Combination Therapy with Rituximab and Temozolomide for Recurrent and Refractory Primary Central Nervous System Lymphoma

High-dose methotrexate-based chemotherapy has extended survival in patients with primary central nervous system lymphoma (PCNSL). However, although salvage treatment is necessary in recurrent and refractory PCNSL, this has not been standardized. We herein describe the efficacy of a combination of rituximab and temozolomide (TMZ) in two consecutive patients with recurrent and refractory PCNSL. Based on the immunohistochemical study, case 1 had a non-germinal center B-cell-like (non-GCB) subtype, was positive for bcl-2 and negative for O6-methylguanine-DNA methyltransferase (MGMT). Case 2 was GCB subtype, bcl-2-, and MGMT+. Because of the positive expression of MGMT, interferon-beta was additionally given in case 2. Complete responses and partial responses were obtained after the third and fourth cycles of combination therapy, respectively. This was maintained for 12 months, with acceptable toxicity. The combination of rituximab and TMZ was effective in tumors with different immunohistochemical profiles. This combination therapy warrants further study in a larger population

A phase I study of single-agent BEZ235 special delivery system sachet in Japanese patients with advanced solid tumors

Purpose: BEZ235 is a dual kinase inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), which are key components of the PI3K pathway. This was an open-label, multicenter, dose-escalation, phase I study of single-agent BEZ235 in Japanese oncology patients to determine the maximum tolerated dose (MTD) of BEZ235 based on dose-limiting toxicities (DLTs). Methods: Dose escalation was guided by a standard 3+3 method and was based on DLTs observed in Cycle 1 and other safety, pharmacokinetic, and pharmacodynamic information. A total of 35 adult Japanese patients with advanced solid tumors received BEZ235 according to once daily (qd; n=27) or twice daily (bid; n=8) dosing schedules. Results: Two DLTs, namely, allergic reaction and thrombocytopenia, were observed at 1200 and 1400 mg qd, respectively, while liver dysfunction was reported as a DLT at 400 mg bid. The most common adverse events suspected to be related to BEZ235 in both dosing schedules were diarrhea, nausea, decreased appetite, stomatitis, and thrombocytopenia. Conclusions: Although the MTD was not established, the maximum clinically tolerable dose was determined to be 1200 mg because two out of six patients required dose reduction in Cycle 2. The recommended dose was determined to be 1000 mg qd, which was comparable with the results of the first-in-human BEZ235 study in Western patients with advanced solid tumors (NCT00620594). Additionally, the tolerability of BEZ235 400 mg bid in Japanese oncology patients was confirmed in this stud

Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors

This phase I study aimed to determine tolerability and preliminary efficacy of single-agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28-day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose-limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all-grade treatment-suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression-free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors

Phase I dose‐escalation study of capmatinib ( INC

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). Primary objective was to determine maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics, and preliminary anti-tumor activity. Dose-escalation was guided by a Bayesian logistic regression model dependent on dose-limiting toxicities (DLTs) in cycle 1. Forty-four adult Japanese patients with confirmed advanced solid tumors were enrolled; 29 patients received capmatinib capsules (doses ranging from 100 mg once daily [qd] to 600 mg twice daily [bid]), and 15 patients received tablets (200 mg bid and 400 mg bid). DLTs occurred in 2 patients: grade 2 suicidal ideation (600 mg bid capsule) and grade 3 depression (400 mg bid tablet). MTD was not reached. The highest studied dose determined to be safe in tablets was 400 mg bid, while it was not yet determined with capsules. Most common adverse events suspected to be drug related were blood creatinine increased, nausea, decreased appetite, vomiting, and diarrhea. Following repeated daily dosing up to day 15 by qd or bid regimen using capsules, median Tmax ranged from 1.0 to 4.0 hours, while absorption was more rapid after dosing using tablet, with median Tmax of 1.0 hour on both day 1 and day 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib. (Trial registration no. NCT01546428

Phase I dose-escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors.

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). Primary objective was to determine maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics, and preliminary anti-tumor activity. Dose-escalation was guided by a Bayesian logistic regression model dependent on dose-limiting toxicities (DLTs) in cycle 1. Forty-four adult Japanese patients with confirmed advanced solid tumors were enrolled; 29 patients received capmatinib capsules (doses ranging from 100 mg once daily [qd] to 600 mg twice daily [bid]), and 15 patients received tablets (200 mg bid and 400 mg bid). DLTs occurred in 2 patients: grade 2 suicidal ideation (600 mg bid capsule) and grade 3 depression (400 mg bid tablet). MTD was not reached. The highest studied dose determined to be safe in tablets was 400 mg bid, while it was not yet determined with capsules. Most common adverse events suspected to be drug related were blood creatinine increased, nausea, decreased appetite, vomiting, and diarrhea. Following repeated daily dosing up to day 15 by qd or bid regimen using capsules, median Tmax ranged from 1.0 to 4.0 hours, while absorption was more rapid after dosing using tablet, with median Tmax of 1.0 hour on both day 1 and day 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib. (Trial registration no. NCT01546428