Study of Low-Dose Fractionated Radiotherapy in Patients With Locally Advanced Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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People with pancreatic cancer usually have a large amount of the cancer in the area of the pancreas and around it when they are diagnosed with it. Or their cancer has spread (metastasized)outside that area of the abdomen and is not able to be surgically removed (resected). For patients with metastatic disease, one standard treatment is the combination of gemcitabine and erlotinib. This combination has shown slightly longer survival compared to getting gemcitabine alone. For patients with localized but unresectable disease, the standard treatment remains controversial. Early studies showed that chemotherapy and radiation together was better than either one used alone. The greatest benefit of external beam radiotherapy may be after a period of full-dose chemotherapy alone, to help the rapid spread. A problem of beginning treatment with standard radiotherapy is that the doses of chemotherapy usually have to be reduced sometimes by half. Studies have already shown that low dose radiotherapy (LDRT)is safe. This study will evaluate the safety of LDRT instead of standard doses with full dosing of gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer. Patients will be enrolled in groups of 3 to 6 each with a slightly higher dose of LDRT and erlotinib. For patients with locally advanced disease, this protocol also may help because most patients develop and die from spread to the liver and abdominal cavity.

Detailed Description
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Pancreatic cancer is nearly universally fatal, with approximately 38,000 new cases and 34,000 deaths expected in 2008.1 The majority of patients present with disease that is not amenable to curative resection. For patients with metastatic disease, one standard treatment is the combination of gemcitabine with the small molecule epidermal growth factor tyrosine kinase inhibitor erlotinib. This combination results in a modest survival benefit compared to single agent gemcitabine.2 For patients presenting with localized but unresectable disease, the standard treatment remains controversial. Early studies demonstrated that chemotherapy and radiation was superior to either modality alone.3 However, recent studies of systemic therapy alone have typically included a small but real minority of patients with locally advanced disease, supporting that systemic therapy alone is a reasonable treatment option.2 Adding to the confusion are recent European reports that systemic therapy alone may be superior to combined modality therapy, at least when used initially.4 The greatest benefit of external beam radiotherapy may be after a period of full-dose chemotherapy alone, to ensure that rapid metastases do not develop.5 A limitation of beginning treatment with conventional external beam radiotherapy is a requirement to reduce dosing of gemcitabine by 40-50%. Given the safety and preclinical rationale for LDRT, we propose this phase I study to evaluate the safety of LDRT with standard dosing of gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer. Patients will be enrolled in cohorts with escalating doses of low dose radiotherapy. Radiation ports will be uniform between patients as described in Section 5.6 below. As LDRT is administered to sites of disease in liver and abdominal cavity to iliac crest, patients with metastatic disease confined to these areas will be eligible. For patients with locally advanced disease, this protocol also has high rationale, as the overwhelming majority of patients develop and succumb to recurrences in liver and abdominal cavity,10 areas which would be covered by the proposed radiation field. The dose of 2880 cGy is the limit because of kidney and other upper abdominal organ potential for toxicity.

Official Title
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Phase I Study of Low-Dose Fractionated Radiotherapy as a Chemosensitizer for Gemcitabine and Erlotinib in Patients With Locally Advanced or Limited Metastatic Pancreatic Cancer

Conditions
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Pancreatic Carcinoma Non-resectable, Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: gemcitabine
* Drug: Erlotinib
* Radiation: low dose fractionated radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of adenocarcinoma of the pancreas that is not amenable to curative surgical resection. Patients with locally advanced unresectable disease and those patients with metastatic disease that can be encompassed in the radiation fields for this study (as assessed by treating radiation oncologist) are eligible. Patients may not have received any prior chemotherapy for locally advanced or metastatic pancreatic cancer. Prior adjuvant chemotherapy completed >1 year previously is allowed. Patients must be able to provide informed consent and HIPAA consent. Patients must be ≥18 years of age Adequate hematologic and organ function: ANC ≥ 1,000/μL, platelets ≥ 100,000/μL, hemoglobin ≥ 9.0/dL Bilirubin: ≤1.5X ULN ALT/AST < 3.0 X upper limit of normal Serum Creatinine: WNL Albumin > 2.5 g/dL Measurable and non-measurable disease are permitted ECOG performance status 0-1 Patients must be able to swallow oral medications Patients must be able to comply with study and follow up procedures Exclusion Criteria: No prior radiation therapy to the abdomen. Patients must not have any other active illness (e.g. active/uncontrolled infection, uncontrolled cardiac disease, etc.) that would preclude safe therapy in the judgment of the treating physicians. Patients may be enrolled while still on antibiotics as long as clinical signs of active infection are absent. Patients with concurrent active malignancy requiring therapy are not eligible. Patients with a history of malignancy within any timeframe not requiring ongoing therapy are eligible.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: radiotherapy and chemotherapy<br>gemcitabine will be administered at 1000mg/m2 IV on days 1 and 8 of each 21 day cycle. erlotinib at either 100mg (cohort 1-3) or 150mg (cohort 4) PO daily. Low dose fractionated radiotherapy (LDRT) will be given BID on days 1 and 2 and 8 and 9 of each 21 day cycle | Drug: gemcitabine<br>* gemcitabine 1000mg/m2 days 1 and 8 of each 21 day cycle.<br>* Other names: Gemzar;Drug: Erlotinib<br>* Erlotinib 100mg or 150mg daily of each 21 day cycle<br>* Other names: Tarceva;Radiation: low dose fractionated radiotherapy<br>* low dose fractionated radiotherapy day 1 and 2, day 8 and 9 of each 21 day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Dose Limiting Toxicities |  | weekly physician and nurse assessment and in between as needed until 30 days after treatment termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Measure Progression Free Survival and Overall Survival |  | Evaluate CT scans after every 2 cycles of therapy (about every 6 weeks) and long term follow up every 3 months once off treatment for survival | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreatic cancer, locally advanced, unresectable, metastatic pancreatic cancer