Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948)

Chandrajit P Raut, Yves Boucher, Dan G Duda, Jeffrey A Morgan, Richard Quek, Marek Ancukiewicz, Johanna Lahdenranta, J Paul Eder, George D Demetri, Rakesh K Jain, Chandrajit P Raut, Yves Boucher, Dan G Duda, Jeffrey A Morgan, Richard Quek, Marek Ancukiewicz, Johanna Lahdenranta, J Paul Eder, George D Demetri, Rakesh K Jain

Abstract

Purpose: Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density.

Patients and methods: Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1-2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP).

Results: In 15 patients accrued, the median TTP was 45 days (range 14-228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression.

Conclusions: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.

Trial registration: ClinicalTrials.gov NCT00330421.

Conflict of interest statement

Competing Interests: Chandrajit P. Raut is a Novartis - Honorarium. Johanna Lahdenranta has an employment/leadership position at Merrimack Pharmaceuticals. J. Paul Eder is currently employed at AstraZeneca PLC. George D. Demetri is a Consultant for Novartis, Pfizer, Ariad, Johnson & Johnson, Genentech, Infinity Pharmaceuticals, ZioPharm, Alnylam, Idera, Momenta Pharma, EMD-Serono, Glaxo Smith Kline, Amgen, Daiichi-Sankyo, ArQule, Enzon, Millenium/Takeda, PamGene (no compensation), Plexxikon, N-of-One (no compensation), Champions Biotechnology, and Kolltan Pharmaceuticals; on the Scientific Advisory Board of ZioPharm, PamGene, Plexxikon, N-of-One, Kolltan Pharmaceuticals (chair); on the Medical Advisory Board at Kolltan Pharmaceuticals (chair); an Honorarium at Novartis and Pfizer; provides research support (to Dana-Farber Cancer Institute for clinical trial) at Novartis, Pfizer, Ariad, Johnson & Johnson, Bristol-Myers Squib, Infinity Pharmaceuticals, and Daiichi-Sankyo; and has equity (minor stake, non-public) at PamGene, Plexxikon, N-of-One, Champions Biotechnology, and Kolltan Pharmaceuticals. Rakesh K. Jain has a Consultant/advisory role at Millenium, Dyax, AstraZeneca, Regeneron, Astellas-Fibrogen, MorphoSys AG, Genzyme, SynDevRx, and Noxxon; is Honoraria at Pfizer and Genzyme (honoraria for lecture); provides research funding/contracted research at Dyax, AstraZeneca and MedImmune; and has ownership interest in SynDevRx. There are no patents or products in development or marketed products to declare. This does not alter the authors′ adherence to all the PLoS ONE policies on sharing data and materials. Yves Boucher, Dan G. Duda, Jeffrey A. Morgan, Richard Quek and Marek Ancukiewicz declare no competing interest.

Figures

Figure 1. Flow Diagram.
Figure 1. Flow Diagram.
Figure 2. Sorafenib reduces the vessel density…
Figure 2. Sorafenib reduces the vessel density in sarcoma lesions.
Immunostaining of CD31-positive (brown) or CD31 and α-SMA-positive (brown and pink) tumor vessels before (A) and 28 days after (B) the initiation of sorafenib treatment. Sections were counterstained with hematoxylin. Note the reduced vessel density and cellular content in the sorafenib-treated lesion.

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