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®) paclitaxel. Methods Patients received escalating azacytidine doses daily for 5 days, followed by nab-paclitaxel at the standard 100mg/m2 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/m2 of azacytidine had DLT of prolonged grade 4 neutropenia. Therefore, the MTD of azacitidine in this regimen is 75 mg/m2. 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/m2 daily for 5 days, followed by weekly nab-paclitaxel 100 mg/m2 weekly was well tolerated and results in dramatic responses pre-treated cancer patients.