological; grade 3-4 neutropenia occurred in 2336 (16·9%) of 13â847 patients, lymphopenia in 1230 (8·9%), anaemia in 894 (6·5%), and thrombocytopenia in 979 (7·1%). The overall response rate for all trials during the study period was 12·2% (95% CI 11·5-12·8; 1133 of 9325 patients) and complete response rate was 2·7% (2·4-3·0; 249 of 9325). Overall response increased from 9·6% (95% CI 8·7-10·6) in 2000-05 to 18·0% (15·7-20·5) in 2013-19, and complete response rates from 2·5% (2·0-3·0) to 4·3% (3·2-5·7). Overall response rates for combination therapy were substantially higher than for monotherapy (15·8% [15·0-16·8] vs 3·5% [2·8-4·2]). The overall response by class of agents differed across diseases. Anti-angiogenesis agents were associated with higher overall response rate for bladder, colon, kidney and ovarian cancer. DNA repair inhibitors were associated with higher overall response rate in ovarian and pancreatic cancer. The rates of overall response over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer. INTERPRETATION: During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours. FUNDING: National Cancer Institute.
Assuntos
Antineoplásicos , Desenvolvimento de Medicamentos , Ensaios Clínicos Fase I como Assunto , Drogas em Investigação , Feminino , Humanos , Masculino , National Cancer Institute (U.S.) , Neoplasias/tratamento farmacológico , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal. METHODS: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal. RESULTS: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9-11.1%). Median PFS was 2.3 months (95% CI 1.9-2.6) and mOS was 7.8 months (95% CI 5.4-10.1). CONCLUSIONS: GDC-0449 was well tolerated, reached tumor, and inhibited CD133+ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/patologia , Proteínas Hedgehog/metabolismo , Recidiva Local de Neoplasia/patologia , Glioma/patologia , Antineoplásicos/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Encefálicas/patologiaRESUMO
Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Gossipol/análogos & derivados , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Estudos de Coortes , Feminino , Gossipol/uso terapêutico , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Resultado do TratamentoRESUMO
AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
Assuntos
Inibidores de Histona Desacetilases/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Hepatopatias/fisiopatologia , Fígado/metabolismo , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacocinética , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Infusões Intravenosas , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/complicações , Neoplasias/patologia , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversosRESUMO
Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who were initially treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in 9 phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDI of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In both groups, however, the decreasing RDI over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies.
Assuntos
Antineoplásicos/administração & dosagem , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle (L0). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L0, however dasatinib was reduced to 50 mg (L-1) given side effects observed in the first two patients. At L-1, a DLT occurred in 1/6 patients and dose was re-escalated to L0, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L1) where 1/6 patients experienced a DLT. Although L1 was tolerable, dose escalation was stopped as investigators felt L1 was within the optimal therapeutic window. Most frequent toxicities were anemia (89%), elevated aspartate aminotransferase (79%), fatigue (79%), nausea (79%), elevated alanine aminotransferase (74%), lymphopenia (74%), leukopenia (74%), neutropenia (63%), and thrombocytopenia (63%), most Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno CA-19-9/metabolismo , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Imagem de Difusão por Ressonância Magnética , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Inibidores de Proteínas Quinases/efeitos adversos , GencitabinaRESUMO
BACKGROUND: In phase 1 trials, an important entry criterion is life expectancy predicted to be more than 90 days, which is generally difficult to predict. The Royal Marsden Hospital (RMH) prognostic score that is determined by lactate dehydrogenase level, albumin level, and number of metastatic sites of disease was developed to help project patient outcomes. There have been no systematic analyses to evaluate the utility of the RMH prognostic score for esophagogastric cancer patients. METHODS: All nonpediatric phase 1 oncology trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program that began between 2001 and 2013 were considered in this review. RESULTS: Of 4722 patients with solid tumors, 115 patients were eligible for our analysis; 54 (47 %) with cancer of the esophagus, 14 (12 %) with cancer of the esopagogastric junction, and 47 (41 %) with stomach cancer. Eighty-six patients (75 %) had a good RMH prognostic score (0 or 1) and 29 patients (25 %) had a poor RMH prognostic score (2 or 3). Disease control rates were significantly different between patients with good and poor RMH prognostic scores (49 % vs 17 %; two-sided Fisher's exact test P = 0.004). The median treatment duration and overall survival for good and poor RMH prognostic score patients were significantly different (median treatment duration 2.1 months vs 1.2 months respectively, P = 0.016; median overall survival 10.9 months vs 2.1 months respectively, P < 0.001). In the multivariate analysis, age (60 years or older), Eastern Cooperative Oncology Group performance status (2 or greater), and the RMH prognostic score (2 or 3) were significant predictors of poor survival. CONCLUSIONS: The RMH prognostic score is a strong tool to predict the prognosis of esophagogastric cancer patients who might participate in a phase 1 trial.
Assuntos
Ensaios Clínicos Fase I como Assunto , Neoplasias Esofágicas/etiologia , Seleção de Pacientes , Neoplasias Gástricas/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , National Cancer Institute (U.S.) , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Análise de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
Interstitial lung disease is a serious drug-related condition that can cause life threatening organ failure. The incidence and risk factors of drug-induced interstitial lung disease (DILD) are unknown in oncology phase I trials. This study analyzed clinical information from 8906 patients with malignancies who were enrolled in 470 phase I trials sponsored by the Cancer Therapy Evaluation Program, National Cancer Institute, from 1988 to 2014. Logistic and Cox statistical analyses were utilized to determine clinical differences between patients who developed DILD and patients who did not. In this study, the overall incidence rate of patients with pulmonary toxicity was 2.7%. The overall incidence rate for DILD was 0.77%, whereas for grade 3 or 4 DILD it was 0.31%. Median time to occurrence of DILD was 1.4 months. The Cox hazard analysis indicated smaller body surface area and a combination of thoracic radiation with investigational drug regimens were significant risk factors for time to occurrence of interstitial lung disease. Investigators should carefully monitor for DILD in oncology patients enrolled in phase I trials with identified risk factors. A 6-month observation period would be sufficient to detect the onset of most DILD in such patients.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/etiologia , Neoplasias/complicações , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Terapia Combinada , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Fatores de RiscoRESUMO
BACKGROUND: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODS: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTS: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONS: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células Neoplásicas Circulantes , Piridinas/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer. METHODS: In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Pharmacokinetics were obtained during cycle 1. Plasma, peripheral blood mononuclear cells (PBMCs), and percutaneous tumor biopsy samples were collected before cycle 1 and after 6 weeks. The primary endpoint was an objective response or progression-free survival lasting greater than 6 months in a mini-max design. RESULTS: Eleven patients received birinapant; after this, accrual was terminated for lack of a clinical benefit. Birinapant was well tolerated, with predominantly grade 2 adverse events and 1 case of grade 3 lymphopenia. Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 patients, respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in tumors (P = .016) and PBMCs (P < .01). Procaspase 3 also decreased in tumors (P = .031) and PBMCs (P < .01); cleaved caspase 3 colocalized with H2A histone family member X (γ-H2AX) in tumors after birinapant exposure. Peripheral T and B cells decreased significantly after treatment, but natural killer cells did not (P = .04, P = .05, and P = .43, respectively). CONCLUSIONS: Birinapant shows consistent target suppression in vivo without single-agent antitumor activity in this small population. Single-agent pharmacodynamics are necessary to understand the drug's mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials.
Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Endometrioide/tratamento farmacológico , Dipeptídeos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Indóis/uso terapêutico , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Idoso , Antineoplásicos/farmacocinética , Proteínas Reguladoras de Apoptose , Linfócitos B , Carcinoma Endometrioide/metabolismo , Carcinoma Epitelial do Ovário , Caspase 3/metabolismo , Dipeptídeos/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Indóis/farmacocinética , Proteínas Inibidoras de Apoptose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Células Matadoras Naturais , Leucócitos Mononucleares/metabolismo , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Pessoa de Meia-Idade , Proteínas Mitocondriais , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Compostos de Platina/uso terapêutico , Linfócitos T , Falha de Tratamento , Resultado do Tratamento , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The National Cancer Institute-Molecular Analysis for Therapy Choice trial is a clinical trial that will analyze various genetic statuses of patients' tumors to determine whether they contain abnormalities which can be a target for an available drug. National Cancer Institute-Molecular Analysis for Therapy Choice seeks to determine whether improved outcomes can be achieved when cancer treatments are personalized based on molecular abnormalities found in individual patients. As a master protocol, or basket trial, National Cancer Institute-Molecular Analysis for Therapy Choice can add or remove treatments as indicated over the duration of the study. Each treatment will be used in a unique arm, or sub-study, of the trial. The trial initially has 10 arms, each of which will enroll patients to a specific molecularly targeted treatment. It is ultimately anticipated that 20-25 drugs or combination treatments will be tested. To be eligible for the study, participants must have an advanced solid tumor or lymphoma that is no longer responding or never responded to the standard therapy. National Cancer Institute-Molecular Analysis for Therapy Choice investigators plan to obtain tumor biopsy specimens from as many as 3000 patients initially. To identify multiple genetic abnormalities that may respond to the targeted drugs selected for the trial, next-generation deoxyribonucleic acid and ribonucleic acid sequencing will be done in the genetic testing laboratories, analyzing for >4000 different variants across 143 genes. The drugs included in the trial have all either been approved by the US Food and Drug Administration for another cancer indication or are still being tested in other clinical trials, but have shown some clinical levels of evidence against tumors with a particular genetic alteration.
Assuntos
Pesquisa em Genética , Terapia Genética , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão , Terapia Combinada , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Terapia de Alvo Molecular/tendências , National Cancer Institute (U.S.) , Neoplasias/metabolismo , Medicina de Precisão/métodos , Medicina de Precisão/normas , Medicina de Precisão/tendências , Projetos de Pesquisa , Estados UnidosRESUMO
Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.
Assuntos
Antineoplásicos/uso terapêutico , Fasciite/terapia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Mesilato de Imatinib/uso terapêutico , Leucemia/terapia , Dermatopatias/terapia , Adolescente , Adulto , Criança , Esquema de Medicação , Fasciite/imunologia , Fasciite/patologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Articulações/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Leucemia/imunologia , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Projetos Piloto , Prednisona/uso terapêutico , Amplitude de Movimento Articular/efeitos dos fármacos , Recidiva , Dermatopatias/imunologia , Dermatopatias/patologia , Tacrolimo/uso terapêutico , Transplante HomólogoRESUMO
Exciting recent advancements in deep-sequencing technology have enabled a rapid and cost-effective molecular characterization of patient-derived tumor samples. Incorporating these innovative diagnostic technologies into early clinical trials could significantly propel implementation of precision medicine by identifying genetic markers predictive of sensitivity to agents. It may also markedly accelerate drug development and subsequent regulatory approval of novel agents. Particularly noteworthy, a high-response rate in a Phase II trial involving a biomarker-enriched patient cohort could result in a regulatory treatment approval in rare histologies, which otherwise would not be a candidate for a large randomized clinical trial. Furthermore, even if a trial does not meet its statistical endpoint, tumors from a few responders should be molecularly characterized as part of the new biomarker-mining processes. In order to accommodate patient screening and accelerate the accrual process, institutions conducting early clinical trials need to be a part of a multi-institution clinical trials network. Future clinical trial design will incorporate new biomarkers discovered by a 'phenotype-to-genotype' effort with an appropriate statistical design. To help advance such changes, the National Cancer Institute has recently reformed the existing early phase clinical trials network. A new clinical trial network, the Experimental Therapeutics Clinical Trials Network (ET-CTN), was begun and, in addition to its pre-existing infrastructure, an up-to-date clinical trial registration system, clinical trial monitoring system including electronic database and a central Institutional Review Board were formed. Ultimately, these reforms support identifying the most appropriate therapy for each tumor type by incorporating state-of-the-art molecular diagnostic tools into early clinical trials.
Assuntos
Antineoplásicos/farmacologia , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/métodos , Desenho de Fármacos , Marcadores Genéticos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Medicina de Precisão , Antineoplásicos/economia , Ensaios Clínicos Fase I como Assunto/economia , Ensaios Clínicos Fase II como Assunto/economia , DNA de Neoplasias/análise , Humanos , Terapia de Alvo Molecular/economia , National Cancer Institute (U.S.) , Neoplasias/genética , Neoplasias/metabolismo , Medicina de Precisão/economia , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Projetos de Pesquisa/tendências , Pesquisadores , Apoio à Pesquisa como Assunto , Estados UnidosRESUMO
BACKGROUND: A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. METHODS: In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. RESULTS: Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. CONCLUSIONS: AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/sangue , Cisplatino/farmacocinética , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/sangue , Etoposídeo/farmacocinética , Feminino , Gossipol/administração & dosagem , Gossipol/efeitos adversos , Gossipol/análogos & derivados , Gossipol/sangue , Gossipol/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismoRESUMO
BACKGROUND: Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. METHODS: Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p = 0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9-6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. CONCLUSIONS: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Osso e Ossos/enzimologia , Colágeno Tipo I/sangue , DNA de Neoplasias/genética , Dasatinibe , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Peptídeos/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Análise de Sequência de DNA , Taxoides , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/farmacologia , Resultado do Tratamento , Quinases da Família src/antagonistas & inibidoresRESUMO
Treatment of BCR-ABL1(+) leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR-ABL1(+) acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR-ABL1(+) leukemia cells by blocking both calcineurin/NFAT signaling and BCR-ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA-interference we confirm that calcineurin inhibition sensitizes BCR-ABL1(+) cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co-administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti-leukemia benefit of co-administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia.