RESUMEN
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.
Asunto(s)
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 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. METHODS: Patients with previously untreated stage III-IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. RESULTS: Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18-1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. CONCLUSIONS: Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.
Asunto(s)
Anemia , Antieméticos , Neoplasias Ováricas , Trombocitopenia , Humanos , Femenino , Carboplatino/efectos adversos , Antieméticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Ováricas/patología , Paclitaxel , Anemia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
INTELLANCE-J was a phase 1/2 study of a potent antibody-drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux-M), as a second- or first-line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second-line arms, patients with EGFR-amplified recurrent WHO grade III/IV glioma received Depatux-M plus chemotherapy (temozolomide) or Depatux-M alone regardless of EGFR status. In first-line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux-M plus chemoradiotherapy. The study was halted following lack of survival benefit with first-line Depatux-M in the global trial INTELLANCE-1. The primary endpoint was 6-month progression-free survival (PFS) in patients with EGFR-amplified tumors receiving second-line Depatux-M plus chemotherapy. Common nonocular treatment-emergent adverse events (TEAEs) with both second-line and first-line Depatux-M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second-line Depatux-M plus chemotherapy and all patients receiving second-line Depatux-M alone or first-line Depatux-M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6-month PFS estimate was 25.6% (95% confidence interval [CI] 11.4-42.6), and median PFS was 2.1 months (95% CI 1.9-3.9) with second-line Depatux-M plus chemotherapy in the EGFR-amplified subgroup. This study showed acceptable safety profile of Depatux-M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263).
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Temozolomida/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Quimioradioterapia , Quimioterapia , Receptores ErbB/genética , Femenino , Amplificación de Genes , Glioma/genética , Glioma/patología , Glioma/radioterapia , Humanos , Japón , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Análisis de Supervivencia , Temozolomida/efectos adversos , Resultado del TratamientoRESUMEN
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
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
BACKGROUND: Dose escalation is often recommended for loss of response in anti-TNFα-treated patients with Crohn's disease (CD). This 52-week phase 3, multicenter study investigated the efficacy and safety of escalation to adalimumab 80 mg every other week (EOW) in Japanese patients with CD who lost response to maintenance adalimumab 40 mg EOW. METHODS: Twenty-eight patients aged ≥15 years with moderately to severely active CD who had previously attained and subsequently lost clinical response to maintenance ada limumab received open-label adalimumab 80 mg EOW during weeks 0-50. Loss of response was defined as CD activity index (CDAI) ≥200, increases in CDAI ≥50 from minimum observed value, and C-reactive protein (CRP) ≥1 mg/dL at screening. The primary endpoint was the proportion of patients achieving a CDAI decrease ≥50 (CR-50) from baseline at week 8. RESULTS: At weeks 8 and 52, 75.0 and 57.1$ of patients achieved CR-50 and 25.0 and 35.7$ achieved clinical remission (CDAI < 150), respectively; median CRP changes from baseline were -0.39 and -0.77 mg/dL, respectively. Most treatment-emergent adverse events were mild to moderate. CONCLUSIONS: Adalimumab dose escalation to 80 mg EOW improved CD activity in patients who had lost response to maintenance adalimumab, with no new safety signals. (ClinicalTrials.gov Identifier: NCT01958827.).
Asunto(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
In the new Japanese control law for infectious diseases, most varieties of acute viral encephalitis belong to Category IV requiring report of all cases at sentinel hospitals. Herpes simplex virus type 1 (HSV-1) encephalitis comprises the majority of cases. With the increased prevalence of diagnostic procedures such as polymerase chain reaction (PCR), several forms of HSV-1, and -2 central nervous system (CNS) infections, including acute disseminated encephalomyelitis, brainstem encephalitis, and myelitis, have been clarified. Since 1990 we have conducted a survey of HSV CNS infections in the Kyushu and Okinawa regions, and the data are reviewed here. Trends include an increase in a new subtype of non-herpetic acute limbic encephalitis. In contrast, the incidence of Japanese encephalitis (JE) in Japan has dramatically decreased to a few patients per year; however, JE remains a threat for those with decreased or absent immunity to the JE virus. Imported emerging and reemerging CNS infections such as Murray Valley and West Nile encephalitis can occur in Japan. Influenza-associated encephalitis/encephalopathy is also described as a threat for adults as well as young children.