Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma

Abstract

PurposeThiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population.MethodsHDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days − 12, − 11, − 5, and − 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days − 11, − 5, and − 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days − 4 and − 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days − 8 to − 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated.ResultsNine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5–93.9%) for pediatric patients and 100% for adult patients.ConclusionThiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated.Study registrationJapic CTI-163433.Electronic supplementary materialThe online version of this article (10.1007/s00280-019-03914-2) contains supplementary material, which is available to authorized users.

An expanded-access clinical study of thiotepa (DSP-1958) high-dose chemotherapy before autologous hematopoietic stem cell transplantation in patients with malignant lymphoma

“…The safety profile of this treatment regimen was acceptable. The most frequently reported TEAEs (febrile neutropenia and gastrointestinal toxicities) were consistent with those reported in adults with malignant lymphoma in the phase I study [5], and with the European [12] and Japanese [13] product labels. No unexpected safety outcomes were observed.…”

“…A previous single-center analysis of data from 24 patients treated with thioteopa plus busulfan high-dose chemotherapy, which included patients drawn from the phase 1 pharmacokinetic study [5] and also from this expanded access program, reported the occurrence of secondary failure of platelet recovery (SFPR) in three of the patients evaluated after the end of the study period [17]. SFPR is known to be a complication of hematopoietic stem cell transplantation, although it generally occurs more frequently in allogenic than in autologous transplants [18].…”

“…We have previously reported data from a phase 1 study of a thiotepa-containing HDT regimen in nine patients with pediatric solid tumors and 10 adult patients (≥ 16 years) with malignant lymphoma [5]. The results indicated that thiotepa was well-tolerated; the bone-marrow suppression rate was 100% for both pediatric solid tumors and for adult malignant lymphoma, and the engraftment rates were 66.7% and 100%, respectively.…”

“…Thiotepa (DSP-1958), an antineoplastic ethylenimine alkylating agent that inhibits DNA synthesis [4], is used as HDT before autologous HSCT in patients with solid or hematologic malignancies [5]. It has the capacity to cross the blood-brain barrier, and is able to rapidly penetrate into the central nervous system (CNS) [6,7].…”

Thiotepa–melphalan myeloablative therapy for high‐risk neuroblastoma

“…Recently, thiotepa as a drug for thiotepa–melphalan high‐dose therapy was approved in Japan, along with melphalan, with a reduced cumulative dose from 280 to 210 mg/m 2 . The feasibility of this modified regimen has been confirmed in early clinical trials 30 . To confirm the efficacy of this modified regimen, further studies are needed.…”