Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers

Abstract

Background: We performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.

Methods: Patients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.

Results: The study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.

Conclusions: The combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.

Trial registration: ClinicalTrials.gov NCT01113476.

Conflict of interest statement

This was an investigator initiated trial. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. David Hong was the principal investigator of this trial and receives research grant funding from Bayer, Lily, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, Eisai and has a consulting or advisory role at Bayer, Baxter, and Guidepoint Global and ownership interests in OncoResponse. Other authors report no competing interests.

Figures

Fig. 1

Waterfall plot depicting best response as a percent change in target lesion size in all evaluable patients. Patients previously treated with gemcitabine are indicated with blue

Fig. 2

Notable responses to gemcitabine, nab-paclitaxel, and bevacizumab. Representative restaging images of two patients who had notable responses to therapy. a A patient with small cell lung cancer treated on dose level 9 who had a partial response after disease progression on first-line carboplatin plus etoposide and second-line topotecan. b A patient with B-cell lymphoma treated on dose level 5 who had a partial response after disease progression on R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), DHAP (rituximab, cisplatin, cytarabine, and dexamethasone), BR (bendamustine and rituximab), and an experimental interleukin-1 antagonist