Gemcitabine Pharmacokinetics After Preoperative Chemoradiation Therapy

Tissue Pharmacokinetics of Intraoperative Gemcitabine in Adenocarcinoma of the Pancreas After Preoperative Chemoradiation Therapy

Status

Terminated

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01938716

Enrollment

Registered

2013-09-10

Start date

2012-03-31

Completion date

2019-06-03

Last updated

2020-11-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pancreatic Cancer

Keywords

Pancreatic Cancer, Adenocarcinoma of the Pancreas, Intratumoral gemcitabine levels, Pancreatic surgery, Pharmacokinetic testing, PK, Gemcitabine, Gemcitabine Hydrochloride, Gemzar

Brief summary

The goal of this clinical research study is to learn if gemcitabine given during surgery can enter pancreas cancer cells in patients who have already received chemotherapy and radiation. Gemcitabine is a drug used to treat pancreatic cancer. However, it has not previously been studied if gemcitabine can enter pancreatic cancer cells. Gemcitabine is designed to block the growth of cancer cells, which may cause cancer cells to die.

Detailed description

Surgery: If you agree to take part in this study, your surgery will be performed in the same way as it would be even if you were not taking part in this study. You will sign a separate consent form for surgery. The length of the surgery and the time you are under anesthesia will not be changed by taking part in the study. During surgery, you will have routine procedures to learn if the disease has spread to other areas. If the disease has spread beyond the pancreas, surgical removal will not be possible. If there are no signs of spread or other reasons the cancer cannot be removed, the surgeon will begin the process of removing the disease. Study Drug Administration: You will receive gemcitabine by vein during surgery. Gemcitabine will be given through an infusion catheter that is placed in your arm or chest in the operating room after you are asleep. The infusion catheter is a standard-of-care procedure for all participants who are having this surgery. You will be asked to sign a separate consent form for the infusion catheter. The infusion will take either 50 or 75 minutes, depending upon when you joined the study. The first 5 participants will receive gemcitabine over 50 minutes and the rest of the participants will receive gemcitabine over 75 minutes. Blood and Tissue Collection: Up to 8 blood samples (about 1 tablespoon each time) will be drawn over 70-95 minutes for pharmacokinetic (PK) testing on the day of surgery. PK testing measures the levels of study drug in your blood at different time points. The blood will also be used for biomarker testing. Biomarkers are chemical markers found in the blood and tissue that may be related to your reaction to the study drug. Some of the tumor tissue and normal tissue removed during surgery will be collected to learn if gemcitabine is able to enter the tissue cells and for biomarker testing. Length of Participation: If for any reason during the surgery the surgeon decides that removal of the pancreas is not possible, you will not receive gemcitabine and your participation in this study will end. Your active participation in this study will be over once you have had surgery and completed the follow-up. Follow-Up: One (1) time each day while you are in the hospital recovering from the surgery and then at the time of a routine clinic visit or by phone call at least 1 time a week, for up to 30 days after surgery, you will be asked if you have had any side effects. This is an investigational study. Gemcitabine is FDA approved and commercially available for the treatment of pancreatic cancer. Its use during surgery is investigational. Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Interventions

DRUGGemcitabine

500 mg/m2 at a fixed dose rate of 10 mg/m2/min by vein for the first 5 patients during pancreatic surgery. Next 15 subsequent patients receive 750 mg/m2 by vein at a fixed dose rate of 10 mg/m2/min.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Cytologic or histologic proof of adenocarcinoma of the pancreas is required. Patients with Islet cell tumors are not eligible. 2. Patients do not have known metastases. 3. Patients must have potentially resectable or borderline resectable pancreatic cancer and have agreed to undergo surgical resection at MD Anderson Cancer Center if operable. They will have undergone staging (physical examination, chest x-ray, contrast enhanced CT or MRI (if CT contraindicated) and/or angiogram) to determine resectability. 4. Patients have completed radiation and chemotherapy with either fluoropyrimidines (5-FU or capecitabine) or gemcitabine as a radiosensitizing agent as part of their preoperative therapy. Previous systemic chemotherapy alone is not allowed. Preoperative therapy will be completed at least 4 weeks prior to surgery. 5. Patients with Karnofsky performance status \> 70 are eligible. 6. There will be no upper age restriction. Patients less than 18 years of age are excluded from the protocol because adenocarcinoma of the pancreas is rarely seen in the pediatric population. 7. Adequate renal and bone marrow function: Leukocytes \>= 3,000/uL; Absolute neutrophil count \>= 1,500/uL; Platelets \>= 100,000/Ul; Serum creatinine \<= 2.0 mg/dL; Creatinine clearance \>= 60 ml/min (calculated by the Cockcroft -Gault equation) 8. Adequate Hepatic function (endoscopic or percutaneous drainage as needed): Total bilirubin \< = 3 X institutional upper limits of normal (ULN); AST (SGOT)/ALT (SGPT) \<= 5 X institutional ULN 9. Patients must have no fever or evidence of infection or other coexisting medical condition that would preclude administration of gemcitabine. Patients with uncontrolled congestive heart failure, unstable angina and myocardial infarction within 3 months will be excluded. 10. Patient is not pregnant. Women of childbearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods (abstinence, intrauterine device \[IUD\], oral contraceptive or double barrier device) and refrain from breast-feeding, as specified in the informed consent. 11. Patients must sign a study-specific consent form.

Exclusion criteria

1. Major cardiovascular or pulmonary comorbidity that precludes use of general anesthesia (NYHA \[New York Heart Association\] Class III and IV). 2. Identification of metastatic disease. 3. Patients with a known hypersensitivity to Gemcitabine. 4. Pregnant women 5. Inability to comply with study and/or follow-up procedures. 6. Patients \< 18 years of age.

Design outcomes

Primary

Measure	Time frame	Description
To Quantifiably Assess Intratumoral Gemcitabine Levels in Human Pancreatic Cancer Tissue After a Single Intraoperative Infusion in Patients.	through study completion, up to 2 years and 6 months	The quantification of serum, PBMC, and cancer tissue levels of gemcitabine from frozen samples will be assessed using standardized techniques in high performance liquid chromatography-mass spectometry (HPLC/MS).

Secondary

Measure	Time frame	Description
To Measure Intra-DNA Gemcitabine (dFdC) Levels Using a Novel Assay Liquid Chromatography-mass Spectometry (LC/MS/MS).	through study completion, up to 2 years and 6 months	Gemcitabine incorporation in DNA will be quantified by a proprietary LC/MS/MS method developed by Eli Lilly and performed by Advion BioServices. DNA extracted from the tissue samples to be sent to Advion.
To Assess and Validate Previously Described Markers That May be Predictive of Gemcitabine Sensitivity or Resistance.	through study completion, up to 2 years and 6 months	The mRNA level is measured using real time PCR and protein expressed by IHC, Gene expression level will be correlated to the gemcitabine measurements. Additionally measure markers of proliferation and apoptosis by p21and ki67 IHC and fluorescent TUNEL analysis.
To Measure the Impact of Microvessel Density and the Molecular Expression Level of the Hh Signaling Pathway on Gemcitabine Delivery and DNA Incorporation.	through study completion, up to 2 years and 6 months	The mRNA and protein expression of SHH, Gli, and SMO will be measured by RT-PCR and IHC method, respectively.
To Correlate Intratumoral Gemcitabine Levels and Its Tumoricidal Activity With Ki67 Index and Intratumoral Apoptosis.	through study completion, up to 2 years and 6 months	Measure markers of of proliferation and apoptosis by p21 and ki67 IHC and fluorescent TUNEL analysis.

Countries

United States

Participant flow

Recruitment details

Recruitment period: March 2012 to February 2015. All recruitment done at The University of Texas, MD Anderson Cancer Center.

Participants by arm

Arm	Count
Intraoperative Gemcitabine Administration Gemcitabine administered intravenously at dose of 500 - 750 mg/m2 at a fixed dose rate of 10mg/m2/min, 50-75 minutes prior to complete gross tumor removal.	12
Total	12

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Physician Decision	2
Overall Study	Withdrawal by Subject	2

Baseline characteristics

Characteristic	Intraoperative Gemcitabine Administration
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	7 Participants
Age, Categorical Between 18 and 65 years	5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 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	0 Participants
Race (NIH/OMB) White	12 Participants
Region of Enrollment United States	12 participants
Sex: Female, Male Female	2 Participants
Sex: Female, Male Male	10 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 8
other Total, other adverse events	8 / 8
serious Total, serious adverse events	0 / 8

Outcome results

Primary

To Quantifiably Assess Intratumoral Gemcitabine Levels in Human Pancreatic Cancer Tissue After a Single Intraoperative Infusion in Patients.

The quantification of serum, PBMC, and cancer tissue levels of gemcitabine from frozen samples will be assessed using standardized techniques in high performance liquid chromatography-mass spectometry (HPLC/MS).