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.
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.
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.
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).
Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.
Abstract
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.
Venetoclax-azacitidine was well tolerated in the Japanese subgroup of VIALE-A (N = 37) and showed improved efficacy versus placebo-azacitidine in patients with acute myeloid leukemia ineligible for intensive chemotherapy, supporting use as first-line standard-of-care.
Interstitial lung disease (ILD) is important drug related toxicity because it commonly forced to discontinue the treatment.
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).
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.
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.
Abstract
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.
In the Japanese subgroup of VIALE-C patients (n = 27), venetoclax plus low-dose cytarabine (LDAC) was well tolerated and showed high response vs placebo plus low-dose cytarabine in patients with acute myeloid leukaemia ineligible for intensive chemotherapy.
ABSTRACT
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.
Telisotuzumab vedotin (formerly ABBV‐399) is an antibody‐drug conjugate targeting c‐Met–overexpressing tumor cells, irrespective of MET gene amplification status. 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 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.
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.
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.
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.
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.
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.
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.
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%).
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.
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.
PDF
