Adenocarcinoma of the Pancreas, Pancreatic Cancer
Conditions
Keywords
Zolinza
Brief summary
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
* 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.
Interventions
RADIATIONRadiation therapy
Once per day, 5 days a week for 6 weeks
DRUG5-FU
Intravenously over 24 hours, 7 days per week during each week of radiation therapy
DRUGVorinostat
Taken orally. Dose will depend upon time of enrollment and how well previous participants tolerated the drug
Sponsors
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Merck Sharp & Dohme LLC
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximally Tolerated Dose (MTD) of Vorinostat in Combination With Infusional 5-FU and Radiation Therapy. | 6 weeks | 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. |
| Progression Free Survival (PFS) at 7 Months From Registration | 7 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 1 year | Percentage of participants still alive at 1 year after enrollment on study |
| Progression Free Survival | 2 years | 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. |
| Resectability Rate | 5 months | Percentage of patients able to undergo surgical resection after protocol therapy. |
| Response Rate | 1 year | 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%). |
| Number of Participants Experiencing Unacceptable Toxicity | 1 year | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat, 5-FU, Radiation Therapy 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 therapy: Once per day, 5 days a week for 6 weeks
5-FU: Intravenously over 24 hours, 7 days per week during each week of radiation therapy
Vorinostat: Taken orally. Dose will depend upon time of enrollment and how well previous participants tolerated the drug | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1: 200 mg Vorinostat | Adverse Event | 1 | 0 |
| Period 1: 200 mg Vorinostat | Protocol Violation | 1 | 0 |
| Period 2: 100 mg Vorinostat | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Vorinostat, 5-FU, Radiation Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 60.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 6 / 6 |
| serious Total, serious adverse events | 1 / 4 | 1 / 6 |
Outcome results
Primary
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.
Time frame: 6 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Maximally Tolerated Dose (MTD) of Vorinostat in Combination With Infusional 5-FU and Radiation Therapy. | NA milligrams per day |
Primary
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.
Time frame: 7 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Progression Free Survival (PFS) at 7 Months From Registration | NA months |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Number of Participants Experiencing Unacceptable Toxicity | 1 Participants |
| Vorinostat 100 mg | Number of Participants Experiencing Unacceptable Toxicity | 1 Participants |
Secondary
Overall Survival
Percentage of participants still alive at 1 year after enrollment on study
Time frame: 1 year
Population: One participant excluded from this analysis due to non-compliance with study drug administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Overall Survival | 6 Participants |
Secondary
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.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Progression Free Survival | 9.375 months |
Secondary
Resectability Rate
Percentage of patients able to undergo surgical resection after protocol therapy.
Time frame: 5 months
Population: One participant excluded from this analysis due to non-compliance with study drug administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Resectability Rate | 2 Participants |
Secondary
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%).
Time frame: 1 year
Population: One participant excluded from this analysis due to non-compliance with study drug administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat, 5-FU, Radiation Therapy | Response Rate | 6 Participants |