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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.

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.

Romidepsin (Brand name: ISTODAX

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.

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma associated with poor prognosis. There is no consensus on standard therapy, and options are limited for patients with relapsed/refractory (R/R) disease. Romidepsin, a potent histone deacetylase inhibitor, has US FDA approval for patients with >=1 prior treatment for PTCL based on 25%-38% overall response rates (ORR) and durable responses (Piekarz et al, Blood. 2011;117:5827; Coiffier et al, J Clin Oncol. 2012;30:631). Here we report results from the phase I/II, multicenter, open-label study of romidepsin in Japanese patients with R/R PTCL or cutaneous T-cell lymphoma (CTCL) (TCL-001; NCT01456039). Methods: Patients aged >=20 years with R/R PTCL or CTCL received romidepsin via a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle until progressive disease or unacceptable toxicity. The phase I portion of the study used a 3+3 design to identify any dose-limiting toxicity (DLT; phase I primary endpoint) with romidepsin 9 mg/m2 (cohort 1) and 14 mg/m2 (cohort 2). The phase II dose was based on the highest dose where =1 day. Assessments of the intent-to-treat (ITT) population included all patients receiving at least 1 dose of romidepsin. Results: The ITT population comprised 48 patients with PTCL and 2 with CTCL (1 each in the 9 and 14 mg/m2 cohorts). The common PTCL subtypes were angioimmunoblastic T-cell lymphoma (AITL, n=21, 44%), PTCL not otherwise specified (PTCL-NOS, n=20, 42%), and anaplastic large-cell lymphoma (ALCL ALK-1 negative, n=3, 6%). Most patients had a favorable ECOG performance status (86% 0-1) and 72% were >=65 years of age. Patients had received a median of 2 prior therapies (range, 1-9). Of 9 patients assessable in phase I (n=3 at 9 mg/m2 and n=6 at 14 mg/m2), none experienced a DLT. The recommended phase II dose was 14 mg/m2 in 40 subsequently treated patients. The overall population received a median of 10 doses (range, 1-135) for a median treatment duration of 12.9 weeks (range, 0.1-184.3; 8 patients were treated for >=36 weeks). The common all-grade adverse events (AEs) were thrombocytopenia (n=49, 98%), lymphopenia (n=44, 88%), leukopenia (n=42, 84%), neutropenia (n=40, 80%), pyrexia (n=33, 66%), dysgeusia (n=31, 62%), decreased appetite (n=28, 56%), and nausea (n=27, 54%). The common grade >=3 AEs were lymphopenia (n=37, 74%), neutropenia (n=27, 54%), leukopenia (n=23, 46%), and thrombocytopenia (n=19, 38%). Of the 39 patients whose CD4+ T-cell counts were monitored, while decreased CD4+ T-cell counts ( Among the 40 patients with PTCL (phase II), the ORR was 43% (95% CI, 27%-58%), including 10 patients (25%) with complete response (CR) or CR unconfirmed (CRu) and 7 (17%) with partial responses (PR) (Table 1). The obtained ORR was significantly higher compared with the threshold ORR of 10% (P Conclusions: Results from this phase I/II study identified a tolerable dose of romidepsin and indicated that romidepsin has an acceptable toxicity profile with clinically meaningful, efficacy in Japanese patients with R/R PTCL. The efficacy and safety data were comparable with results from other romidepsin phase II studies. Disclosures Ogura: Celltrion, Inc.: Consultancy, Honoraria; SymBio Pharmaceuticals: Consultancy, Honoraria. Maruyama:Janssen: Honoraria; Takeda: Honoraria. Tobinai:Chugai Pharma: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Celgene: Research Funding; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Ishizawa:SymBio Pharmaceuticals: Research Funding. Laille:Celgene: Employment, Equity Ownership. Ro:Celgene: Employment, Equity Ownership. Tamakoshi:Celgene: Employment, Equity Ownership. Sakurai:Celgene: Employment. Ohtsu:Celgene: Employment, Equity Ownership.