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.
Highlights
Patients and methodsThiotepa (N,N′,N′′-triethylenethiophosphoramide) is an alkylating agent that has been used to treat solid tumors and hematological diseases since the 1950s [1, 2]
Because of its broad-spectrum antitumor activity and relative lack of extramedullary toxicity, thiotepa has been incorporated in high-dose chemotherapy (HDT) with autologous hematopoietic stem cell transplantation (HSCT) for various solid tumors and hematological malignancies [5,6,7,8,9]
In a randomized Phase 2 study (IELSG-32) of consolidative therapies in patients with primary central nervous system (CNS) lymphoma, HDT with thiotepa and carmustine followed by HSCT showed comparable efficacy with no increase in cognitive impairment compared with whole-brain irradiation [6]
Summary
Patients and methodsThiotepa (N,N′,N′′-triethylenethiophosphoramide) is an alkylating agent that has been used to treat solid tumors and hematological diseases since the 1950s [1, 2]. Because of its broad-spectrum antitumor activity and relative lack of extramedullary toxicity, thiotepa has been incorporated in high-dose chemotherapy (HDT) with autologous hematopoietic stem cell transplantation (HSCT) for various solid tumors and hematological malignancies [5,6,7,8,9]. Both thiotepa and TEPA efficiently cross the blood–brain barrier, with cerebrospinal fluid levels in excess of 90% of serum levels [10]. Two randomized Phase 2 studies (PRECIS [NCT00863460] and CALGB51101 [NCT01511562]), a non-randomized, single-group, openlabel study [NCT01505569], and a Phase 3 study (MATRix [NCT02531841]) of thiotepa-based HDT/HSCT in primary CNS lymphoma and high-risk or relapsed solid tumors are ongoing [13,14,15,16]
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