First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer

Abstract

Background: Preclinical studies showed a Chinese botanical formula, PHY906, has synergistic anti-tumor activity with capecitabine. Our phase I study determined maximal tolerated dose of capecitabine 1,500 mg/m(2) BID day 1-7 and PHY906 800 mg BID day 1-4 every 2 weeks. We conducted this phase II study to explore the efficacy of capecitabine and PHY906 in patients with advanced pancreatic cancer who were previously treated with gemcitabine-based regimens.

Methods: Patients with pancreatic cancer and an Eastern Cooperative Oncology Group performance status of 0-2 received PHY906 and capecitabine. Toxicity was assessed per NCI-CTCAE v3.0 and response per response evaluation criteria in solid tumors q 6 weeks. Correlative studies of cytokines, chemokines and growth factors were tested using a cytometric bead array. Quality of life was assessed by utilizing Edmonton symptom assessment system. The primary objective was overall survival.

Results: The study enrolled 25 patients. Median progression-free survival (mPFS) was 10.1 weeks (range 0.4-54.1) and median overall survival (mOS) was 21.6 weeks (range 0.4-84.1). Eighteen patients received at least 2 cycles, and achieved mPFS of 12.3 weeks and mOS of 28 weeks. Six-month survival rate was 44 % (11/25). Unsupervised clustering of patients grouped those with shortened survival together by their cytokine profile showed that only IL-6 had a significant difference (p < .001) between short- and long-term survivors.

Conclusions: Capecitabine plus PHY906 provides a safe and feasible salvage therapy after gemcitabine failure for APC. Role of IL-6 in tumor progression and tumor cachexia needs to be investigated with respect to its relation to pathophysiology of pancreatic cancer and development of anti-IL-6 therapeutics.

Figures

Figure 1

Effect of PHY906 with capecitabine in Panc-1 tumor bearing NCR-nude mice.

Figure 2

Figure 2a: Survival data for all intended to treat patients (N=25): median progression free survival (mPFS) 71 days (10.1 weeks), median overall survival (mOS): 151 days (21.6 wks) Figure 2b: Survival data for all patients received 2 cycles and above (n=20), mPFS: 86 days (12.3 wks), mOS: 196 days (28 wks)

Figure 3

Relationship of serum IL-6 levels with the survival in patients with pancreatic cancer (Cytokine/chemokine cluster analysis). Detection limit of the assay was 3 pg/ml.

Figure 4

Cytokine data appears to show less expression of several cytokines in patients with higher HFS scores