This open-label, single-arm, phase 2 study (ClinicalTrials.gov, NCT03128411) evaluated the efficacy, safety, and pharmacokinetics of bosutinib at a starting dose of 400 mg once daily (QD) in Japanese ...patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). The primary endpoint was major molecular response (MMR) at Month 12 in the modified as-treated population (Philadelphia chromosome-positive Ph+ patients with e13a2/e14a2 transcripts). Sixty Japanese patients with CP CML were treated with bosutinib; median age was 55 years (range 20–83), 60.0% were males, and all were Ph+ and had e13a2/e14a2 transcripts. After median follow-up of 16.6 months (range 11.1–21.9), 41 (68.3%) patients remained on bosutinib. The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval: 44.4–65.6). There were no on-treatment transformations to accelerated/blast phase, and no patient died on treatment or within 28 days of the last bosutinib dose. The most common treatment-emergent adverse events were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). The primary objective of this phase 2 study was met, and there were no new safety signals for bosutinib. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML.
Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to ...prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (
n
= 33 vs 34) and non-Asian (
n
= 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.
Lorlatinib is a potent, brain‐penetrant, third‐generation anaplastic lymphoma kinase (ALK)/ROS proto‐oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance ...mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK‐rearranged/ROS1‐rearranged advanced non–small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC‐ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK‐rearranged/ROS1‐rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty‐one ALK‐rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC‐ORR. The ORR and the IC‐ORR for Japanese patients in EXP2‐5 were 54.8% (95% confidence interval CI: 36.0‐72.7) and 46.7% (95% CI: 21.3‐73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9‐81.6). The most common treatment‐related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single‐dose and multiple‐dose pharmacokinetic profiles among Japanese patients were similar to those in non–Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK‐rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
Lorlatinib showed clinically meaningful responses (54.8%; 95% CI: 36.0‐72.7) and intracranial responses (46.7%; 95% CI: 21.3‐73.4) among ALK‐rearranged Japanese patients with non–small cell lung cancer who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only (42.9%; 95% CI: 9.9‐81.6). Lorlatinib was generally well tolerated, with a similar adverse event profile among Japanese patients to that among the overall population.
Bosutinib has been investigated in multiple clinical trials globally, including Japan, for treatment of chronic myeloid leukemia (CML). A pooled analysis of seven Pfizer-sponsored clinical trials ...evaluated the safety of bosutinib in Japanese (
n =
138) vs non-Japanese (
n =
1210) patients with CML. First-line bosutinib was administered in 54.3% vs 41.4% of patients, and second-line or later bosutinib in the remainder. Median treatment duration was 1.4 vs 2.3 years, and median relative dose intensity 78.1% vs 90.0%. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% vs 98.9% (grade ≥ 3: 81.9% vs 75.2%). In both groups, the most common TEAEs relevant to bosutinib were gastrointestinal (92.8% vs 84.7%), liver function (72.5% vs 34.8%), rash (63.8% vs 37.4%), and myelosuppression (55.1% vs 50.7%). TEAEs led to dose reduction in 65.2% vs 50.6%, dose interruption in 78.3% vs 68.8%, and permanent treatment discontinuation in 30.4% vs 25.4% of patients. The safety profile of bosutinib in Japanese patients was generally consistent with that in non-Japanese patients, despite a higher incidence of gastrointestinal, liver function, and rash events. TEAEs were largely manageable with dose modifications and supportive care in both groups. These data may help optimize TEAE management and outcomes in Japanese patients receiving bosutinib for CML.
Trial registration
ClinicalTrials.gov: NCT02130557, NCT03128411, NCT00574873, NCT00261846, NCT01903733, NCT00811070, NCT02228382.
Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor–kappa B ligand (RANKL), suppresses bone resorption. This open‐label, multicenter, phase 1 study evaluated the ...safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer–related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for ≥ 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade ≤ 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment‐related; other treatment‐related AE were grade ≤ 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose‐linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N‐telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from –61.9% to –90.8%. No dose‐limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non‐Japanese populations. (Cancer Sci 2008; 99: 1237–1242)
Abstract Purpose This prospective analysis of the Japanese subpopulation of the varenicline reduce to quit study was conducted to evaluate whether results for Japanese participants were consistent ...with the full study population. Methods Patients received varenicline or placebo for a 24-week treatment period (12-week smoking reduction phase then a 12-week smoking abstinence phase) followed by a 28-week nontreatment, follow-up phase. Participants were to reduce the daily number of cigarettes smoked by at least 50% by week 4 and by a further 50% by week 8, with the goal of achieving complete abstinence by week 12. The primary efficacy end point was the carbon monoxide–confirmed continuous abstinence during weeks 15 to 24. Findings Overall, 210 Japanese patients were randomly assigned to 1 of the 2 study groups (varenicline, 107; placebo, 103). Continuous abstinence rates for weeks 15 to 24 were higher for participants in the varenicline group versus the placebo group (46.7% vs 12.6%; odds ratio = 14.68; 95% CI, 5.38–40.05), and the 7-day point prevalence of abstinence rates were higher for varenicline versus placebo at week 12 (odds ratio = 13.76; 95% CI, 5.28–35.86). The number of participants with a ≥50% reduction in the number of daily cigarettes smoked from baseline to week 4 and a ≥75% reduction by week 8 was greater in the varenicline group versus the placebo group (week 4: 59.8% vs 30.1%; week 8: 38.3% vs 12.6%). Serious adverse events were reported in 3.7% of varenicline participants and 1.0% of placebo participants. Implications The efficacy and tolerability results of this analysis are consistent with those of the full varenicline reduce to quit study. Varenicline treatment and cigarette reduction before quitting may provide an alternative approach to smoking cessation in Japanese smokers who are not ready to quit immediately. ClinicalTrials.gov identifier: NCT01370356.
Abstract Background The efficacy of the smoking-cessation agent varenicline has been reported in Asian smokers; however, few studies have investigated factors that contribute to lapse and relapse. ...Objective This post hoc analysis aimed to identify predictors of smoking lapse and relapse. Methods This was a post-hoc analysis based on a double-blind, placebo-controlled, randomized, parallel-group study in which Japanese smokers (aged 20–75 years) who smoked ≥10 cigarettes/day and were motivated to quit were randomized to receive varenicline (0.25 mg twice daily BID, 0.5 mg BID, 1 mg BID) or placebo for 12 weeks followed by a 40-week non-treatment follow-up. For inclusion in this analysis, participants must have been nicotine dependent (Tobacco Dependence Screener score ≥5) and must have successfully quit smoking continuously for 4 weeks (weeks 9–12). Lapse was defined by answering yes to ≥1 question in the Nicotine Use Inventory. Relapse was defined by participants having smoked for ≥7 days during follow-up measured by the Nicotine Use Inventory. Results Of the 619 randomized individuals, 515 had a Tobacco Dependence Screener score of ≥5, and 277 quit smoking continuously from weeks 9 to 12. Approximately 75% were male, with a mean (SD) BMI of 23.0 (3.0) kg/m2 . Maximum length of continuous abstinence (CA) during treatment and age (both P < 0.0001) were significant predictors of lapse. Maximum CA ( P < 0.0001), age ( P = 0.0002), Minnesota Nicotine Withdrawal Scale (MNWS) score for urge to smoke ( P = 0.0019), and having made ≥1 serious quit attempt ( P = 0.0063) were significant predictors of relapse. For participants with a maximum CA of 4 to 6 weeks versus those with a maximum CA of 10 to 11 weeks, the ORs for lapse and relapse were 4.649 (95% CI, 2.071–10.434) and 3.337 (95% CI, 1.538–7.239), respectively. In participants aged 21–34 years versus those aged 47–72 years, the ORs for lapse and relapse were 3.453 (95% CI 1.851, 6.441) and 3.442 (95% CI 1.795, 6.597), respectively. Participants with a MNWS urge to smoke score of 2 to 4 versus 0 had an OR for relapse of 3.175 (95% CI, 1.166–8.644). Participants having made ≥1 versus no serious quit attempts had an OR for relapse of 2.108 (95% CI, 1.168–3.805). Conclusion Shorter maximum CA and younger age at quit attempt were associated with increased risk of lapse and relapse. Higher MNWS urge to smoke score and having made ≥1 serious quit attempt were associated with increased relapse risk. ClinicalTrials.gov identifier: NCT00139750.
Abstract Background Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate ...or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. Objective Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. Methods This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. Results A total of 69 patients (celecoxib, 42/64 65.6%; placebo, 27/58 46.6%) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 64.1%) compared with the placebo group (15/58 25.9%) rated the study medication as “good” or “excellent” ≥2 hours after the additional dose ( P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group ( P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group ( P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). Conclusions Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.
AMG 531 is a novel thrombopoiesis‐stimulating peptibody being investigated for the treatment of chronic immune thrombocytopenic purpura. This double‐blind, phase I study evaluated the safety, ...pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531/placebo) to receive 1 dose of AMG 531 (0.3, 1, or 2 μg/kg) or placebo by subcutaneous injection; subjects were evaluated for 6 weeks. AMG 531 was generally well tolerated, with adverse events similar to placebo. Treatment‐related adverse events (headache, “feeling hot,” malaise) were reported for 5 of 24 AMG 531‐treated subjects. Platelets generated after exposure to AMG 531 functioned normally. Four of 8 subjects receiving 1 μg/kg and 7 of 8 receiving 2 μ/kg had platelet count increases ≥1.5‐fold over baseline, an effect similar to that seen in non‐Japanese subjects. Serum AMG 531 concentrations were below the lower limit of quantification in all but 2 subjects receiving 2 μg/kg.
To assess the long-term safety and efficacy of pregabalin for the treatment of Japanese patients with fibromyalgia (FM).
This 53-week, open-label extension study was conducted at 20 study sites in ...Japan in patients with FM who had completed a preceding 16-week, placebo-controlled, double-blind trial. Patients received pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day. The primary endpoint was safety, and secondary endpoints included measures of pain, sleep, and physical functioning.
106 patients entered the trial and received at least one dose of the study drug. The most common treatment-related adverse events were somnolence, dizziness, increased weight, and constipation. There were no treatment-related serious or severe adverse events. There were five (4.7%) discontinuations due to adverse events, of which three (2.8%) were considered related to the study drug. Most adverse events resolved over time and could be managed without dose reduction or treatment discontinuation. Improvements in secondary efficacy endpoints of pain, sleep, and physical functioning emerged early in the study and were maintained for the duration of treatment.
These data indicate that the long-term treatment of Japanese FM patients with pregabalin may be both safe and effective.
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