A Phase I Trial of Nab-Paclitaxel in Combination With Gemcitabine for Relapsed/Refractory Pediatric Solid Tumors.

Background: The single-agent pediatric maximum tolerated dose (MTD) of nab-paclitaxel is significantly higher than adult dosing. We conducted a Phase I trial to establish the MTD/recommended Phase 2 dose (RP2D) of nab-paclitaxel with gemcitabine in children with relapsed/refractory solid tumors.

Methods: Nab-paclitaxel was administered intravenously with fixed-dose gemcitabine on days 1, 8, and 15 of 28-day cycles. Three dose levels (DL) of nab-paclitaxel, 180, 210, and 240 mg/m², were evaluated using a rolling six design. Toxicity, nab-paclitaxel pharmacokinetics (PK), and radiologic responses were evaluated. Pretreatment tumor tissue was assessed for SPARC and CAV-1.

Results: Twenty-four patients enrolled, 22 received therapy, and 20 were evaluable for dose-limiting toxicity (DLT): 17 during dose escalation and 3 in dose expansion at the MTD. Median age was 12.5 years. Diagnoses included osteosarcoma (n = 11), neuroblastoma (n = 4), and rhabdomyosarcoma (n = 4). At the starting dose level (gemcitabine 1000 mg/m², nab-paclitaxel 180 mg/m²), two of five patients experienced DLT, prompting an amendment lowering gemcitabine to 675 mg/m²/dose. Post-amendment, nab-paclitaxel 240 mg/m²/dose with gemcitabine 675 mg/m²/dose was identified as the MTD. Grade ≥3 hematologic toxicities were common. Two patients experienced a partial response (Wilms tumor and osteosarcoma), and PK exhibited linearity across DL. SPARC immunoreactivity was present in most tumors, while CAV-1 immunoreactivity was infrequent.

Conclusions: The MTD/RP2D of nab-paclitaxel with gemcitabine in patients with relapsed/refractory pediatric solid tumors is nab-paclitaxel 240 mg/m²/dose and gemcitabine 675 mg/m²/dose on days 1, 8, and 15 of 28-day cycles; responses were limited in this patient population.