Pancreatic Cancer
Conditions
Keywords
recurrent pancreatic cancer, stage III pancreatic cancer, stage IV pancreatic cancer, adenocarcinoma of the pancreas
Brief summary
RATIONALE: Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well sirolimus works in treating patients with advanced pancreatic cancer.
Detailed description
OBJECTIVES: Primary * To determine the proportion of patients with previously treated advanced pancreatic cancer surviving at 6 months after treatment with single agent rapamycin. * To evaluate the relationship between activation of the PI3/Akt/mTOR/S6K signaling pathway in tumor tissues and rapamycin activity in this patient population. * To characterize toxicity of rapamycin in this patient population. Secondary * To determine the response rate, median time to treatment failure, and median survival of patients with previously treated advanced pancreatic cancer who are treated with single agent rapamycin. * To characterize the pharmacokinetics of rapamycin in this patient population. * To explore pharmacogenomic variables that affect rapamycin pharmacokinetics and clinical activity in this patient population. * To determine the pharmacodynamic effects of rapamycin on S6 kinase activation in PBMC, normal skin, and normal oral mucosa obtained from patients treated with the drug and its relationship with rapamycin pharmacokinetics and clinical effects. * To explore biomarkers in tumor tissues that might be associated with rapamycin clinical effects. OUTLINE: Patients receive oral sirolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood, normal skin, and tumor tissue collection at baseline and periodically during study for pharmacological, biological, and genotyping studies. Blood samples are analyzed by LC/MS/MS assay to assess rapamycin pharmacokinetics (PKs) during courses 1 and 2 and to determine baseline CYP3A4 activity. Samples are also analyzed by genotyping studies to assess CYP3A4 polymorphisms. Pharmacodynamic activity of rapamycin is assessed in peripheral blood mononuclear cells isolated from PK blood samples using a kinase assay to measure S6K activity. Tumor tissue is collected from pretreatment tumor samples obtained at the time of diagnosis or surgery or by biopsy from patients for whom pre-study tumor specimens are not available. Patients undergo skin biopsies at baseline and on day 1 of course 2 to obtain samples of normal skin. Patients also undergo oral mucosa smears at baseline and weekly during course 1. Tumor tissue, normal skin, and oral mucosa samples are assessed by IHC staining of S6K and p-S6K and by RT-PCR for cyclin D1 and p27.
Interventions
DRUGsirolimus
Treatment with rapamycin will begin on Day 1 at a single flat dose level of 5 mg/day. Rapamycin will be administered continuously without interruption through all cycles in an outpatient setting. Each cycle will last 28 days.
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: Inclusion criteria: * Histologically proven adenocarcinoma of the pancreas * Locally-advanced or advanced disease which has progressed after one prior gemcitabine-containing regimen * Unidimensionally measurable disease (defined as at least one unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan) OR evaluable disease * Tumor tissue available for IHC assessment OR willingness to undergo a safe biopsy of tumor tissue
Exclusion criteria
* Histologic or cytologic diagnosis that is not consistent with adenocarcinoma, including adenosquamous, islet cell, cystadenoma or cystadenocarcinoma, carcinoid, or small or large cell carcinoma or lymphoma * Adenocarcinoma arising from a site other than the pancreas (e.g., distal common bile duct, ampulla of vater or periampullary duodenum) * Known brain metastases PATIENT CHARACTERISTICS: Inclusion criteria: * ECOG performance status 0-1 * WBC \> 3,500 cells/mm³ * ANC \> 1,500 cells/mm³ * Hemoglobin \> 9 g/dL * Serum creatinine ≤ 2.0 mg/dL * Bilirubin ≤ 2 mg/dL * ALT, AST, and alkaline phosphatase ≤ 5 times upper limit of normal * Triglycerides and total cholesterol \< 2 times upper limit of normal * Not pregnant or nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Overall Survival at 6 Months | 6- month survival rate (6mSR) | — |
| Response Rate (Complete, Partial Response and Stable Disease) as Assessed by RECIST | response at 2 and 6 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression, a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Response for Stable disease was assessed at 2 months and for complete and partial response at 6 months. |
| Severity of Adverse Events as Assessed by NCI CTCAE v3.0 | 6 months | — |
Countries
United States
Participant flow
Pre-assignment details
During baseline evaluation (approximately 72 hours prior to treatment with rapamycin), patients will receive a single dose of 3 mg oral midazolam as phenotypic evaluation of CYP3A4 activity.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus adencarcinoma refractory to gemcitibine | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 16 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 22 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Region of Enrollment United States | 47 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 31 |
| serious Total, serious adverse events | 7 / 31 |
Outcome results
Primary
Percentage of Patients With Overall Survival at 6 Months
Time frame: 6- month survival rate (6mSR)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| One Group | Percentage of Patients With Overall Survival at 6 Months | 26 % of participants |
Primary
Response Rate (Complete, Partial Response and Stable Disease) as Assessed by RECIST
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression, a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Response for Stable disease was assessed at 2 months and for complete and partial response at 6 months.
Time frame: response at 2 and 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| One Group | Response Rate (Complete, Partial Response and Stable Disease) as Assessed by RECIST | stable disease at 2 months | 4 participants |
| One Group | Response Rate (Complete, Partial Response and Stable Disease) as Assessed by RECIST | complete and partial response at 6 months | 0 participants |
Primary
Severity of Adverse Events as Assessed by NCI CTCAE v3.0
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| One Group | Severity of Adverse Events as Assessed by NCI CTCAE v3.0 | Grade 1 | 67 percentage of Adverse Events |
| One Group | Severity of Adverse Events as Assessed by NCI CTCAE v3.0 | Grade 4 | 0 percentage of Adverse Events |
| One Group | Severity of Adverse Events as Assessed by NCI CTCAE v3.0 | Grade 2 | 24 percentage of Adverse Events |
| One Group | Severity of Adverse Events as Assessed by NCI CTCAE v3.0 | Grade 3 | 9 percentage of Adverse Events |