Carfilzomib monotherapy in Japanese patients with relapsed or refractory multiple myeloma: A phase 1/2 study.

This multicenter, open-label phase 1/2 study evaluated single-agent carfilzomib in 50 heavily pretreated Japanese patients with relapsed/refractory multiple myeloma (median of five prior treatments). In phase 1, patients were dosed at three levels: 15, 20, or 20/27 mg/m2 . Maximum tolerated dosage was not reached at the tolerability evaluation. Patients in phase 2 were treated with 20/27 mg/m2 carfilzomib. Median duration of exposure to carfilzomib in the 20/27 mg/m2 group at this final analysis was 4.7 months (range: 0.3-39.4). Overall response rate in the 20/27 mg/m2 group, primary endpoint of the study, was 22.5% (n = 9) (95% confidence interval, 12.3-37.5) with 2.5% (n = 1) stringent complete response. Median progression-free survival and overall survival in the 20/27 mg/m2 group were 5.1 months (95% CI, 2.8-13.6) and 22.9 months (95% CI, 14.1-not estimable), respectively. Frequently occurring grade ≥3 adverse events in the 20/27 mg/m2 group included lymphopenia (72.5%), neutropenia (40.0%), and leukopenia (32.5%). Giving long-term carfilzomib monotherapy led to long-term overall survival for heavily pretreated multiple myeloma patients with a favorable safety profile. Carfilzomib monotherapy can be a good option for heavily pretreated multiple myeloma patients.

Weekly carfilzomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma: A phase 1 and PK/PD trial.

This open-label multicenter phase 1 study evaluated the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of weekly carfilzomib and dexamethasone (Cd) in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Carfilzomib was administered by 30-minute intravenous infusion on Days 1, 8 and 15 in a 28-day cycle starting at 20 mg/m2 on Day 1/Cycle 1 and 70 mg/m2 thereafter until progressive disease or unacceptable toxicity. Dexamethasone 40 mg was administered on Days 1, 8, 15 and 22 in Cycles 1-9 and on Days 1, 8 and 15 thereafter. Six patients were enrolled between March 2015 and June 2015. Patients had received a median of 4.5 (range, 4-8) prior regimens; all patients had previous therapies with bortezomib and immunomodulatory drugs. Of the 6 patients, 1 had a dose-limiting toxicity (DLT), and tolerability was confirmed. The DLT was grade 3 thrombotic microangiopathy, which was considered serious and occurred on Day 11/Cycle 1. All 6 patients (100%) experienced at least 1 grade ≥3 adverse event (AE). Two patients (33.3%) experienced AE (also considered adverse drug reactions) leading to study discontinuation: thrombotic microangiopathy (Day 11/Cycle 1) and thrombotic thrombocytopenic purpura (Day 6/Cycle 2). The overall response rate was 83.3% (95% confidence interval, 43.6-97.0). The weekly Cd regimen at a carfilzomib dose of 20/70 mg/m2 was well-tolerated among Japanese patients with RRMM. Our results could be the basis for the further development of carfilzomib treatment considering safety profiles including microangiopathy-related events and efficacy.

Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan.

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open-label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2 , followed by 27 mg/m2 . Lenalidomide and dexamethasone were administered at 25 mg (days 1-21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty-six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High-risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.

A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma.

We conducted a phase 1/2 study of single-agent carfilzomib in Japanese patients with relapsed/refractory multiple myeloma. Safety, pharmacokinetics and pharmacodynamics of carfilzomib were examined in phase 1. The primary endpoint in phase 2 was the overall response rate (ORR). Carfilzomib was administered in a twice-weekly, consecutive-day dosing schedule. In Phase 1, doses of 15 or 20 mg/m(2) were administered on this schedule or 20 mg/m(2) on Days 1 and 2 of Cycle 1 and then 27 mg/m(2) in the 20/27 mg/m(2) cohort. Patients had a median of five prior therapies, including bortezomib and an immunomodulatory agent. The dose level did not reach the maximum tolerated dose. The most common adverse events were haematological. Notably, carfilzomib either induced new hypertension (n = 4) or aggravated previously existing hypertension (n = 6) in 10 of 50 patients. Four of the eight patients who previously experienced peripheral neuropathy (PN) experienced a recurrence with carfilzomib use, but no new cases of PN occurred. The ORR of the 20/27 mg/m(2) 40 patient cohort was similar to that in the pivotal US study. The dose was efficacious and tolerable in heavily pre-treated Japanese patients; however, meticulous control of hypertension may be necessary for further carfilzomib use.

Final results of a phase I study of carfilzomib, lenalidomide, and dexamethasone for heavily pretreated multiple myeloma.

We report the final results from a multicenter, open-label phase I study of carfilzomib plus lenalidomide and dexamethasone in Japanese patients with heavily pretreated relapsed and/or refractory multiple myeloma (RRMM). Twenty-six RRMM patients were enrolled and received a median of 4.0 prior regimens; 12/26 patients (46.2%) completed the planned 18 administration cycles (mean number of cycles: 14.5 ± 4.9). The safety profile was consistent with that of previous carfilzomib studies. All patients experienced adverse events (AEs), but no new safety concerns were observed. The most common grade ≥ 3 AEs (incidence: ≥ 10%) were lymphocyte count decreased (46.2%), platelet count decreased (42.3%), and neutrophil count decreased (34.6%). The overall response rate was 88.5% (23/26; 90% confidence interval: 72.8-96.8). Complete response (CR) or better was achieved by 30.8% of patients compared with 3.8% in the interim analysis. The median time to CR or better response was 9.4 months. Median progression-free survival and duration of response were 19.5 months and 20.3 months, respectively. Median overall survival was not reached. Long-term administration of carfilzomib produced deep response and long-term disease control. The combination of carfilzomib plus lenalidomide and dexamethasone was well tolerated and showed promising clinical efficacy for heavily pretreated RRMM patients. CLINICAL TRIAL REGISTRATION: This clinical trial was registered in the database clinicaltrials.jp (clinical trial registration number: Japic CTI 142677).

Phase I dose escalation study of high dose carfilzomib monotherapy for Japanese patients with relapsed or refractory multiple myeloma.

We conducted a multicenter, open-label Phase I study of single-agent carfilzomib in Japanese patients with relapsed or refractory multiple myeloma. The primary endpoints were tolerability and safety. Carfilzomib was administrated for 30 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. In cycle 1, doses for days 1 and 2 were 20 mg/m2, followed by 45 or 56 mg/m2. Three and four subjects were enrolled in the 20/45 mg/m2 cohort and 20/56 mg/m2 cohort. No dose-limiting toxicity was observed, and the tolerability of carfilzomib was confirmed. Pyrexia, hypertension, nausea and vomiting were considered as noteworthy adverse events (AE) when carfilzomib was administered at high doses. Moreover, pyrexia, blood creatinine increased, and body weight gain were observed as acute dose effects. These findings suggest that addition of dexamethasone is important to alleviate acute dose effect. The overall response rates of the 20/45 mg/m2 and 20/56 mg/m2 cohort were 66.7 % (two out of three) and 50 % (two out of four), respectively. Carfilzomib administrated at up to 20/56 mg/m2 was well tolerated and seemed active in Japanese patients with relapsed or refractory multiple myeloma. CLINICAL TRIAL REGISTRATION: JapicCTI-122020.