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

Shiraj Sen,Joann Lim,Shumei Kato,Vivek Subbiah,Razelle Kurzrock,Chad Tang,Siqing Fu,Aung Naing,Rishi Agarwal,Shubham Pant,Xifeng Wu,Apostolia M Tsimberidou ,Daniel D Karp ,Sarina A Piha-Paul ,Kenneth R Hess ,Gerald S Falchook ,Shannon N Westin ,Ly M Nguyen ,Funda Meric‐Bernstam ,Filip Janků ,Lauren A Byers ,Stacie Bean,Yuanqing Ye,Allison Bass,David S Hong

doi:10.1038/s41416-018-0068-z

Abstract

BackgroundWe 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.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe 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.ConclusionsThe 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.

Highlights

Paclitaxel, an anti-microtubule agent approved by the U.S Food and Drug Administration (FDA), has demonstrated significant activity alone and in combination with other chemotherapeutic or biologic agents in ovarian, breast, and lung cancer and AIDSrelated Kaposi sarcoma.[1]
Because nabpaclitaxel and bevacizumab were given sequentially in escalating doses, we investigated a variety of dose levels using a modified 3 + 3 study design,[9] which enabled us to determine multiple potential maximum tolerated dose (MTD) of each drug given in combination
Gemcitabine remains a backbone for the treatment of pancreatic, ovarian, lung, and breast cancer

Summary

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. The median age was 60 years (range, 17–85 years), and 55 patients (50%) had gemcitabine-refractory disease. 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. CONCLUSIONS: The combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. 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.

INTRODUCTION

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DISCUSSION