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

Purpose Salvage high-dose chemotherapy with autologous stem cell transplant (ASCT), consisting of 2–3 sequential cycles of high-dose (HD) carboplatin and etoposide (CE) can achieve durable remissions in approximately one-half of relapsed germ cell tumor patients. To improve upon 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 plus ifosfamide (TI), substituting carboplatin for cisplatin to allow dose escalation. Patients and Methods Treatment consisted of 1–2 cycles of TI and granulocyte colony stimulating factor for stem cell mobilization followed by three cycles of HD TI plus carboplatin (TIC) with ASCT every 21–28 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/m2, ifosfamide 9990 mg/m2, carboplatin area under the curve = 24) was considered the MTD. Phase II employed a Simon two-stage design to estimate the complete response (CR) rate at the MTD. With 7/11 phase II patients achieving CR, efficacy was demonstrated. However, three patients developed delayed chronic kidney disease, resulting in premature trial closure. Conclusion TI-TIC was active in relapsed GCT but emergent chronic renal impairment, possibly from overlapping ifosfamide and carboplatin, preclude its further use. TI-CE, consisting of two cycles of TI plus three cycles of HD CE remains the standard-of-care HD chemotherapy regimen at Memorial Sloan Kettering Cancer Center.

Recent developments in the management of germ cell tumors

“…The TI-CE regimen consists of paclitaxel and ifosfamide induction for up to 2 cycles followed by high-dose carboplatin and etoposide with autologous SCT every 21–28 days for 3 cycles. The efficacy of this approach was demonstrated in a phase I/II trial that reported a 47% 5-year disease-free survival and 52% overall survival [40]. The TIGER trial (NCT02375204 at www.clinicaltrials.gov) is an ongoing multicenter, open-label phase III study comparing second-line TI-CE vs TIP in patients with relapsed or refractory GCTs.…”

Ototoxicity associated with high‐dose carboplatin for patients with previously treated germ cell tumors

“…Patients were treated with TI-CE on a clinical trial, [9][10][11] TI-CE as standard of care, or TI followed by high-dose paclitaxel, ifosfamide, and carboplatin (TI-TIC) on a clinical trial. 19 For the TI-CE program, one or two cycles of TI with mesna were given 14 days apart (Cycles 1 and 2) followed by three cycles of high-dose CE with autologous stem cell support every 21-28 days (Cycles 3-5; Table S1). Carboplatin dosing was by target area under the curve (AUC) and varied during phase 1 of the TI-CE clinical trial.…”