Phase I/II Study of Paclitaxel Plus Ifosfamide Followed By High-Dose Paclitaxel, Ifosfamide, and Carboplatin with Autologous Stem Cell Reinfusion for Salvage Treatment of Germ Cell Tumors

Background:  High-dose chemotherapy (HDCT) can achieve durable remissions in 30-60% of GCT patients (pts) requiring salvage treatment. This Phase I/II study investigated safety and efficacy of a novel high-dose regimen (TI-TIC) in this population.

Methods: Pts age ≥18 with GCT and progression after ≥1 cisplatin-based regimen were eligible. TI-TIC consists of 1-2 cycles of conventional-dose paclitaxel plus ifosfamide (TI) q14-21 days followed by 3 cycles of high-dose TIC with ASCT q21-28 days. TI dosing was constant. In Phase I, high-dose TIC was administered in 1 of 5 cohorts (I: 6, 8 or 10g/m²; T: 200 or 250mg/m²; C: AUC=21 or 24) using a standard 3+3 dose escalation design to determine the maximal tolerated dose (MTD). In Phase II, Simon’s 2-stage optimal design was used to estimate the complete response (CR) rate at MTD.

Results: Of 26 pts (25 male; median age 31; 21 nonseminoma, 5 seminoma) enrolled, 23 received ≥1 cycle of high-dose TIC. Primary sites included testis (n=15), mediastinum (n=6), other (5). In Phase I, 0/18 pts had dose-limiting toxicity (DLT) during TIC cycle 1, making cohort 5 (T 250mg/m², I 10g/m², C AUC=24) the MTD. Toxicities were similar to those reported with TI-CE (Feldman JCO 2010) with little variation across cohorts. However, 2/18 pts in Phase I (1 in cohort 4, 1 in cohort 5) developed grade 3 acute renal insufficiency after TIC cycles 1 and 2 (cycle 3 not given). Both later developed chronic renal insufficiency with 1 pt requiring dialysis 10 months after TI-TIC. A third pt treated in Phase II developed a similar acute and then chronic renal insufficiency pattern with TIC cycles 1 and 2. In Phase II, 7/11 evaluable pts (64%, 90% one-sided CI 40%-100%) achieved a CR, 1 had a partial response with negative markers, and 3 had incomplete responses.  Although the CR rate was sufficient to move to the second Simon’s stage, renal toxicity led to premature trial closure.

Conclusions: Although there was preliminary evidence of efficacy, high dose TI-TIC was associated with acute and chronic renal insufficiency.  TI-CE remains the standard high dose regimen for salvage treatment of GCT at MSKCC.