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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

Phase 1
18 Years
Open (Enrolling)
Pancreatic Cancer, Adenocarcinoma of the Pancreas

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Trial Information

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

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.

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

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

15. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of study

16. Evidence or history of bleeding diathesis or coagulopathy.

17. Chronic, daily treatment with aspirin or other nonsteroidal anti-inflammatory

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

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the safety and tolerability of the combined treatment with Gemcitabine with Sorafenib and radiotherapy in patients with localized unresectable pancreatic cancer.

Outcome Time Frame:

completion of study

Safety Issue:


Principal Investigator

Romnee Clark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

IU Simon Cancer Center


United States: Institutional Review Board

Study ID:

0607-09; IUCRO-0155



Start Date:

September 2006

Completion Date:

November 2013

Related Keywords:

  • Pancreatic Cancer
  • Adenocarcinoma of the Pancreas
  • Phase I
  • Pancreas Cancer
  • Chemo-radiotherapy
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms



Indiana University Simon Cancer Center Indianapolis, Indiana  46202