Phase 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy.

PURPOSE: High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1-10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted. METHODS: The primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20 min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them. RESULTS: The rate of CIR was 76.9% (95% confidence interval, 46.2-95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events. CONCLUSION: Glucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.

[Romidepsin (Istodax® for intravenous injection 10†mg): pharmacokinetics, pharmacodynamics and clinical study outcome].

Romidepsin (Brand name: ISTODAX® for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T-cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U.S. and other countries. Thereafter, domestic phase I/II studies were planned. The phase I study was designed to evaluate the tolerability of romidepsin in Japanese patients with relapsed or refractory PTCL/CTCL and thereby determine the recommended dose, as patients were administered romidepsin by intravenous infusion at a dose of 9 or 14 mg/m2 over 4 hours on days 1, 8 and 15 of each 28-day cycle, and 14 mg/m2 was determined as the recommended dose for phase II. While the phase II study was designed to include 40 Japanese patients with relapsed or refractory PTCL to evaluate the efficacy and safety of romidepsin. Treatment response was 42.5% and the most common AEs of Grade ≥ 3 were lymphopenia (74.0%), neutropenia (54.0%), leukocytopenia (46.0%) and thrombocytopenia (38.0%). The overall safety profile was considered to be within the acceptable range. On the basis of these result, romidepsin was approved in July 2017 for the treatment of relapsed or refractory PTCL in Japan.

Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study.

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039.

Using the tannase gene to rapidly and simply identify Staphylococcus lugdunensis.

The coagulase-negative Staphylococcus lugdunensis, a bacterium similar to Staphylococcus aureus, produces tannase that degrades tannin. We developed a polymerase chain reaction-based method to rapidly and simply identify this species by detecting the tanA gene for S. lugdunensis tannase.