A phase I dose escalation study of high-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous peripheral blood stem cell transplantation (PBSCT) in patients with solid tumors and hematologic malignancies

The purpose of this study was to determine the maximum tolerated dose of ca rboplatin administered with 500 mg/m(2) thiotepa and 100 mg/m(2) melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patien ts with refractory malignancies. Twenty-eight patients with refractory mali gnancies received high-dose thiotepa (500 mg/m(2), melphalan (100 mg/m(2)) and escalating doses of carboplatin 900-1500 mg/m(2)) followed by infusion of cryopreserved autologous PBSCs, The maximum tolerated doses were determi ned to be 500 mg/m(2) thiotepa, 100 mg/m(2) melphalan and 1350 mg/m(2) carb oplatin. Two consecutive patients receiving 1500 mg/m(2) carboplatin experi enced grade 3 mucositis and colitis, Ten patients were enrolled at the maxi mum tolerated dose and none had grade 3-4 regimen-related toxicity and mort ality. All patients at this level experienced grade 1-2 mucositis, 90% grad e 1-2 gastrointestinal toxicity, 30% grade 1-2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity, The median time to achieve a granulocyte count of 0.5 x 10(9)/l was 9 days (range 7-12 days) and platele t count of 20 x 10(9)/l was 10 days (range 7-15 days), Of eight patients wi th stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of sev en patients with non-Hodgkin's lymphoma (n = 4) or Hodgkin's disease (n = 3 ), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be a dministered in high doses with tolerable mucositis as the major side-effect . This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy -sensitive malignancies are warranted.