Vorinostat With XRT and 5-FU for Locally Advanced Adenocarcinoma of the Pancreas

Study Overview
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Brief Summary
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The durg vorinostat (Zolinza) is a type of drug called an histone deacetylase (HDAC) inhibitor. It inhibits a group of enzymes called histone deacetylases. These enzymes help cancer cells survive. By inhibiting these enzymes, vorinostat helps kill cancer cells. In this research study vorinostat will be given along with radiation therapy and the drug 5-FU. This is the first research study in which vorinostat will be given along with radiation therapy and 5-FU. The purpose of this research study is to find the highest dose of vorinostat that can be given safely along with radiation therapy and 5-FU. The investigators will also begin to get information about whether vorinostat combined with radiation and 5-FU may help to treat pancreatic cancer.

Detailed Description
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Since we are looking for the highest dose of vorinostat that can be administered safely without severe or unmanageable side effects, not everyone who participates will receive the same dose. The dose will depend upon the number of participants enrolled on the study and how well they have tolerated their doses. 5-FU will be given intravenously over 24 hours 7 days per week during each week of radiation therapy. In order for participants to be able to receive the 5-FU as an outpatient, they will need to have central line catheter placed. Radiation therapy will be given once per day, 5 days per week, for 6 weeks. Vorinostat is taken orally. Participants will be seen once per week during the 6 weeks that they are receiving 5-FU, radiation therapy and vorinostat.

Official Title
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Phase 1/2 Study of Vorinostat in Combination With Radiation Therapy and Infusional 5-FU in Patients With Locally Advanced Adenocarcinoma of the Pancreas

Conditions
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Pancreatic Cancer, Adenocarcinoma of the Pancreas

Intervention / Treatment
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* Radiation: Radiation therapy
* Drug: 5-FU
* Drug: Vorinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven adenocarcinoma of the pancreas Evaluable disease Must have received 3-4 months of gemcitabine-based chemotherapy and have had stable disease by RECIST criteria. Regimens include: gemcitabine alone gemcitabine and erlotinib gemcitabine and oxaliplatin gemcitabine and cisplatin gemcitabine and capecitabine 18 years of age or older Life expectancy of greater than 4 months ECOG Performance Status 0-1 Normal organ and marrow function as outlined in the protocol Ability to drink at least 2 liters of fluid daily Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation Patients must be able to swallow capsules Exclusion Criteria: Chemotherapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Participants may not be receiving any other study agents Known distant metastases to any organ History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or 5-FU Patients taking warfarin due to potential interactions of both 5-FU and vorinostat. Low molecular weight heparin should be substituted when appropriate Patients who have received upper abdominal radiation therapy which fields would overlap with that determined necessary to treat the primary tumor. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or breastfeeding women Individuals with history of a different malignancy are ineligible unless they are deemed by the investigator to be at low risk of recurrence of that malignancy. Patients may not have a concurrent second malignancy. Active HIV or hepatitis Prior exposure to HDAC inhibitor (except valproic acid, provided there is a 30 day washout period)

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: Vorinostat, 5-FU, Radiation Therapy<br>Vorinostat at varying doses; orally, days 1-7, weeks 1-6 5-FU 225 mg/m2/day; intravenous; days 1-5, weeks 1-6 until completion of radiation therapy; Radiation therapy; 180cGy daily Monday-Friday; 28 days of treatment (6 weeks) | Radiation: Radiation therapy<br>* Once per day, 5 days a week for 6 weeks<br>Drug: 5-FU<br>* Intravenously over 24 hours, 7 days per week during each week of radiation therapy<br>* Other names: Efudex, Carac, Fluoroplex, Adrucil;Drug: Vorinostat<br>* Taken orally. Dose will depend upon time of enrollment and how well previous participants tolerated the drug<br>* Other names: Zolinza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally Tolerated Dose (MTD) of Vorinostat in Combination With Infusional 5-FU and Radiation Therapy. | The maximum tolerated dose (MTD) is defined as one dose level below the dose level at which participants experience an unacceptable rate of dose-limiting toxicity. | 6 weeks | 
| Progression Free Survival (PFS) at 7 Months From Registration | Progression free survival was defined as the duration of time from registration on study to time of objective disease progression. Death was regarded as a progression event. Progression was defined by the Response Evaluation Criteria in Solid Tumors (RECIST) as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions as seen on radiologic evaluation. | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival for this endpoint was defined as the duration of time from beginning of the patients' initial chemotherapy to time of objective disease progression. Death was regarded as a progression event. Progression was defined by the Response Evaluation Criteria in Solid Tumors (RECIST) as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions as seen on radiologic evaluation. | 2 years | 
| Number of Participants Experiencing Unacceptable Toxicity | All participants who receive at least one dose of study treatment were evaluable for toxicity. Unacceptable toxicity is based on the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Most grade 3 (severe) or 4 (life-threatening) events are considered to be unacceptable toxicities -- exceptions include nausea or vomiting, fatigue, and alopecia. Hematologic toxicities need to be either grade 4 or last for protocol-defined durations to be considered unacceptable. | 1 year | 
| Overall Survival | Percentage of participants still alive at 1 year after enrollment on study | 1 year | 
| Response Rate | Participants who have either a complete response (disappearance of all target lesions), partial response (at least 30% decrease in sum of longest diameter of target lesions) or stable disease (decrease in size of less than 30% or increase in size of less than 20%). | 1 year | 
| Resectability Rate | Percentage of patients able to undergo surgical resection after protocol therapy. | 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Zolinza