RESUMEN
BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.
Asunto(s)
Adenina/análogos & derivados , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Sulfonamidas , Adulto , Humanos , Anciano , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Japón , Piperidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan. METHODS: Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1-28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1-10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed. RESULTS: Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61-84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome. CONCLUSIONS: The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events.
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Leucemia Mieloide Aguda , Síndrome de Lisis Tumoral , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/uso terapéutico , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndrome de Lisis Tumoral/etiología , Síndrome de Lisis Tumoral/prevención & control , Síndrome de Lisis Tumoral/tratamiento farmacológicoRESUMEN
BACKGROUND: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients. METHODS: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle. RESULTS: Median follow-up was 16.3 months (range, 1.0-20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation. CONCLUSIONS: This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.
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Azacitidina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes , Humanos , Japón/epidemiología , Leucemia Mieloide Aguda/tratamiento farmacológico , SulfonamidasRESUMEN
BACKGROUND: Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to co-morbidities. METHODS: In this phase 1/2 study (NCT02265731), Japanese patients (≥60 years) with untreated (ineligible for induction chemotherapy) or relapsed/refractory acute myeloid leukaemia received oral venetoclax 400 mg/day (3-day ramp up in cycle 1) plus subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 per 28-day cycle until disease progression or unacceptable toxicity. RESULTS: As of 10 December 2019, six patients were enrolled (median age: 75 years; untreated: n = 5; relapsed/refractory: n = 1); median treatment duration: 10.3 months (range, 0.7-29.4). Most common grade ≥ 3 adverse events were lymphopaenia and febrile neutropaenia (n = 4 each). Four patients reported serious adverse events; only an event of grade 3 fungal pneumonia was considered possibly related to both study drugs, requiring dose interruption of venetoclax and delay of azacitidine. Five (83%) patients had responses (complete remission: n = 3). Median time to first response of complete remission/complete remission with incomplete count recovery was 1.0 month (range, 0.8-5.5); median overall survival: 15.7 months (95% confidence interval: 6.2, not reached). CONCLUSIONS: Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Azacitidina/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Humanos , Japón/epidemiología , Leucemia Mieloide Aguda/mortalidad , Masculino , Inducción de Remisión , Sulfonamidas/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27). METHODS: VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1-28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1-10). The primary endpoint was median overall survival. RESULTS: In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each). CONCLUSIONS: Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy.
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Citarabina , Leucemia Mieloide Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes , Citarabina/uso terapéutico , Humanos , Japón , Leucemia Mieloide Aguda/tratamiento farmacológico , SulfonamidasRESUMEN
BACKGROUND: Interstitial lung disease (ILD) is important drug related toxicity because it commonly forced to discontinue the treatment. METHODS: To characterize the prevalence and patterns of pemetrexed induced ILD, an independent ILD advisory board composed of external experts performed reassessment of ILD in two post marketing surveillance (PMS) studies for malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). RESULTS: ILD incidences were originally 1.6% and 2.6% in 903 MPM and 683 NSCLC patients in safety analyses, respectively. Based on the reassessment by the board, the incidence was 1.1% MPM and 1.8% NSCLC. Common possible risk factors of ILD in MPM and NSCLC patients were male gender, 60 years or older age, and pre-existing ILD. Asbestosis in MPM, and smoking history in NSCLC are also considered as risk, respectively. In terms of computed tomography (CT) pattern, 7 of 10 cases in MPM patients had acute interstitial pneumonia pattern, which four were fatal. Eight of the 12 NSCLC patients had diffuse grand glass opacity, which all had recovered. Onset of ILD in MPM varied between the first and the fifth courses of pemetrexed treatment, and the latest onset was 48 days after the last administration. For NSCLC, it was between the second and the ninth course, 7 and 56 days after the last administration. CONCLUSIONS: The risk of pemetrexed-related ILD is similar level as other anti-cancer drugs under clinical settings. Careful observations continuously during and at least for 2 months after the last administration of pemetrexed are advised.
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Antineoplásicos/efectos adversos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Pemetrexed/efectos adversos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Enfermedades Pulmonares Intersticiales/patología , Masculino , Mesotelioma/tratamiento farmacológico , Persona de Mediana Edad , Vigilancia de Productos Comercializados , Factores de RiesgoRESUMEN
The safety and effectiveness of pemetrexed(PEM)in patients with non-small cell lung cancer(NSCLC)were reviewed using data from post-marketing surveillance. Among 699 patients registered from June 2009 to May 2010, 683 patients were analyzed(343, first-line therapy: 340, second-line therapy or beyond). Patient backgrounds were as follows: median age=65 years(16.1%B75 years old); 64.7% male; 91.9% performance status 0-1; 83.2% Stage IV; 99.0% non-squamous cell cancer. Also, 86% of the first-line and 20% of the second-line cohort were receiving a concomitant anti-cancer drug(mostly platinum agents). The incidence rate of adverse drug reactions(ADR)was 76.7%, including serious cases(18.0%). The most common ADRs were decreased white blood cell count(26.8%), decreased neutrophil count(25.3%), anemia(19.2%), decreased platelet count(17.0%), and nausea(23.0%). The incidence of interstitial lung disease, which is a concern during chemotherapy, was 2.6%. Peripheral neuropathy and alopecia, events influencing a patient's quality of life, were less than 1%. The estimated median survival time was 23.2 months[95%CI: 19.8 months-not calculable]in the first-line cohort, and 11.8 months[95% CI: 10.5-13.7 months]in the B second-line cohort. The surveillance results showed no apparent difference in total ADRs in this current study compared to the safety profile established in clinical trials previously conducted in Japan and overseas. These results demonstrate the safety and effectiveness of PEM treatment for NSCLC patients in daily clinical settings.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Femenino , Glutamatos/efectos adversos , Guanina/efectos adversos , Guanina/uso terapéutico , Humanos , Japón , Neoplasias Pulmonares/patología , Masculino , Mercadotecnía , Persona de Mediana Edad , Estadificación de Neoplasias , Pemetrexed , Resultado del TratamientoRESUMEN
OBJECTIVE: Gemcitabine was approved for the treatment of biliary tract cancer in 2006 in Japan. While biliary tract cancer is usually associated with patients 70 years of age or older and/or those who tend to have underlying liver dysfunction, data on this population were limited in the Japanese Phase II study of gemcitabine. Thus, further evaluation of safety and effectiveness in this population was planned. This special post-marketing surveillance was conducted as an observational study on the use of gemcitabine in a clinical practice setting. METHODS: Gemcitabine-naïve patients with biliary tract cancer were enrolled from 2006 to 2008 and observed over 12 months; one or more doses of gemcitabine were administered during the period. Data such as patient background, treatment details, adverse events occurring during the observational period, laboratory values of liver enzyme and survival status were collected 3 and 12 months after the start of therapy. RESULTS: Of the 285 patients registered for the study, 260 were included in the analysis. The mean age was 66.9 years. There were 120 patients (46.2%) classified as elderly (70 years or older). Haematotoxicities were the most common adverse drug reactions. In the elderly and the non-elderly, adverse drug reactions (serious) occurred in 48.3% (20.8%) and 50.7% (12.9%), respectively. The overall estimated 1-year survival rate was 52.5% (95% confidence interval, 45.9-58.7%). CONCLUSIONS: In line with previous clinical and post-marketing studies conducted in Japan, the results of this study suggest that gemcitabine could be used safely and effectively for biliary tract cancer patients including the elderly.
Asunto(s)
Neoplasias del Sistema Biliar/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Vigilancia de Productos Comercializados , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Pueblo Asiatico , Neoplasias del Sistema Biliar/etnología , Neoplasias del Sistema Biliar/metabolismo , Biomarcadores de Tumor/análisis , Antígeno CA-19-9/análisis , Antígeno Carcinoembrionario/análisis , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Exantema/inducido químicamente , Femenino , Fiebre/inducido químicamente , Humanos , Japón , Estimación de Kaplan-Meier , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven , GemcitabinaRESUMEN
To elucidate the detailed profiles of major adverse events associated with gemcitabine hydrochloride, such as myelosuppression and interstitial pneumonitis (IP), we reanalyzed the results from Japanese clinical studies conducted by Eli Lilly Japan K. K. in patients with various types of cancer. Myelosuppression was clearly apparent after starting therapy at 2-3 weeks in the 28- day course monotherapy group, and at 2 weeks in the 21-day course combination therapy group with paclitaxel, cisplatin, or docetaxel. Increases in the number of courses did not necessarily lead to worsening of myelosuppression. IP possibly related to gemcitabine was seen in 6 out of 5 23 monotherapy patients and 5 out of 233 combination therapy patients. Five of these 11 patients were diagnosed in the first course; however, another patient was diagnosed with IP in Course 6. Two of these patients died of IP, one of whom had a past history of interstitial lung disease. These results indicate that ample attention should be paid to myelosuppression 2-3 weeks after the start of therapy, and to IP during the entire course of therapy.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Desoxicitidina/análogos & derivados , Antimetabolitos Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Humanos , Japón , Enfermedades Pulmonares Intersticiales/inducido químicamente , Células Mieloides/efectos de los fármacos , Neoplasias/tratamiento farmacológico , GemcitabinaRESUMEN
Telisotuzumab vedotin (formerly ABBV-399) is an antibody-drug conjugate targeting c-Met-overexpressing tumor cells, irrespective of MET gene amplification status. Safety, pharmacokinetics, and preliminary efficacy of telisotuzumab vedotin were evaluated outside of Japan. This phase 1 open-label study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Telisotuzumab vedotin was administered intravenously at either 2.4 mg/kg (n = 3) or 2.7 mg/kg (n = 6) every 3 weeks, following a 3 + 3 design. Maximum tolerated dose was not reached on the basis of the study design; no dose-limiting toxicity events were observed. The most common treatment-emergent adverse events related to telisotuzumab vedotin were peripheral sensory neuropathy (44%), and nausea, decreased appetite, and decreased white blood cell count (33% each). Most frequent grade ≥3 treatment-emergent adverse events, irrespective of relationship to telisotuzumab vedotin, were decreased neutrophil count and hypoalbuminemia, reported in two patients (22%) each. Systemic exposure of telisotuzumab vedotin at both dose levels was approximately dose proportional. Pharmacokinetic profile in Japanese patients was similar to that previously reported in non-Japanese patients. Two (22%) patients achieved a partial response, six (67%) had stable disease, one (11%) had progressive disease. Overall disease control rate was 89% (eight of nine patients; 95% confidence interval: 51.8%-99.7%]). Median progression-free survival was 7.1 months (95% confidence interval: 1.2-10.4). In conclusion, telisotuzumab vedotin demonstrated a manageable safety profile, with antitumor activity in Japanese patients with advanced solid tumors; the recommended phase 2 dose was confirmed as 2.7 mg/kg every 3 weeks. ClinicalTrials.gov registration number: NCT03311477.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Inmunoconjugados/efectos adversos , Neoplasias/terapia , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Intervalos de Confianza , Esquema de Medicación , Trastornos de Alimentación y de la Ingestión de Alimentos/inducido químicamente , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacocinética , Japón , Leucopenia/etiología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Supervivencia sin ProgresiónRESUMEN
Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have limited treatment options. Venetoclax is a potent BCL-2 inhibitor that induces apoptosis in CLL cells. This open-label, phase 1/2 study (NCT02265731) evaluated the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with R/R CLL/SLL. Patients enrolled in phase 1 received 400 mg/day venetoclax monotherapy. Patients enrolled in phase 2 received 400 mg/day venetoclax, plus rituximab. Venetoclax was administered with a weekly stepwise ramp-up in doses. In phase 2, efficacy was evaluated by objective response rate (ORR). Twelve patients were enrolled, six in each arm. The most common grade ≥ 3 adverse events were neutropenia (83%), lymphopenia (67%), leukopenia (33%), and thrombocytopenia (17%). Patients receiving venetoclax monotherapy achieved an ORR of 100%, including a complete remission (CR) rate of 17%. Patients receiving combination therapy had an ORR of 67% and a CR rate of 50%. The venetoclax pharmacokinetics profile in Japanese patients was similar to that of Western patients. Venetoclax 400 mg/day monotherapy or in combination with rituximab was well-tolerated and induced promising responses in Japanese patients with R/R CLL/SLL. Although patient numbers were small, the safety profile was largely consistent with other Western studies. Clinical trial registration: clinicaltrials.gov; NCT02265731.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Japón , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Supervivencia sin Progresión , Rituximab/administración & dosificación , Rituximab/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVES: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. MATERIALS AND METHODS: Patients received Rova-T (0.2 or 0.3â¯mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8â¯mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. RESULTS: Rova-T exhibited toxicity that was generally manageable in Japanese patients (Nâ¯=â¯29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. CONCLUSIONS: These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Benzodiazepinonas/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Benzodiazepinonas/administración & dosificación , Benzodiazepinonas/efectos adversos , Benzodiazepinonas/farmacocinética , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Japón , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Recurrencia , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Resultado del TratamientoAsunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pueblos del Este de Asia , Rituximab/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antineoplásicos/uso terapéuticoRESUMEN
PURPOSE: Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies. Although multidisciplinary treatments have been introduced, patients with this disease rarely survive longer than 1 year. These findings prompted us to investigate the antitumor activity of molecular targeting agents in thyroid cancer cells. METHODS: Two tyrosine kinase inhibitors, gefitinib and imatinib, were tested in a poorly differentiated thyroid cancer cell line, KTC-1, and two ATC cell lines, KTC-2 and KTC-3. RESULTS: All cell lines expressed not only a target molecule of gefitinib, HER1, but also a cognate receptor, HER2. They also expressed target molecules of imatinib, c-ABL and platelet-derived growth factor receptors at various levels. Both agents had modest antitumor activity in these cell lines. Combined treatment with gefitinib and imatinib led to an additional antitumor effect. Each agent induced apoptosis and their combined treatment enhanced apoptosis associated with the down-regulation of antiapoptotic proteins, Bcl-2 and Bcl-xL. Moreover, their combined treatment additionally inhibited the growth of KTC-3 xenografts in nude mice. CONCLUSIONS: These are the first findings to suggest that both gefitinib and imatinib have antitumor activity against ATC cells and that their combined use has greater activity than either drug alone.
Asunto(s)
Antineoplásicos/farmacología , Piperazinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Quinazolinas/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Benzamidas , Línea Celular Tumoral , Cartilla de ADN/genética , Sinergismo Farmacológico , Femenino , Gefitinib , Humanos , Mesilato de Imatinib , Ratones , Quinazolinas/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Tiroides/tratamiento farmacológicoRESUMEN
BACKGROUND: Preclinical studies have indicated that BRCA1 functions differentially to modulate the chemosensitivity of cancer cells. PATIENTS AND METHODS: To clarify these findings, BRCA1 expression in primary tumors was evaluated by immunohistochemistry in 50 patients with metastatic breast cancer. RESULTS: BRCA1 expression was absent in 29 (58.0%) out of the 50 breast tumors tested. BRCA1-absent tumors were more frequently progesterone receptor-negative (p=0.019) than BRCA1-present tumors. Taxane-based chemotherapy was administered to 19 patients. Although BRCA1 expression did not relate to the clinical tumor response to taxane-based chemotherapy, time-to-progression (TTP) was significantly shorter in patients with BRCA1-absent tumors than in BRCA1-present tumors (mean+/-SD: 6.5 +/- 4.9 and 14.7 +/- 5.9 months, respectively; p=0.006). The Cox proportional hazard model revealed that BRCA1 absence was an independent predictor of progression (hazard ratio: 3.22; p=0.035). CONCLUSION: These results suggest that the absence of BRCA1 expression is an independent predictor of shorter TTP in advanced breast cancer patients treated with taxane-based chemotherapy.
Asunto(s)
Proteína BRCA1/biosíntesis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Paclitaxel/uso terapéutico , Taxoides/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/deficiencia , Neoplasias de la Mama/patología , Difosfonatos/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Inmunohistoquímica , Acetato de Medroxiprogesterona/administración & dosificación , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pamidronato , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Taxoides/administración & dosificación , Trastuzumab , Resultado del TratamientoRESUMEN
Thymidilate synthase (TS) is a major target of 5-fluorouracil (5-FU) and dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the degradation of 5-FU. Intratumoral activity and expression levels of both enzymes are suggested to be predictive markers for response to 5-FU-based chemotherapy in cancer patients. Several different methods are used to measure intratumoral levels of TS and DPD. We developed new enzyme-linked immunosorbent assays (ELISAs) for these enzymes. New ELISAs were produced using anti-TS and anti-DPD polyclonal antibodies obtained using recombinant human TS and purified DPD from pig liver, respectively. Intra-assay coefficients of variations (CVs) were less than 5% in both ELISAs. Inter-assay CVs tested using the extract from 20 breast cancer specimens were 1.5-24.2% for TS-ELISA and 0.4-7.2% for DPD. Importantly, TS and DPD levels measured by the respective ELISAs closely related to TS activity (r(2)=0.8492) and DPD activity (r(2)=0.7666), respectively, measured by the respective substrate assays. To investigate the correlations between clinicopathological characteristics and intratumoral TS and DPD levels, data on 52 breast cancer patients were analyzed. Estrogen receptor (ER)-negative tumors had significantly higher TS and DPD levels than ER-positive tumors. Progesterone receptor (PgR)-negative tumors showed a significantly higher DPD level than PgR-positive tumors. There was no significant correlation of the TS or DPD levels with other clinicopathological factors in this preliminary study. Further studies are warranted to investigate predictive and prognostic values of intratumoral TS and DPD levels in various malignancies using these ELISAs.
Asunto(s)
Neoplasias de la Mama/enzimología , Dihidrouracilo Deshidrogenasa (NADP)/análisis , Ensayo de Inmunoadsorción Enzimática/métodos , Regulación Neoplásica de la Expresión Génica , Timidilato Sintasa/análisis , Neoplasias de la Mama/diagnóstico , Dihidrouracilo Deshidrogenasa (NADP)/inmunología , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Regulación Enzimológica de la Expresión Génica , Humanos , Estándares de Referencia , Timidilato Sintasa/inmunología , Timidilato Sintasa/metabolismoRESUMEN
Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Estradiol/análogos & derivados , Genes erbB-1/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Antineoplásicos Hormonales/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Fulvestrant , Gefitinib , Regulación de la Expresión Génica/genética , Genes erbB-1/genética , Humanos , Quinazolinas/farmacología , Transducción de Señal/genéticaRESUMEN
We reviewed therapeutic effects and harmful side effects in 33 patients with advanced or recurrent breast cancer who underwent treatment with Anastrozole 1 mg/day in our department. The patients ranged in age from 40 to 83 years old (median, 59). The Performance Status was 0-2, and there was 1 case of advanced breast cancer and 32 cases of recurrent breast cancer. The duration of disease was from 5 to 233 months (median, 50 months). The estrogen and/or progesterone receptor-positive rate was 72.7%. Metastatic sites were in multiple organs in 9 cases, in the lung only in 1 case, in bone only in 12 cases, and in soft tissue only in 10 cases. First-line therapy was used in 10 cases, second-line therapy in 6 cases, and above third-line therapy in 17 cases. There was a complete response in 3 cases, partial response in 5 cases, no long change in 13 cases, no change in 9 cases, and progressive disease in 3 cases. The response rate was 24.3%, The response period ranged from 2 to 22 months (median, 8 months), and clinical benefit was achieved in 63.7%. The clinical benefit rates for first-line were 60%, second-line 83.3% and above third-line therapy 58.8%. The response rate for patients with breast cancer resistant to Anthracyclines and/or Taxanes was 20%. Time-to-progression ranged from 2 to 28 months (median, 11 months), and overall survival ranged from 7 to 30 months (median, 15 months). The most frequent harmful side effects were rise in total cholesterol, general fatigue, hot flashes and arthralgia (9.1%). In this study, we confirmed the availability and safety of Anastrozole, which was suggested to be a useful drug in salvage therapy for patients having resistance to Anthracyclines and/or Taxanes, not only but also useful as a first- or second-line therapy.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nitrilos/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anastrozol , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Colesterol/sangre , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Terapia Recuperativa , Tasa de SupervivenciaRESUMEN
Our department recently began using paclitaxel in treating patients with breast cancer. Retrospective analysis was conducted to clarify its clinical usefulness. Forty-one patients with metastatic breast cancer were treated with paclitaxel between November 2000 and September 2002. Hospital records of the patients, except for one unsensored patient, were retrospectively reviewed. Characteristics of the patients were as follows: age, 36-81 Y (median, 56); 8 stage IV and 32 recurrent diseases; most frequent dominant site of metastasis was the liver (22 patients, 55%); number with previous chemotherapy was 0-5 (median, 2); anthracycline-based treatment and docetaxel treatment were previously performed in 21 (53%) and 15 (38%) patients, respectively; weekly dose of paclitaxel was 30-150 mg/body (median, 100); and total dose administered was 600-6, 480+ mg/body (median, 1,820). Objective response and clinical benefit rates were 35% and 80%, respectively. Median duration of response, time-to-progression and overall survival were 27+, 33+ and 41.5 weeks, respectively. Common adverse events were sensory neuropathy (45%) and nausea/vomiting (37.5%). Most were graded as 1 or 2. Various agents, such as hormonal agents and trastuzumab, were administered with paclitaxel in 26 patients (65%). No significant difference was observed in efficacy or toxicity among patients treated with paclitaxel alone or paclitaxel plus other agents. Paclitaxel seems to be a feasible, safe and active agent for patients with metastatic breast cancer.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/farmacología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Mama/patología , Docetaxel , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Hepáticas/secundario , Persona de Mediana Edad , Náusea/inducido químicamente , Recurrencia Local de Neoplasia/patología , Paclitaxel/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/farmacología , Trastuzumab , Vómito Precoz/etiologíaRESUMEN
Irinotecan hydrochloride has been administered to patients with breast cancer resistant to anthracyclines and/or taxanes in our department. A retrospective analysis of the efficacy and toxicity of irinotecan therapy was conducted to clarify its clinical usefulness. A total of 35 consecutive patients with advanced or recurrent breast cancer were treated with irinotecan between June 1996 and March 2002. The patients ranged in age from 37 to 66 years old (median, 52). The most frequent metastatic lesion was in the liver. The number of previous chemotherapy was 2 to 7 regimens (median, 3). Ninety-one percent and 97% of the tumors were anthracycline- and taxane-resistant, respectively. The weekly dose of irinotecan was 40-160 mg/body (median, 100), and the total dose was 40-6, 110 mg/body (median, 840). An objective response rate of 6% and a clinical benefit rate of 23% were obtained. The median time-to-progression and overall survival were 3 months and 8 months, respectively. Severe toxicity (grade 3 or 4) was observed in 34% of the patients for a decrease in the white blood count, in 26% for neutropenia, in 17% for nausea/vomiting and in 6% for diarrhea. Although this study suggests that irinotecan is a clinically useful treatment of anthracycline- and/or taxane-resistant breast cancer, its anti-tumor effect was not satisfactory. The activity of first-line irinotecan therapy or the combined use of irinotecan with other agents should be investigated in clinical studies.