Phase I Study of Gemcitabine, Sorafenib and Radiotherapy in Patients With Unresectable Pancreatic Cancer
The purpose of this study is to evaluate the safety and tolerability of the combined treatment of Sorafenib (BAY 43-9006) with Gemcitabine and radiotherapy in patients with localized unresectable pancreatic cancer.
Adenocarcinoma of the Pancreas
Drug: Gemcitabine, Sorafenib
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Gemcitabine With Novel RAF Kinase-Vascular Endothelial Growth Factor Receptor Inhibitor Sorafenib (BAY 43-9006) and Radiotherapy in Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma|
- To evaluate the safety and tolerability of the combined treatment with Gemcitabine with Sorafenib and radiotherapy in patients with localized unresectable pancreatic cancer. [ Time Frame: completion of study ] [ Designated as safety issue: Yes ]
- To evaluate the response rate (CR + PR), clinical benefit (CR + PR + SD) and tumor shrinkage (CR + PR + SD that shrinks) of Gemcitabine with Sorafenib and radiotherapy [ Time Frame: completion of study ] [ Designated as safety issue: No ]
- To evaluate time to disease progression and overall survival. [ Time Frame: completion of study ] [ Designated as safety issue: No ]
- To evaluate pharmacodynamic changes in tumor vascular parameters (e.g blood flow, blood volume, time to peak in ROC -receiver operator characteristics curve) by DCE-MRI and correlate with outcomes. [ Time Frame: completion of study ] [ Designated as safety issue: No ]
- To evaluate biologic markers such as VEGF, eNOS and HIF1-alpha, VEGF-R2 genetic polymorphisms and serum proteomics, and correlate with outcomes. [ Time Frame: completion of study ] [ Designated as safety issue: No ]
- To evaluate resectability rates of tumors after treatment. [ Time Frame: completion of treatment ] [ Designated as safety issue: No ]
- To evaluate the maximum tolerated dose (MTD) for Sorafenib during Chemo-radiation. [ Time Frame: completion of treatment ] [ Designated as safety issue: Yes ]
|Study Start Date:||September 2006|
|Estimated Study Completion Date:||November 2013|
|Primary Completion Date:||November 2010 (Final data collection date for primary outcome measure)|
Experimental: Gemcitabine + Sorafenib & radiotherapy
Induction: Gemcitabine with Sorafenib for 4 weeks (1 cycle). Chemo-radiotherapy: Gemcitabine with Sorafenib and Radiotherapy for 5 weeks. Sorafenib will be given in escalating dose cohorts.
Sorafenib only: Sorafenib alone for 4 weeks. Consolidation: Gemcitabine with Sorafenib for 16 weeks (4 cycles). Maintenance: Sorafenib alone until disease progression.
Drug: Gemcitabine, Sorafenib
Gemcitabine is given IV
Sorafenib is given orally of varying doses:
Other Names:Procedure: Radiotherapy
1.8 Gy CTV daily for 5 weeks
Pancreatic cancer treatment is hampered by its resistance to both chemo and radiotherapy. Gemcitabine-based chemoradiotherapy has become one of the standard therapies for localized unresectable pancreatic cancer, but with poor responses and survival rates of less than 12 months. Radiotherapy increases VEGF expression and activates the Ras/MEK/ERK pathway which may contribute to radioresistance, thus the addition of anti-angiogenic agents and/or Ras/ERK inhibitors could enhance radiation mediated cytotoxicity. Sorafenib is a novel dual-action Raf kinase and vascular endothelial growth factor receptors (VEGF-R2 and VEGF-R3) inhibitor targeting both angiogenic and Ras-Raf-1 signal transduction pathways. Based upon preliminary laboratory and clinical data Sorafenib holds promise for improving outcomes of therapy for patients with locally advanced unresectable pancreatic cancer.
Polymorphisms in genes involved in the angiogenesis pathway (VEGF, VEGF-R2, HIF-1 and eNOS) may contribute to the process of angiogenesis, tumor behavior, and may explain the heterogeneity in efficacy (and toxicity) of agents whose major mechanism of action is blocking angiogenesis33-37. Proteomic analysis may also contribute to identify patterns of response or resistance to therapies, and potentially predict outcomes.
Dynamic contrast enhanced (DCE)-MRI has been shown to be a useful pharmacodynamic marker of biological activity for anti-angiogenic agents38-40 and may also predict radiation therapy-induced vascular changes41. In vivo imaging of angiogenesis using DCE-MRI and the analysis of angiogenesis markers genetic polymorphisms may predict response and clinical benefit to therapy for unresectable pancreatic cancer patients. These biologic and pharmacodynamic endpoints will be analysed to correlate with the tumor activity seen.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00375310
|United States, Indiana|
|Indiana University Simon Cancer Center|
|Indianapolis, Indiana, United States, 46202|
|Principal Investigator:||Romnee Clark, MD||IU Simon Cancer Center|