title: Phase I/II Trial of Paclitaxel With Ifosfamide Followed by High-Dose Paclitaxel, Ifosfamide, and Carboplatin (TI-TIC) With Autologous Stem Cell Reinfusion for Salvage Treatment of Germ Cell Tumors.
abstract: BACKGROUND
  Salvage high-dose (HD) chemotherapy with autologous stem cell transplant (ASCT), consisting of 2 to 3 sequential cycles of HD carboplatin and etoposide (CE) can achieve durable remissions in approximately half of patients with relapsed germ cell tumors. To improve on these results and based on success with paclitaxel, ifosfamide, and cisplatin (TIP) as salvage conventional-dose chemotherapy, we conducted a phase I/II trial of HD paclitaxel with ifosfamide (TI), substituting carboplatin for cisplatin to allow dose escalation.
  
  
  METHODS
  Treatment consisted of 1 to 2 cycles of TI and granulocyte colony-stimulating factor for stem cell mobilization followed by 3 cycles of HD TI with carboplatin (TIC) with ASCT every 21 to 28 days. Twenty-six patients were enrolled. For phase I, a standard 3+3 dose-escalation design was used.
  
  
  RESULTS
  With no dose-limiting toxicities observed, the maximum tolerated dose (MTD) was not reached and the highest prespecified dose level (paclitaxel 250 mg/m(2), ifosfamide 9990 mg/m(2), carboplatin area under the curve 24) was considered the MTD. In phase II, a Simon 2-stage design was used to estimate the complete response (CR) rate at the MTD. With 7 of 11 phase II patients who achieved a CR, efficacy was demonstrated. However, 3 patients developed delayed chronic kidney disease, resulting in premature trial closure.
  
  
  CONCLUSIONS
  TI-TIC was active in relapsed germ cell tumors but treatment-emergent chronic renal impairment, possibly from overlapping ifosfamide and carboplatin, preclude its further use. TI-CE, consisting of 2 cycles of TI with 3 cycles of HD CE remains the standard of care HD chemotherapy regimen at Memorial Sloan Kettering Cancer Center.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY. Electronic address: feldmand@mskcc.org.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Feldman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Ilya
authors.initials: I
authors.lastname: Glezerman
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Van Alstine
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fischer
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Amanad
authors.initials: A
authors.lastname: Hughes
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Joel
authors.initials: J
authors.lastname: Sheinfeld
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Manjit
authors.initials: M
authors.lastname: Bains
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Lilian
authors.initials: L
authors.lastname: Reich
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Woo
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Sergio
authors.initials: S
authors.lastname: Giralt
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: George J
authors.initials: GJ
authors.lastname: Bosl
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000328:Adult; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000601:surgery*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D016879:Salvage Therapy; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D016190:Carboplatin; D017239:Paclitaxel; D007069:Ifosfamide
keywords: Intensive chemotherapy; Second-line; Stem cell transplant; Testicular cancer