A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors.

Background: Secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, is downregulated by hypermethylation in many cancers. Hypomethylating agents such as azacitidine can upregulate SPARC in tumors, which may enhance the accumulation of albumin-bound drugs at tumor site. The objectives of this phase I trial was to determine the safety and maximum tolerated dose and to assess any clinical activity of the combination of azacytidine and weekly nanoparticle-albumin-bound (nab (R)) paclitaxel. Methods: Patients received escalating azacytidine doses daily for 5 days, followed by nab-paclitaxel at the standard 100mg/m(2) weekly dose for 3 weeks in 4-week cycles. Dose-limiting toxicities (DLTs) were monitored during the first cycle. Serum was obtained at baseline, during and after treatment for correlative study. Results: All sixteen total patients enrolled were evaluable for toxicity, while 13 patients were evaluable for response. Two of five patients treated with 100mg/m(2) of azacytidine had DLT of prolonged grade 4 neutropenia. Therefore, the MTD of azacitidine in this regimen is 75 mg/m(2). Three additional patients were treated with no grade 4 toxicity in cycle 1. Clinical activity included 1 complete response (CR) in refractory DLBCL, 2 CR in ovarian cancer, 4 partial responses (PR) in ovarian and endometrial cancer, 4 stable diseases (SD) in lung, sarcoma and pancreatic cancer, 1 unconfirmed PR in breast cancer, and 1 progression of disease in CLL/SLL. Conclusions: Priming with azacitidine 75 mg/m(2) daily for 5 days, followed by weekly nab-paclitaxel 100 mg/m(2) weekly was well tolerated and results in dramatic responses pre-treated cancer patients.