Phase II Trial of Gemcitabine and Nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation

PURPOSE: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients aged 12 to 30 years with recurrent osteosarcoma and measurable disease. PATIENTS AND METHODS: A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 weekly × 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response. RESULTS: Eighteen patients received 56 total cycles (median 2, range 1-12). Two patients (11%) experienced confirmed partial response and six (33%) received >2 cycles. The PFS-4 was 28% (95% confidence interval, 13%-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs and 10 had ctDNA identified. All eight patients with MYC amplification at study entry experienced disease progression. CONCLUSIONS: Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.