RESUMEN
BACKGROUND: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma. METHODS: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12). RESULTS: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy. CONCLUSIONS: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Liposarcoma/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Indazoles , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estudios Prospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Condrosarcoma/tratamiento farmacológico , Cordoma/tratamiento farmacológico , Dasatinib/uso terapéutico , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Tumores Fibrosos Solitarios/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Neoplasias Óseas/mortalidad , Condrosarcoma/mortalidad , Cordoma/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Sarcoma de Parte Blanda Alveolar/mortalidad , Tumores Fibrosos Solitarios/mortalidad , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODS: Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%. RESULTS: A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients. CONCLUSIONS: Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity.
Asunto(s)
Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Teorema de Bayes , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Resultado del TratamientoRESUMEN
PURPOSE: Aggressive fibromatoses (AF; desmoid tumors) are rare clonal neoplastic proliferations of connective tissues that can be locally aggressive despite wide surgical resection and/or radiation therapy. The Sarcoma Alliance for Research through Collaboration (SARC) initiated a prospective phase II trial to investigate the outcome of patients treated with imatinib, a multiple tyrosine kinase inhibitor, in patients with AF, or 1 of 10 sarcoma subtypes. Here, we report specifically on the outcome of patients with AF as well as evaluations undertaken to examine the mechanism of imatinib. EXPERIMENTAL DESIGN: Patients ≥10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg twice daily [body surface area (BSA) ≥ 1.5 m(2)], 200 mg twice daily (BSA = 1.0-1.49 m(2)), or 100 mg twice daily (BSA < 1.0 m(2)). Response outcomes at 2 and 4 months were assessed. Tissue specimens were analyzed by immunohistochemistry for expression of cKIT, platelet-derived growth factor receptor α (PDGFRα), PDGFRß, AKT, PTEN, FKHR, and ß-catenin. Tumor DNA was analyzed for PDGFRα exon 18 and APC mutations by allelic discrimination PCR. RESULTS: Fifty-one patients were enrolled. The median number of prior regimens was 1. Kaplan-Meier estimates of 2- and 4-month progression-free survival rates were 94% and 88%, respectively, and 1-year progression-free survival was 66%. Objective response rate was 6% (3 of 51). Expression and polymorphisms of target proteins were identified in tissue samples, but no significant correlation with outcome was observed using the samples available. CONCLUSION: Imatinib may have a role in the management of unresectable or difficult to resect desmoid tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Fibromatosis Agresiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Benzamidas , Niño , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fibromatosis Agresiva/diagnóstico , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide. PATIENTS AND METHODS: Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m(2) 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m(2) 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images. RESULTS: Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted. CONCLUSION: Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.
Asunto(s)
Antraciclinas/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Dioxoles/administración & dosificación , Resistencia a Antineoplásicos , Ifosfamida/uso terapéutico , Leiomiosarcoma/tratamiento farmacológico , Liposarcoma/tratamiento farmacológico , Tetrahidroisoquinolinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/efectos adversos , Australia , Dioxoles/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Europa (Continente) , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Leiomiosarcoma/secundario , Liposarcoma/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , América del Norte , Modelos de Riesgos Proporcionales , Medición de Riesgo , Tetrahidroisoquinolinas/efectos adversos , Factores de Tiempo , Trabectedina , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
PURPOSE The purpose of this trial was to assess the efficacy of imatinib in patients with one of 10 different subtypes of advanced sarcoma. PATIENTS AND METHODS Eligible patients were treated daily with imatinib dosed at 300 mg twice a day (for body-surface area > or = 1.5 m(2)). The primary end point was response (clinical benefit response [CBR]), defined as complete (CR) or partial response (PR) at 2 months, or stable disease, CR, or PR at 4 months. Rules for early termination within each disease type were based on a Bayesian hierarchical probability model (BHM) accounting for correlation of the responses of the 10 subtypes. Available tissue samples were analyzed for molecules within the KIT/platelet-derived growth factor receptor (PDGFR) signal transduction pathway. Results One hundred eighty-five assessable patients with one of 10 subtypes of sarcoma were treated. One CR and three PRs were achieved. A CBR was achieved in 28 patients treated overall and by subtype: two angiosarcomas (n = 16), 0 Ewing (n = 13), one fibrosarcoma (n = 12), six leiomyosarcomas (n = 29), seven liposarcomas (n = 31), three malignant fibrous histiocytomas (n = 30), five osteosarcomas (n = 27), one malignant peripheral-nerve sheath tumor (n = 7), 0 rhabdomyosarcoma (n = 2), and three synovial sarcomas (n = 22). Variable expression and mutations within the KIT/PDGFR pathway were observed. CONCLUSION This is the first phase II study of a new agent in sarcoma to include sufficient patients with each of the common histologic subtypes to permit generalizable conclusions. The BHM is an effective method for studying rare diseases and their subtypes, when it is reasonable to assume that their response rates are exchangeable. Although rare dramatic responses were seen, imatinib is not an active agent in advanced sarcoma in these subtypes.
Asunto(s)
Antineoplásicos/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Benzamidas , Supervivencia sin Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma. METHODS: In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m(2) immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m(2) on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed. RESULTS: Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m(2) and doxorubicin 60 mg/m(2). Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration. CONCLUSION: The combination of doxorubicin 60 mg/m(2) followed by trabectedin 1.1 mg/m(2) every 21 days is safe and active in patients with soft-tissue sarcoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sarcoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Dioxoles/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Leiomiosarcoma/sangre , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/patología , Liposarcoma/sangre , Liposarcoma/tratamiento farmacológico , Liposarcoma/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Sarcoma/sangre , Sarcoma/patología , Tasa de Supervivencia , Tetrahidroisoquinolinas/administración & dosificación , Trabectedina , Adulto JovenRESUMEN
PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a highly fatal, mainly peritoneal cell origin cancer which predominantly affects young adult males. This predilection in young males led us to examine the role of androgen receptors (AR), testosterone, and growth factors in the biology of DSRCT. METHODS: Slides were prepared from 27 multi-institutional patients all with end-stage DSRCT. Slides were stained for AR, c-Kit, various growth factors, and drug resistance-associated proteins. Immunohistochemical (IHC) expression was scored semi-quantitatively. Western blot and MTT studies were performed to validate the IHC findings of over-expression of the AR and its functional status by stimulation of growth by dihydrotestosterone, respectively. Six patients with positive AR status were treated solely with combined androgen blockade (CAB) as used for prostate cancer. RESULTS: Twenty-two patients were male (81%) and five were female (19%) with a median age at diagnosis of 23. All patients had failed at least two prior multi-agent chemotherapy regimens and 44% had progressed after autologous stem cell transplant. DSRCT samples from 10 of 27 patients were >or=2+ IHC positive for AR (37%,P=0.0045) and 7 of 20 patients were >or=2+ IHC positive for c-Kit (35%, P=0.018). We found elevated IHC expression of GST-pi, MRP and thymidylate synthase in smaller subsets of patients. In vitro studies for AR by Western blot and stimulation of growth by dihydrotestosterone in MTT assays suggest that the AR in DSRCT cells is functional. Six patients with positive AR status were treated with CAB alone and three of six attained clinical benefit (1-PR, 1-MR, 1-SD) in a range of 3-4 months. The three patients who responded to CAB had normal testosterone levels before CAB, while the three who did not respond to CAB had baseline castrate levels of testosterone. CONCLUSIONS: DSRCT has significant IHC expression of AR and c-Kit in heavily pre-treated patients. The presence of significant AR expression in 37% suggests that these patients could possibly respond to CAB. The significance of c-Kit expression in 35% of DSRCT patients is unknown and warrants further investigation.
Asunto(s)
Carcinoma de Células Pequeñas/química , Proteínas Proto-Oncogénicas c-kit/análisis , Receptores Androgénicos/análisis , Neoplasias de los Tejidos Blandos/química , Adolescente , Adulto , Anciano , Carcinoma de Células Pequeñas/tratamiento farmacológico , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Lactante , Masculino , Persona de Mediana Edad , Receptor ErbB-2/análisis , Neoplasias de los Tejidos Blandos/tratamiento farmacológicoRESUMEN
PURPOSE: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. EXPERIMENTAL DESIGN: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. RESULTS: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. CONCLUSIONS: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carmustina/administración & dosificación , Carmustina/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/análogos & derivados , Humanos , Inmunohistoquímica , Lactante , Inyecciones Intravenosas , Leiomiosarcoma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Análisis de Supervivencia , Taquicardia Supraventricular/inducido químicamente , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
The incidence of breast cancer increases with age. This trial evaluated the efficacy and safety of oral UFT (ftorafur plus uracil) plus leucovorin in elderly patients with advanced breast cancer. Eligibility criteria included age > or =65 years, locally advanced or metastatic breast cancer, < or =1 prior chemotherapy regimens in the setting of metastatic disease, performance status 0-2, and adequate end-organ function. UFT at 300 mg/m2 per day as 2 divided doses and 30 mg leucovorin with each dose were administered orally daily for 21 days, followed by a 7-day rest period. Ten patients were accrued. Six patients received treatment in their first relapse and 3 in their second. One patient was chemotherapy-naive. The dose-limiting toxicity was diarrhea with grade 3 or 4 diarrhea occurring more often in the oldest patients (1 of 6 patients between 65 and 69 vs. 3 of 4 patients > or =70 years old). Protocol treatment was discontinued in 2 patients (ages 78 and 83) secondary to severe gastrointestinal toxicity. One patient achieved a partial response. Although UFT/leucovorin had efficacy in 1 patient, toxicity in the patients over 70 years of age was increased. Careful evaluation of anticancer drug toxicity in very elderly patients is important as our population ages.