RESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha. PATIENTS AND METHODS: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites. RESULTS: Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life. CONCLUSION: No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.
Assuntos
Antineoplásicos/administração & dosagem , Isoenzimas/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/administração & dosagem , Proteína Quinase C/efeitos dos fármacos , Tionucleotídeos/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Área Sob a Curva , Terapia Combinada , Relação Dose-Resposta a Droga , Eletroforese Capilar , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/terapia , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/sangue , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Proteína Quinase C-alfa , Tionucleotídeos/efeitos adversos , Tionucleotídeos/sangue , Tionucleotídeos/farmacocinética , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Recipients of allogeneic bone marrow transplants (BMTs) who have relapsed may attain complete remissions when treated with transfusions of leukocytes obtained from the original bone marrow donor. We performed a retrospective study to characterize better this new treatment modality. PATIENTS AND METHODS: We surveyed 25 North American BMT programs regarding their use of donor leukocyte infusions (DLI). Detailed forms were used to gather data regarding the original BMT, relapse, DLI, response to DLI, complications of DLI, and long-term follow-up evaluation. Reports of 140 patients were thus available for analysis. RESULTS: Complete responses were observed in 60% (95% confidence interval [CI], 51.9% to 68.1%) of chronic myelogenous leukemia (CML) patients who received DLI and did not receive pre-DLI chemotherapy; response rates were higher in patients with cytogenetic and chronic-phase relapse (75.7%; 95% CI, 68.2% to 83.2%) than in patients with accelerated-phase (33.3%; 95% CI, 19.7% to 46.9%) or blastic-phase (16.7%; 95% CI, 1.9% to 31.9%) relapse. The actuarial probability of remaining in complete remission at 2 years was 89.6%. Complete remission rates in acute myelogenous leukemia (AML) (n = 39) and acute lymphocytic leukemia (ALL) (n = 11) patients who had not received pre-DLI chemotherapy were 15.4% (95% CI, 9.6% to 21.2%) and 18.2% (95% CI, 6.6% to 29.8%), respectively. Complete remissions were also observed in two of four assessable myeloma patients and two of five assessable myelodysplasia patients. Complications of DLI included acute graft-versus-host disease (GVHD) (60%; 95% CI, 51.4% to 68.6%), chronic GVHD (60.7%; 95% CI, 50.3% to 71.1%), and pancytopenia (18.6%; 95% CI, 12.2% to 25.0%). Pre-DLI characteristics predictive of complete response in CML patients were post-BMT chronic GVHD, pre-DLI disease status of chronic phase, and time interval between BMT to DLI less than 2 years. Acute and chronic GVHD post-DLI were highly correlated with disease response (P < .00001). CONCLUSION: DLI results in complete remissions in a high percentage of patients with relapsed chronic-phase CML. Complete remissions are observed less frequently in patients with advanced CML and acute leukemia. GVHD and pancytopenia occur commonly; GVHD is highly correlated with response.
Assuntos
Neoplasias Hematológicas/terapia , Leucócitos , Análise Atuarial , Adolescente , Adulto , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/imunologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Doadores de Tecidos , Transplante Homólogo , Resultado do TratamentoRESUMO
The purpose of this study was to determine the safety and antitumor activity of IFN-gamma retroviral vector in patients with advanced melanoma. Seventeen patients (9 single courses, 8 multiple courses) received a total of 363 intratumor injections of IFN-gamma retroviral vector (1 x 10(7) PFU/ml administered at 0.3, 0.5, and 1.0 ml per cohort). No grade III/IV adverse events were attributed to study medication. Replication-competent retrovirus was not detected in any of the 17 patients by polymerase chain reaction studies. Eight patients showed elevated anti-tumor antibody responses in comparison with baseline by ELISA. One of nine patients treated with a single course had an optimal response of stable disease, compared with eight of eight multiple-injected patients. Median survival of single-injected patients was 150 days, and patients who received multiple injections have still not achieved median survival duration, with four of eight still living (p = 0.0462, Wilcoxon; p = 0.0273, log rank). We conclude that intratumor injection of IFN-gamma is safe and well tolerated. Evidence of antitumor activity is suggested in patients with advanced malignancy that received multiple injections.
Assuntos
Antineoplásicos/uso terapêutico , Terapia Genética/métodos , Vetores Genéticos , Interferon gama/uso terapêutico , Melanoma/secundário , Melanoma/terapia , Vírus da Leucemia Murina de Moloney , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antineoplásicos/imunologia , Antineoplásicos/imunologia , Estudos de Coortes , Feminino , Terapia Genética/efeitos adversos , Humanos , Injeções , Interferon gama/genética , Interferon gama/imunologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Células Tumorais CultivadasRESUMO
BACKGROUND: Interferon-gamma (IFN-gamma) gene/retroviral vector cell vaccinations have generated protective responses from unmodified tumor cell challenges as well as a regression of established tumors in animal models. The purpose of this trial was to determine the feasibility and safety of a direct intratumoral injection of IFN-gamma retroviral vector in advanced melanoma patients. METHODS: This was a phase I study, in which 13 patients received a single daily injection of a retroviral vector with the IFN-gamma gene for 5 consecutive days (1.5 x 10(8) colony-forming units total dose); patients subsequently underwent resection of the injected lesion to confirm DNA transduction in situ. RESULTS: No toxicity related to the injected vector was observed. Replication competent retrovirus was not observed in any prepared samples (n = 65). IFN-gamma expression was confirmed in 3 of 10 harvested tumor samples; one was equivocal, and DNA transduction was unable to be confirmed by enzyme-linked immunospot assay in six samples. CONCLUSIONS: An injection of IFN-gamma gene/retroviral vector is well tolerated. DNA transduction was demonstrated in human subjects, confirming the feasibility of the direct injection approach for the gene therapy of solid tumors. Further trials to determine optimal schedule and potential efficacy are indicated.
Assuntos
Terapia Genética/efeitos adversos , Interferon gama/uso terapêutico , Melanoma/terapia , Retroviridae/genética , Adulto , Idoso , DNA Viral/genética , Feminino , Vetores Genéticos/efeitos adversos , Humanos , Injeções Intralesionais , Interferon gama/genética , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Resultado do Tratamento , Integração ViralRESUMO
The purpose of this study was to determine the safety of treating melanoma patients with retroviral vector-mediated interferon (IFN)-gamma gene-transduced autologous tumor cells. We designed a phase I study, in which irradiated, autologous, transduced melanoma cells expressing the IFN-gamma gene were injected subcutaneously every 2 weeks with escalating cell doses for six injections. Tumor tissue was harvested from 58 patients with metastatic melanoma. Twelve patients had sufficient expansion of autologous tumor (0.56-160 x 10(7) cells) and adequate IFN-gamma expression after gene transduction (2-79,000 U/10(6) cells/24 hours) for injections. Five patients received injections. No toxicity was attributed to the IFN-gamma retroviral vector in the patients injected. One of the injected patients remains disease-free after 13 injections, following the surgical removal of brain, adrenal, and lung metastases. We found that injections of autologous tumor cells transduced by IFN-gamma gene were well tolerated. However, the ability to develop primary autologous melanoma cell lines was limited, and only a minority of patients were injected.
Assuntos
Terapia Genética/métodos , Interferon gama/genética , Interferon gama/uso terapêutico , Melanoma/secundário , Melanoma/terapia , Adolescente , Adulto , Idoso , Anticorpos Antineoplásicos/sangue , Feminino , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Humanos , Injeções , Interleucina-2/uso terapêutico , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Pessoa de Meia-Idade , Transplante de Neoplasias , Retroviridae/genética , Taxa de Sobrevida , Resultado do Tratamento , Células Tumorais Cultivadas/efeitos da radiação , Células Tumorais Cultivadas/virologiaRESUMO
This study determines the prognostic role of c-fos protein expression in patients with colon cancer who previously failed therapy with 5-fluorouracil (5-FU). Patients with advanced colorectal who were refractory to 5-FU therapy received irinotecan (CPT-11) by a 90-minute intravenous infusion at a dose of 125 mg/m2 weekly for four weeks followed by a 2-week rest period were eligible for oncogene assessment. C-fos protein expression was evaluated using archival formalin-fixed, paraffin-embedded tumor tissue, and an automated immunoperoxidase histochemical technique. Thirty-five patients were found to have > 25% positive c-fos activity. Nine patients had no detectable c-fos expression. Characteristics of patient subgroups were not different, however, the median survival of patients with elevated c-fos expression from the time of treatment with CPT-11 was 436 days, whereas patients with no detectable c-fos expression had a median survival of 365 days (p = 0.045). C-fos exhibits a casual role in the initiation of apoptosis and is implicated in differentiation and proliferation. It has been shown to correlate with poor survival in breast cancer, but improved survival in patients with astrocytic glioma. In this analysis, there is a suggestion that elevated c-fos expression is a good prognostic marker for patients with refractory colorectal carcinoma.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Adulto , Idoso , Camptotecina/uso terapêutico , Neoplasias Colorretais/mortalidade , Feminino , Fluoruracila/uso terapêutico , Humanos , Técnicas Imunoenzimáticas , Irinotecano , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Falha de TratamentoRESUMO
We determined the prognostic role of K-ras mutation in tumor tissue of patients with refractory colon cancer who received Marimastat (BB2516). DNA was extracted from paraffin-stored tumor tissue of 27 patients who previously failed 5-fluorouracil and were treated with BB2516. The presence of K-ras mutation was characterized by Polymerase Chain Reaction using ras- and p53-specific primers. ras and p53 oncoprotein expression was analyzed by an automated biotin-avidin immunoproxidase technique. Seventeen patients had a normal K-ras sequence and 10 patients had a K-ras mutation. Median survival of patients with a normal ras sequence was 330 days from the time of BB2516 treatment compared with 160 days for patients with a K-ras mutation (p = 0.0442, Wilcoxon; 0.0130 Log-Rank). No differences in age, sex, cancer stage, surgical treatment, or chemotherapy treatment were observed. Abnormalities involving ras expression did not affect survival. By comparison, median survival for patients with p53 mutation or p53 overexpression was both 158 days after BB2516 treatment. Patients having both K-ras and p53 mutations had the poorest median survival of 113 days (p = 0.035). There is a suggestion by univariate analysis that the presence of a K-ras mutation may predict survival in patients with progressive colon cancer. Further assessment with larger patient numbers and multivariate analysis is indicated.