| Abstract: |
In this phase I/II study of paclitaxel with ifosfamide followed by high-dose paclitaxel, ifosfamide, and carboplatin as salvage treatment for patients with relapsed or refractory germ cell tumors, we observed evidence of antitumor activity at all dose levels, particularly the maximum tolerated dose. However, development of chronic progressive renal insufficiency with the highest ifosfamide dose led to premature study closure. Thus, this study adds to the literature regarding the toxicity of combining high-dose ifosfamide with high-dose carboplatin in this population. 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. Patients and 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/m2, ifosfamide 9990 mg/m2, 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. Conclusion: 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. © 2015 Elsevier Inc. All rights reserved. |
