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Phase I Study of Gemcitabine, Sorafenib and Radiotherapy in Patients With Unresectable Pancreatic Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00375310
Recruitment Status : Completed
First Posted : September 12, 2006
Last Update Posted : February 29, 2016
Information provided by (Responsible Party):
Indiana University ( Indiana University School of Medicine )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pancreatic Cancer Adenocarcinoma of the Pancreas Drug: Gemcitabine, Sorafenib Procedure: Radiotherapy Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : September 2006
Actual Primary Completion Date : November 2010
Actual Study Completion Date : November 2014

Arm Intervention/treatment
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:

  1. Sorafenib 200 mg po qd ( during combination therapy)
  2. Sorafenib 400 mg po qd ( during combination therapy)
  3. Sorafenib 400 mg po bid ( during combination therapy)
Other Names:
  • Gemzar ( gemcitabine)
  • Sorafenib (BAY 43-9006)

Procedure: Radiotherapy
1.8 Gy CTV daily for 5 weeks

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. To evaluate time to disease progression and overall survival. [ Time Frame: completion of study ]
  3. 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 ]
  4. 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 ]
  5. To evaluate resectability rates of tumors after treatment. [ Time Frame: completion of treatment ]
  6. To evaluate the maximum tolerated dose (MTD) for Sorafenib during Chemo-radiation. [ Time Frame: completion of treatment ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Histologically/pathologically confirmed locally advanced unresectable or borderline unresectable pancreatic cancer & no evidence of metastatic disease. Diagnosis of locally advanced unresectable pancreatic cancer is based on assessment by dual-phase CT scan and/or endoscopic ultrasound (EUS).
  2. Age ≥ 18 years at time of consent
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  4. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) & obtained by dual-phase CT scan within 14 days prior to being registered for protocol therapy.
  5. Tumor size ≥ 2 cm on dual-phase computed tomography scan.
  6. Adequate organ function documented within 14 days of registration as laboratory tests per protocol.
  7. Patients with biliary obstruction must have percutaneous transhepatic drainage or endoscopic stent placement prior to starting study treatment
  8. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Women of childbearing potential & men must agree to use adequate contraception (barrier method of birth control) prior to study entry & for the duration of study participation & for at least three months after the last administration of sorafenib.
  9. Ability to understand & the willingness to sign a written informed consent. A signed informed consent & authorization for release of personal health information must be obtained prior to any study specific procedures.
  10. Patients with a history of malignancy are eligible provided they have been curatively treated & demonstrate no evidence for recurrence of that cancer.

Exclusion Criteria:

  1. Prior treatment with Gemcitabine within 6 months prior to registration.
  2. Prior treatment with Sorafenib or other Ras or VEGF pathway inhibitors.
  3. Prior radiation therapy to the upper abdomen
  4. Evidence of metastatic disease
  5. Clinical evidence of duodenal mucosal invasion by tumor (as documented by endoscopy or endoscopic ultrasound).
  6. Minor surgical procedure (e.g. fine needle aspiration or needle biopsy) within 14 days of study registration.
  7. Major surgical procedure, significant traumatic injury, or serious non-healing wound, ulcer or bone fracture within 21 days of study registration; investigator has to document adequate healing has occurred prior to study registration.
  8. Any of the following within 6 months prior to study drug administration: severe/unstable angina (anginal symptoms at rest), new onset angina (began within the last 3 months) or myocardial infarction, congestive heart failure, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
  9. History of thrombotic or embolic events such as cerebrovascular accident or transient ischemic attack within the past 6 months. History of aneurysm or arteriovenous malformation.
  10. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
  11. Active clinically serious infection > Common Toxicity Criteria for Adverse Effects (CTCAE) grade 2.
  12. Receipt of any investigational agent within 4 weeks of study registration.
  13. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
  14. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of study registration
  15. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of study registration
  16. Evidence or history of bleeding diathesis or coagulopathy.
  17. Chronic, daily treatment with aspirin or other nonsteroidal anti-inflammatory medications.
  18. Use of St. John's Wort, rifampin (rifampicin), ketoconazole, itraconazole, ritonavir or grapefruit juice.
  19. Known or suspected allergy to Sorafenib or any agent given in the course of this trial.
  20. Any condition that impairs patient's ability to swallow whole pills.
  21. Any malabsorption problem.
  22. Other severe, acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results & in the judgment of the investigator would make the patient inappropriate for entry into this study.
  23. History of collagen vascular disease.
  24. Any contraindication to undergo magnetic resonance imaging

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00375310

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United States, Indiana
Indiana University Simon Cancer Center
Indianapolis, Indiana, United States, 46202
Sponsors and Collaborators
Indiana University School of Medicine
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Principal Investigator: Romnee Clark, MD IU Simon Cancer Center
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Responsible Party: Indiana University School of Medicine Identifier: NCT00375310    
Other Study ID Numbers: 0607-09; IUCRO-0155
First Posted: September 12, 2006    Key Record Dates
Last Update Posted: February 29, 2016
Last Verified: February 2016
Keywords provided by Indiana University ( Indiana University School of Medicine ):
Phase I
Pancreas Cancer
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors