Gemcitabine Pharmacokinetics After Preoperative Chemoradiation Therapy

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01938716
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 87.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Drug: Gemcitabine	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Tissue Pharmacokinetics of Intraoperative Gemcitabine in Adenocarcinoma of the Pancreas After Preoperative Chemoradiation Therapy
• Actual Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Jun 3, 2019
• Actual Study Completion Date: Jun 3, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Gemcitabine Infusion Gemcitabine administered intravenously as a dose of 500 mg/m2 at a fixed dose rate of 10 mg/m2/min for the first 5 patients (to validate hematologic safety). Next 15 subsequent patients receive 750 mg/m2 at a fixed dose rate of 10 mg/m2/min. The drug infusion started 50-75 minutes prior to complete gross tumor removal (timing dependent on dose) in order to have drug administration complete at tumor removal.

Drug: Gemcitabine; 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.; Other Names: Gemcitabine Hydrochloride Gemzar

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Gauri Varadhachary, MD, MBBS, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 30, 2011

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01938716
• Other Study ID Numbers: 2011-0703; NCI-2013-02211
• First Posted: Sep 10, 2013
• Last Update Posted: Nov 5, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Pancreatic Cancer; Adenocarcinoma of the Pancreas; Intratumoral gemcitabine levels; Pancreatic surgery; Pharmacokinetic testing; PK; Gemcitabine; Gemcitabine Hydrochloride; Gemzar
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine

Study Results

Participant Flow

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

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Period Title: Overall Study
STARTED	12
COMPLETED	8
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 41.7%
>=65 years	7 58.3%
Sex: Female, Male (Count of Participants)
Female	2 16.7%
Male	10 83.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 25%
Not Hispanic or Latino	9 75%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	12 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	To Quantifiably Assess Intratumoral Gemcitabine Levels in Human Pancreatic Cancer Tissue After a Single Intraoperative Infusion in Patients.
Description	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).
Time Frame	through study completion, up to 2 years and 6 months

Outcome Measure Data

Analysis Population Description

Samples inadequate for testing to meet objective; early termination of protocol due to low accrual.

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Measure Participants	0

2. Secondary Outcome

Title	To Measure Intra-DNA Gemcitabine (dFdC) Levels Using a Novel Assay Liquid Chromatography-mass Spectometry (LC/MS/MS).
Description	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.
Time Frame	through study completion, up to 2 years and 6 months

Outcome Measure Data

Analysis Population Description

Samples inadequate for testing to meet objective; early termination of protocol due to low accrual.

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Measure Participants	0

3. Secondary Outcome

Title	To Assess and Validate Previously Described Markers That May be Predictive of Gemcitabine Sensitivity or Resistance.
Description	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.
Time Frame	through study completion, up to 2 years and 6 months

Outcome Measure Data

Analysis Population Description

Samples inadequate for testing to meet objective; early termination of protocol due to low accrual

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Measure Participants	0

4. Secondary Outcome

Title	To Measure the Impact of Microvessel Density and the Molecular Expression Level of the Hh Signaling Pathway on Gemcitabine Delivery and DNA Incorporation.
Description	The mRNA and protein expression of SHH, Gli, and SMO will be measured by RT-PCR and IHC method, respectively.
Time Frame	through study completion, up to 2 years and 6 months

Outcome Measure Data

Analysis Population Description

Samples inadequate for testing to meet objective; early termination of protocol due to low accrual.

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Measure Participants	0

5. Secondary Outcome

Title	To Correlate Intratumoral Gemcitabine Levels and Its Tumoricidal Activity With Ki67 Index and Intratumoral Apoptosis.
Description	Measure markers of of proliferation and apoptosis by p21 and ki67 IHC and fluorescent TUNEL analysis.
Time Frame	through study completion, up to 2 years and 6 months

Outcome Measure Data

Analysis Population Description

Samples inadequate for testing to meet objective; early termination of protocol due to low accrual.

Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
Measure Participants	0

Adverse Events

Time Frame	Adverse event data collected from intraoperative gemcitabine infusion, during post-surgery hospitalization and followed for 30 day post surgery
Arm/Group Title	Intraoperative Gemcitabine Administration
Arm/Group Description	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.
All Cause Mortality
	Intraoperative Gemcitabine Administration
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	Intraoperative Gemcitabine Administration
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Intraoperative Gemcitabine Administration
	Affected / at Risk (%)	# Events
Total	8/8 (100%)
Blood and lymphatic system disorders
Anemia	1/8 (12.5%)
Investigations
White blood cell decreased	5/8 (62.5%)
Neutrophilcount decreased	3/8 (37.5%)
Platelet count decreased	4/8 (50%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.